生信网-文献期刊

Front Immunol

2022 Nov 9

Florêncio KGD, Edson EA, Fernandes KSDS

2. Development and evaluation of low-volume tests to detect and characterize antibodies to SARS-CoV-2.

Front Immunol

2022 Nov 9

Halliday A, Long AE, Baum HE

3. Proposed new prognostic model using the systemic immune-inflammation index for primary central nervous system lymphoma: A prospective-retrospective multicohort analysis.

Front Immunol

2022 Nov 9

Li S, Xia Z, Cao J

4. Generation of high affinity ICAM-1-specific nanobodies and evaluation of their suitability for allergy treatment.

Front Immunol

2022 Nov 9

Zettl I, Ivanova T, Zghaebi M

The nasal cavity is an important site of allergen entry. Hence, it represents an organ where trans-epithelial allergen penetration and subsequent IgE-mediated allergic inflammation can potentially be inhibited. Intercellular adhesion molecule 1 (ICAM-1) is highly expressed on the surface of respiratory epithelial cells in allergic patients. It was identified as a promising target to immobilize antibody conjugates bispecific for ICAM-1 and allergens and thereby block allergen entry. We have previously characterized a nanobody specific for the major birch pollen allergen Bet v 1 and here we report the generation and characterization of ICAM-1-specific nanobodies. Nanobodies were obtained from a camel immunized with ICAM-1 and a high affinity binder was selected after phage display (Nb44). Nb44 was expressed as recombinant protein containing HA- and His-tags in Escherichia coli (E.coli) and purified via affinity chromatography. SDS-PAGE and Western blot revealed a single band at approximately 20 kDa. Nb44 bound to recombinant ICAM-1 in ELISA, and to ICAM-1 expressed on the human bronchial epithelial cell line 16HBE14o- as determined by flow cytometry. Experiments conducted at 4°C and at 37°C, to mimic physiological conditions, yielded similar percentages (97.2 ± 1.2% and 96.7 ± 1.5% out of total live cells). To confirm and visualize binding, we performed immunofluorescence microscopy. While Texas Red Dextran was rapidly internalized Nb44 remained localized on the cell surface. Additionally, we determined the strength of Nb44 and ICAM-1 interaction using surface plasmon resonance (SPR). Nb44 bound ICAM-1 with high affinity (10-10 M) and had slow off-rates (10-4 s-1). In conclusion, our results showed that the selected ICAM-1-specific nanobody bound ICAM-1 with high affinity and was not internalized. Thus, it could be further used to engineer heterodimers with allergen-specific nanobodies in order to develop topical treatments of pollen allergy.

5. ZC3H11A loss of function enhances NF-κB signaling through defective IκBα protein expression.

Front Immunol

2022 Nov 9

Darweesh M, Younis S, Hajikhezri Z

6. Analysis of macular structure in age-related cataract patients with different antibody levels of severe acute respiratory syndrome coronavirus-2 vaccine.

Front Immunol

2022 Nov 9

Li X, Cao X, Pan Z

OBJECTIVE: To analyze the macular structure of age-related cataract (ARC) patients with different antibody levels after COVID-19 vaccine injection, in order to obtain the effect of COVID-19 vaccine on the macular structure, and speculate whether the COVID-19 vaccine has adverse effects on the macular structure. METHODS: This retrospective study is conducted to analysis on the status of COVID-19 vaccine and the thickness of different layers at different positions in the macular area of ARC patients. In the age, sex and eye axial length matched population, in the un-injection, no-antibody, IgM and IgG positive groups after vaccination, the choroid, ganglion cell complex, nerve fiber layer and retinal thickness at different positions of ETDRS zoning in the macular area were discussed. RESULTS: A total of 164 patients (164 eyes) were included in the analysis. There were 63 males and 101 females. The average age was 65.99 ± 8.43 years. There was no significant difference in age and sex among the groups (p>0.05). The average axial length of 164 eyes was 23.56 ± 1.46mm, and no significant difference between the groups (p>0.05). Non parametric test and ANOVA test for the thickness of choroid, retina, ganglion cell complex and retinal nerve fiber layer in each division of ETDRS showed no significant difference in the four groups of un-injection, no-antibody, IgM and IgG (p>0.05). There was no correlation between the antibody concentration and the thickness of macular structure (p>0.05). CONCLUSION: There was no significant difference in the thickness of choroid, retina, ganglion cell complex and retinal fiber layer in different macular areas after COVID-19 vaccine injection. There was no linear correlation between the thickness of choroid, retina, ganglion cell complex and retinal fiber layer and the antibody concentration produced after COVID-19 vaccine injection. It suggests that the injection of COVID-19 vaccine might have no significant effect on the macular structure of eye.

7. Granzyme B in circulating CD8+ T cells as a biomarker of immunotherapy effectiveness and disability in neuromyelitis optica spectrum disorders.

Front Immunol

2022 Nov 9

Shi Z, Du Q, Wang X

BACKGROUND AND OBJECTIVE: Neuromyelitis optica spectrum disorders (NMOSD) are chronical inflammatory demyelinating diseases of the central nervous system (CNS) and the underlying mechanism remains unclear. Several recent studies have demonstrated that T cells play a pivotal role in the pathogenesis of NMOSD.In this study, we investigated CD8+ T cell phenotypes and levels of the cytotoxic protein granzyme B (GzmB), as well as their potential clinical application in NMOSD. METHODS: In this study, 90 peripheral blood samples were collected from 59 NMOSD patients with seropositive anti-aquaporin-4 (AQP4) antibodies and 31 sex- and age-matched healthy donors (HDs). Flow cytometry was used to detect circulating levels of GzmB and CD8+ T cell subpopulations, including naïve (TN, CCD7+CD45RA+), central memory (TCM, CCD7+CD45RA-), effector memory (TEM, CCD7-CD45RA-), terminal differentiation effector memory cells (TEMRA, CCD7-CD45RA+) in both groups. The associations between GzmB levels in CD8+T cells and clinical characteristics of NMOSD were evaluated. RESULTS: NMOSD patients exhibited significantly decreased proportions of CD8+TN cells and increased proportions of highly differentiated CD8+T cells (TEMRA) compared with HDs. In addition, levels of GzmB in CD8+ T cells were markedly higher in NMOSD patients than in HDs. Moreover, we observed that high proportions of GzmB-expressing CD8+ T cells were more common in patients with a poor response to immunotherapies, and showed a good potential to distinguish poor responders from responders (ACU=0.89). Clinical correlation analysis indicated that high levels of GzmB in CD8+ T cells were not only related to severe disability but also significantly associated with increased serum levels of neurofilament light (NFL) and glial fibrillary acidic protein (GFAP). Multivariate linear regression analyses further suggested that GzmB expression in CD8+ T cells was predominantly associated with disability and immunotherapy effectiveness in NMOSD, independent of the sex, age, and disease phase. Transcription factor T-bet in CD8+ T cells were also significantly elevated in NMOSD and were associated with increasing number of circulating CD8+TEMRA cells and GzmB-expressing CD8+T cells. CONCLUSIONS: Our study support the involvement of GzmB-expressing CD8+ T cells in the inflammatory response in patients with NMOSD and provide a potential biomarker for disease immunotherapy effectiveness and disability progression.

8. Predictive models for thromboembolic events in giant cell arteritis: A US veterans health administration population-based study.

Front Immunol

2022 Nov 9

Michailidou D, Zhang T, Kuderer NM

9. SARS-CoV-2-specific humoral and cellular immune responses to BNT162b2 vaccine in Fibrodysplasia ossificans progressiva patients.

Front Immunol

2022 Nov 9

Smetanova J, Milota T, Rataj M

10. Circular RNAs as emerging regulators in COVID-19 pathogenesis and progression.

Front Immunol

2022 Nov 9

Gao X, Fang D, Liang Y

11. A longitudinal study of C1q and anti-C1q autoantibodies in homologous and heterologous pregnancies for predicting pre-eclampsia.

Front Immunol

2022 Nov 9

Agostinis C, Zito G, Toffoli M

C1q, the recognition molecule of the classical pathway of the complement system, plays a central role in pregnancy. Lack of C1q is characterized by poor trophoblast invasion and pregnancy failure. C1q can be the target of an antibody response: anti-C1q autoantibodies (anti-C1q) are present in several infectious and autoimmune diseases. The presence of these autoantibodies has been detected also in 2-8% of the general population. Recent evidence indicates that women who undergo assisted reproductive technology (ART) have an increased risk of developing pre-eclampsia (PE), particularly oocyte donation (OD) pregnancies. The aim of this study was to characterize the levels of C1q and anti-C1q in PE gestations, in healthy spontaneous, homologous and heterologous ART pregnancies. Serum of the following four groups of women, who were followed throughout two or three trimesters, were collected: PE, patients diagnosed with PE; OD, oocyte donation recipients; HOM, homologous ART women; Sp, spontaneous physiological pregnancy. Our results indicate that PE patients have lower levels of anti-C1q. In ART pregnant women, the trend of C1q and anti-C1q levels were similar to PE patients, even though these women did not develop PE-like symptoms during pregnancy. This finding suggests an immunological dysfunction at the foetal-maternal interface in ART pregnancies, a hypothesis confirmed by the observation of C1q deposition in placentae derived from OD, comparable to PE. Since significantly lower levels of anti-C1q were detected in PE compared to healthy control sera, we hypothesize the possible binding on placental syncytiotrophoblast microvesicles (STBM), which are increased in the circulation of PE mothers. Furthermore, the characterization of the binding-epitope of anti-C1q revealed that "physiological" autoantibodies were mainly directed against C1q globular domain. We concluded that anti-C1q could have a physiological role in pregnancy: during the healthy spontaneous pregnancy the raised levels of these autoantibodies can be important for the clearance of STBM. In PE and in pathological pregnancies (but also in OD pregnancies), the increase in syncytiotrophoblast apoptosis and consequent increase of the circulating STMB levels lead to a consumption of C1q and anti-C1q.

12. Association between systemic rheumatic diseases and dementia risk: A meta-analysis.

Front Immunol

2022 Nov 9

Wang YC, Lin MS, Huang AP

13. Corrigendum: Examination of the role of necroptotic damage-associated molecular patterns in tissue fibrosis.

Front Immunol

2022 Nov 9

Liu X, Lu F, Chen X.

14. Splenic protection network revealed by transcriptome analysis in inactivated vaccine-immunized flounder (Paralichthys olivaceus) against Edwardsiella tarda infection.

Front Immunol

2022 Nov 9

Wu X, Xing J, Tang X

The protective immune response produced by fish after vaccination is crucial for vaccine effectiveness. Our previous studies have shown inactivated vaccine against Edwardsiella tarda can induce immune response in flounder (Paralichthys olivaceus). To elucidate the protective immune response at the genetic level, in this study, flounder was immunized with inactivated E. tarda for 5 weeks, and then they were challenged with E. tarda. The spleen was dissected at 7th day post immunization, 1st and 7th day post challenge, respectively. Transcriptome analysis showed that average of 46 million clean reads were obtained per library, while percentage of clean reads being mapped to reference genome was more than 89% in all cases, which suggested good quality of samples. As for differentially expressed genes (DEGs) identification in inactivated E. tarda groups, at 7th day post immunization, 1422 DEGs were identified and significantly enriched in innate immune-related pathways, such as Phagosome, Cell adhesion molecules and NF-kappa B signaling pathway; At 1st post challenge day, 1210 DEGs were identified and enriched to Antigen processing and presentation and Cell adhesion molecules, indicating that the pathogen was rapidly recognized and delivered; At 7th post challenge day, 1929 DEGs were identified, belonged to Toll-like receptor signaling pathway, Antigen processing and presentation, Th1 and Th2 cell differentiation and Th17 cell differentiation. Compared to 7th post immunization day, 73 immune-associated DEGs were identified at 1st post challenge day. Protein-protein interaction networks analysis revealed 11 hub genes (TLR7, TLR3, CXCR4, IFIH1, TLR8 etc), associated with recognition of pathogens and activation of innate immunity; while for 7th post challenge day, 141 immune-associated DEGs were identified. 30 hub genes (IL6, STAT1, HSP90A.1, TLR7, IL12β etc) were associated with stimulation of lymphocyte differentiation and activation of cellular immunity. Ten immune-related genes were randomly selected for RT-qPCR validation at each time point. In conclusion, data revealed protection of flounder against E. tarda infection by inactivated vaccine is mediated via immediate recognition of pathogen and subsequently activation of cellular immunity. Results give new aspect for vaccine protection cascades, is good references for vaccine evaluation.

15. Heparin is required for the formation of granules in connective tissue mast cells.

Front Immunol

2022 Nov 9

Herrera-Heredia SA, Hsu HP, Kao CY

16. Corrigendum: Escape of TLR5 recognition by Leptospira spp.: A rationale for atypical endoflagella.

Front Immunol

2022 Nov 8

Holzapfel M, Bonhomme D, Cagliero J

17. Degree of stemness predicts micro-environmental response and clinical outcomes of diffuse large B-cell lymphoma and identifies a potential targeted therapy.

Front Immunol

2022 Nov 8

Hu F, Li H, Li L

18. Mesenchymal stromal cells as treatment for acute respiratory distress syndrome. Case Reports following hematopoietic cell transplantation and a review.

Front Immunol

2022 Nov 8

Sadeghi B, Ringdén O, Gustafsson B

19. A single birth dose of Hepatitis B vaccine induces polyfunctional CD4(+) T helper cells.

Front Immunol

2022 Nov 8

Strandmark J, Darboe A, Diray-Arce J

20. Single-cell RNA sequencing reveals a novel inhibitory effect of ApoA4 on NAFL mediated by liver-specific subsets of myeloid cells.

Front Immunol

2022 Nov 8

Liu XH, Zhou JT, Yan CX

21. Fibroblast growth factor receptor family mutations as a predictive biomarker for immune checkpoint inhibitors and its correlation with tumor immune microenvironment in melanoma.

Front Immunol

2022 Nov 8

Zhang W, Xia H, Yang R

BACKGROUND: The emergence of immune checkpoint inhibitors (ICIs) has significantly improved the clinical outcomes of patients with metastatic melanoma. However, survival benefits are only observed in a subset of patients. The fibroblast growth factor receptor (FGFR) family genes are frequently mutated in melanoma, yet their impacts on the efficacy of ICIs remain unclear. Our study aimed to explore the association of FGFR mutations with ICIs efficacy in metastatic melanoma. METHODS: The Cancer Genome Atlas (TCGA) data (PanCancer Atlas, skin cutaneous melanoma (SKCM), n = 448) in cBioPortal were collected as a TCGA cohort to investigate the association between FGFR mutations and prognosis of melanoma patients. To explore the impact of FGFR mutations on the efficacy of ICIs in melanoma, clinical and tumor whole-exome sequencing (WES) data of four ICI-treated studies from cBioPortal were consolidated as an ICIs-treated cohort. Moreover, the relationship between FGFR mutations and immunogenicity (tumor mutation burden (TMB), neo-antigen load (NAL), mismatch repair (MMR)-related genes and DNA damage repair (DDR)-related genes) of melanoma was evaluated utilizing data from the ICIs-treated cohort. The influence of FGFR mutations on the tumor immune microenvironment (TIME) of melanoma was also analyzed using the TCGA cohort. RESULTS: In the TCGA cohort, survival in melanoma patients with or without FGFR mutations was nearly equivalent. In the ICIs-treated cohort, patients with FGFR mutations had better survival than those without (median overall survival: 60.00 vs. 31.00 months; hazard ratio: 0.58, 95% CI: 0.42-0.80; P = 0.0051). Besides, the objective response rate was higher for patients harboring FGFR mutations (55.56%) compared to wild-type patients (22.40%) (P = 0.0076). Mechanistically, it was revealed that FGFR mutations correlated with increased immunogenicity (e.g., TMB, NAL, MMR-related gene mutations and DDR-related gene mutations). Meanwhile, FGFR mutant melanoma tended to exhibit an enhanced antitumor TIME compared with its wild-type counterparts. CONCLUSIONS: Our study demonstrated that FGFR mutations is a promising biomarker in stratifying patients with advanced melanoma who might benefit from ICIs therapy.

22. Microglial cells: Sensors for neuronal activity and microbiota-derived molecules.

Front Immunol

2022 Nov 8

D'Alessandro G, Marrocco F, Limatola C.

23. Delamanid suppresses CXCL10 expression via regulation of JAK/STAT1 signaling and correlates with reduced inflammation in tuberculosis patients.

Front Immunol

2022 Nov 8

Qiao M, Li S, Yuan J

24. Effects of gut microbiota on immune responses and immunotherapy in colorectal cancer.

Front Immunol

2022 Nov 8

Hou X, Zheng Z, Wei J

25. Benchmarking freely available HLA typing algorithms across varying genes, coverages and typing resolutions.

Front Immunol

2022 Nov 8

Thuesen NH, Klausen MS, Gopalakrishnan S

Identifying the specific human leukocyte antigen (HLA) allele combination of an individual is crucial in organ donation, risk assessment of autoimmune and infectious diseases and cancer immunotherapy. However, due to the high genetic polymorphism in this region, HLA typing requires specialized methods. We investigated the performance of five next-generation sequencing (NGS) based HLA typing tools with a non-restricted license namely HLA*LA, Optitype, HISAT-genotype, Kourami and STC-Seq. This evaluation was done for the five HLA loci, HLA-A, -B, -C, -DRB1 and -DQB1 using whole-exome sequencing (WES) samples from 829 individuals. The robustness of the tools to lower depth of coverage (DOC) was evaluated by subsampling and HLA typing 230 WES samples at DOC ranging from 1X to 100X. The HLA typing accuracy was measured across four typing resolutions. Among these, we present two clinically-relevant typing resolutions (P group and pseudo-sequence), which specifically focus on the peptide binding region. On average, across the five HLA loci examined, HLA*LA was found to have the highest typing accuracy. For the individual loci, HLA-A, -B and -C, Optitype's typing accuracy was the highest and HLA*LA had the highest typing accuracy for HLA-DRB1 and -DQB1. The tools' robustness to lower DOC data varied widely and further depended on the specific HLA locus. For all Class I loci, Optitype had a typing accuracy above 95% (according to the modification of the amino acids in the functionally relevant portion of the HLA molecule) at 50X, but increasing the DOC beyond even 100X could still improve the typing accuracy of HISAT-genotype, Kourami, and STC-seq across all five HLA loci as well as HLA*LA's typing accuracy for HLA-DQB1. HLA typing is also used in studies of ancient DNA (aDNA), which is often based on sequencing data with lower quality and DOC. Interestingly, we found that Optitype's typing accuracy is not notably impaired by short read length or by DNA damage, which is typical of aDNA, as long as the DOC is sufficiently high.

26. Identification of potential candidate vaccines against Mycobacterium ulcerans based on the major facilitator superfamily transporter protein.

Front Immunol

2022 Nov 8

Ishwarlall TZ, Adeleke VT, Maharaj L

Buruli ulcer is a neglected tropical disease that is characterized by non-fatal lesion development. The causative agent is Mycobacterium ulcerans (M. ulcerans). There are no known vectors or transmission methods, preventing the development of control methods. There are effective diagnostic techniques and treatment routines; however, several socioeconomic factors may limit patients' abilities to receive these treatments. The Bacillus Calmette-Guérin vaccine developed against tuberculosis has shown limited efficacy, and no conventionally designed vaccines have passed clinical trials. This study aimed to generate a multi-epitope vaccine against M. ulcerans from the major facilitator superfamily transporter protein using an immunoinformatics approach. Twelve M. ulcerans genome assemblies were analyzed, resulting in the identification of 11 CD8+ and 7 CD4+ T-cell epitopes and 2 B-cell epitopes. These conserved epitopes were computationally predicted to be antigenic, immunogenic, non-allergenic, and non-toxic. The CD4+ T-cell epitopes were capable of inducing interferon-gamma and interleukin-4. They successfully bound to their respective human leukocyte antigens alleles in in silico docking studies. The expected global population coverage of the T-cell epitopes and their restricted human leukocyte antigens alleles was 99.90%. The population coverage of endemic regions ranged from 99.99% (Papua New Guinea) to 21.81% (Liberia). Two vaccine constructs were generated using the Toll-like receptors 2 and 4 agonists, LprG and RpfE, respectively. Both constructs were antigenic, non-allergenic, non-toxic, thermostable, basic, and hydrophilic. The DNA sequences of the vaccine constructs underwent optimization and were successfully in-silico cloned with the pET-28a(+) plasmid. The vaccine constructs were successfully docked to their respective toll-like receptors. Molecular dynamics simulations were carried out to analyze the binding interactions within the complex. The generated binding energies indicate the stability of both complexes. The constructs generated in this study display severable favorable properties, with construct one displaying a greater range of favorable properties. However, further analysis and laboratory validation are required.

27. Follicular regulatory T cells eliminate HIV-1-infected follicular helper T cells in an IL-2 concentration dependent manner.

Front Immunol

2022 Nov 7

Ollerton MT, Folkvord JM, La Mantia A

28. Exosomal ncRNAs: The pivotal players in diabetic wound healing.

Front Immunol

2022 Nov 7

Shen J, Zhao X, Zhong Y

29. Dendritic cell-specific transmembrane protein is required for synovitis and bone resorption in inflammatory arthritis.

Front Immunol

2022 Nov 7

Garcia-Hernandez ML, Rangel-Moreno J, Garcia-Castaneda M

30. CD160 receptor in CLL: Current state and future avenues.

Front Immunol

2022 Nov 7

Oumeslakht L, Aziz AI, Bensussan A

31. Immune profiling identifies CD8(+) T-cell subset signatures as prognostic markers for recurrence in papillary thyroid cancer.

Front Immunol

2022 Nov 7

Chen Z, Guo ML, Li YY

BACKGROUND: Thyroid tissue has a special immune microenvironment that is not well characterized. Whether immune cells have a prognostic value in the recurrence of papillary thyroid cancer (PTC) needs further investigation. METHODS: Multinodular non-toxic goiter (MNG) was taken as normal tissue for the difficulty in obtaining completely normal thyroid tissue (normal thyroid function, no thyroiditis, and no nodules). We compared the composition of mononuclear cells (MNCs) in peripheral blood and thyroid tissues from MNG and PTC patients by high-dimensional flow cytometry profiling and verified the results by multiplex immunohistochemistry. The recurrence rates of PTC patients with different CD8+T cell subset signatures were compared using TCGA database. RESULTS: We observed that the immune cell composition of MNG was different from that in peripheral blood. Thyroid tissue contains higher percentages of T cells and NK cells. Moreover, the percentages of memory T cells and Treg cells were higher in thyroid than in peripheral blood and increased in PTC tumors. We further focused on the antitumoral CD8+T cells and found that the expression patterns of PD-1, CD39, and CD103 on CD8+T cells were different between MNG and PTC. Importantly, we found higher percentages of PD-1+CD39+CD103+CD8+T and PD-1+CD39+CD103-CD8+T cells in PTC tumor tissues from recurrent patients than non-recurrent patients. By analyzing PTC data from TCGA database, we found that the expression patterns of these molecules were associated with different pathologic types and genders among PTC patients. Moreover, patients with PD-1hiCD39loCD103hiCD8hi, PD-1hiCD39hiCD103loCD8hi, and PD-1loCD39hiCD103hiCD8hi expression patterns have a higher 10-year recurrence-free survival. CONCLUSION: The immune microenvironment in MNG tissue is distinct from that in peripheral blood and paratumor tissue. More memory CD8+T cells were detected in PTC, and expression patterns of PD-1, CD39, and CD103 on CD8+T cells were significantly different in physiology and gender and associated with the recurrence rate of PTC. These observations indicate that CD8+T cell signatures may be useful prognostic markers for PTC recurrence.

32. Single-cell profiling to transform immunotherapy usage and target discovery in immune-mediated inflammatory diseases.

Front Immunol

2022 Nov 7

Chapelle N, Fantou A, Marron T

33. Corrigendum: Plasma exosomal IRAK1 can be a potential biomarker for predicting the treatment response to renin-angiotensin system inhibitors in patients with IgA nephropathy.

Front Immunol

2022 Nov 7

Wu J, Wei X, Li J

34. Bioinformatics and systems biology approaches to identify molecular targeting mechanism influenced by COVID-19 on heart failure.

Front Immunol

2022 Nov 7

Yang K, Liu J, Gong Y

35. Post-vaccination SARS-CoV-2 seroprevalence in children aged 3-11 years and the positivity in unvaccinated children: A retrospective, single-center study.

Front Immunol

2022 Nov 7

Li J, Ge M, Dai S

OBJECTIVE: To analyze the positivity and levels of SARS-CoV-2 antibodies in vaccinated children to evaluate the humoral immune response of vaccination on pediatric population. Analysis on the causes of antibody positivity in unvaccinated children. METHODS: A retrospective study was conducted on children who were admitted to the Children's Hospital Affiliated to Capital Institute of Pediatrics. The clinical data of serological testing of SARS-CoV-2 immunoglobulin M (IgM) and IgG antibodies were collected from SARS-CoV-2 vaccinated or unvaccinated children with no evidence of prior novel coronavirus infection. Chemiluminescence immunoassay was utilized for the in vitro determination of SARS-CoV-2 antibodies. RESULTS: A total of 3,321 healthy children aged 6-11 years received two doses of inactivated SARS-CoV-2 vaccine. At 1 month after the second dose, the positive rate (96.5%) and levels [8.039 (interquartile range (IQR), 6.067-9.098)] of SARS-CoV-2 IgG antibodies reached the peak and remained at a high level for 2-3 months, after which the positive rate and level of vaccine-induced IgG antibody gradually decreased. Compared with 1 month after the second dose of vaccine, the positive rate of IgG antibody decreased to 70.4% at 7 months, and the antibody level decreased by 69.0%. A total of 945 children aged 3-5 years received one or two doses of inactivated vaccine. The positive rate and levels of SARS-CoV-2 IgG antibody in participants remained high for 3 months after vaccination. There was no gender-based difference in positive rate of IgG antibody in children aged 3-11 years old (P>0.05). Among the 5,309 unvaccinated children aged 0 day to 11 years, 105 (2.0%) were positive for SARS-CoV-2 IgG antibody, which was associated with passive infusion. The maternal humoral response to COVID-19 vaccination in noninfected pregnant women was transferred through the placenta to the fetus, and some children obtained SARS-CoV-2-positive antibodies through blood transfusion. CONCLUSIONS: Inactivated SARS-CoV-2 vaccines could induce robust humoral immune response that gradually declined within several months after the second dose. Therefore, it helps to determine whether children receive a booster dose and elicit a long-term memory immune response. Positive SARS-CoV-2 antibodies in unvaccinated children were associated with passive IgG antibody infusion.

36. Genetic mutation and tumor microbiota determine heterogenicity of tumor immune signature: Evidence from gastric and colorectal synchronous cancers.

Front Immunol

2022 Nov 7

Yang W, Zhao Y, Ge Q

37. Tertiary lymphoid structure patterns aid in identification of tumor microenvironment infiltration and selection of therapeutic agents in bladder cancer.

Front Immunol

2022 Nov 7

An Y, Sun JX, Xu MY

38. Editorial: Epigenetics of infectious diseases.

Front Immunol

2022 Nov 4

Kulkarni S, Arumugam T, Chuturgoon A

39. Distinction of early complement classical and lectin pathway activation via quantification of C1s/C1-INH and MASP-1/C1-INH complexes using novel ELISAs.

Front Immunol

2022 Nov 4

Hurler L, Toonen EJM, Kajdácsi E

40. Relationships of circulating CD4(+) T cell subsets and cytokines with the risk of relapse in patients with Crohn's disease.

Front Immunol

2022 Nov 4

Duclaux-Loras R, Boschetti G, Flourie B

41. Identifying hub genes of calcific aortic valve disease and revealing the immune infiltration landscape based on multiple WGCNA and single-cell sequence analysis.

Front Immunol

2022 Nov 4

Wang K, Zheng Q, Liu X

BACKGROUND: Calcific aortic valve disease (CAVD) is a progressive fibrocalcific disease that can be treated only through valve replacement. This study aimed to determine the role of hub genes and immune cell infiltration in CAVD progression. METHODS: In this study, bioinformatics analysis was used to identify hub genes involved in CAVD. The datasets were downloaded from the Gene Expression Omnibus (GEO) database. Gene expression differences were evaluated via pathway and Gene Ontology analyses. Weighted gene co-expression network analysis (WGCNA) and differentially expressed genes were used to screen hub genes. The CIBERSORT algorithm was used to compare immune infiltration into the calcified aortic valve based on the hub genes between high- and low-expression groups. We also performed single-cell RNA sequencing based on six different human aortic valve leaflets. The expression of hub genes was identified in human and mouse samples through quantitative real-time polymerase chain reaction (qPCR), immunohistochemistry, immunofluorescence, and ELISA, and clinical features of the patients were investigated. RESULTS: In total, 454 differentially expressed genes were obtained from the GEO database. WGCNA was used to find 12 co-expression modules in the Array Express database, of which one hub module (brown module) was most correlated with CAVD. Two hub genes were identified after combining the differentially expressed genes S100A8 and S100A9. Regarding these genes, the immune infiltration profiles varied between high- and low-expression groups. Compared with that in the low hub gene expression group, the high hub gene expression group had a higher proportion of activated NK cells (p < 0.01) and M1 macrophages (p < 0.05). The expression of S100A8 and S100A9 was consistent with single-gene RNA sequencing results, confirming that the expression levels of these two hub genes are significantly upregulated in patients with CAVD (p < 0.01). Furthermore, these results were verified using mouse and human samples by performing immunofluorescence, immunohistochemistry, qPCR, and ELISA analyses. Finally, the localization of S100A8 and S100A9 in monocytes and macrophages was confirmed via immunofluorescence using human aortic valves. CONCLUSION: These results demonstrate that S100A8 and S100A9 are two hub genes involved in CAVD, which might play an important role in its development through immune-related signaling pathways.

42. Interferon-inducible SAMHD1 restricts viral replication through downregulation of lipid synthesis.

Front Immunol

2022 Nov 30

An N, Ge Q, Shao H

43. Putative critical quality attribute matrix identifies mesenchymal stromal cells with potent immunomodulatory and angiogenic "fitness" ranges in response to culture process parameters.

Front Immunol

2022 Nov 30

Robb KP, Audet J, Gandhi R

Adipose-derived mesenchymal stromal cells (MSC(AT)) display immunomodulatory and angiogenic properties, but an improved understanding of quantitative critical quality attributes (CQAs) that inform basal MSC(AT) fitness ranges for immunomodulatory and/or angiogenic applications is urgently needed for effective clinical translation. We constructed an in vitro matrix of multivariate readouts to identify putative CQAs that were sensitive enough to discriminate between specific critical processing parameters (CPPs) chosen for their ability to enhance MSC immunomodulatory and angiogenic potencies, with consideration for donor heterogeneity. We compared 3D aggregate culture conditions (3D normoxic, 3D-N) and 2D hypoxic (2D-H) culture as non-genetic CPP conditions that augment immunomodulatory and angiogenic fitness of MSC(AT). We measured multivariate panels of curated genes, soluble factors, and morphometric features for MSC(AT) cultured under varying CPP and licensing conditions, and we benchmarked these against two functional and therapeutically relevant anchor assays - in vitro monocyte/macrophage (MΦ) polarization and in vitro angiogenesis. Our results showed that varying CPP conditions was the primary driver of MSC(AT) immunomodulatory fitness; 3D-N conditions induced greater MSC(AT)-mediated MΦ polarization toward inflammation-resolving subtypes. In contrast, donor heterogeneity was the primary driver of MSC(AT) angiogenic fitness. Our analysis further revealed panels of putative CQAs with minimum and maximum values that consisted of twenty MSC(AT) characteristics that informed immunomodulatory fitness ranges, and ten MSC(AT) characteristics that informed angiogenic fitness ranges. Interestingly, many of the putative CQAs consisted of angiogenic genes or soluble factors that were inversely correlated with immunomodulatory functions (THBS1, CCN2, EDN1, PDGFA, VEGFA, EDIL3, ANGPT1, and ANG genes), and positively correlated to angiogenic functions (VEGF protein), respectively. We applied desirability analysis to empirically rank the putative CQAs for MSC(AT) under varying CPP conditions and donors to numerically identify the desirable CPP conditions or donors with maximal MSC(AT) immunomodulatory and/or angiogenic fitness. Taken together, our approach enabled combinatorial analysis of the matrix of multivariate readouts to provide putative quantitative CQAs that were sensitive to variations in select CPPs that enhance MSC immunomodulatory/angiogenic potency, and donor heterogeneity. These putative CQAs may be used to prospectively screen potent MSC(AT) donors or cell culture conditions to optimize for desired basal MSC(AT) immunomodulatory or angiogenic fitness.

44. Plasma proteomics reveals early, broad release of chemokine, cytokine, TNF, and interferon mediators following trauma with delayed increases in a subset of chemokines and cytokines in patients that remain critically ill.

Front Immunol

2022 Nov 30

Bonaroti J, Billiar I, Moheimani H

Severe injury is known to cause a systemic cytokine storm that is associated with adverse outcomes. However, a comprehensive assessment of the time-dependent changes in circulating levels of a broad spectrum of protein immune mediators and soluble immune mediator receptors in severely injured trauma patients remains uncharacterized. To address this knowledge gap, we defined the temporal and outcome-based patterns of 184 known immune mediators and soluble cytokine receptors in the circulation of severely injured patients. Proteomics (aptamer-based assay, SomaLogic, Inc) was performed on plasma samples drawn at 0, 24, and 72 hours (h) from time of admission from 150 trauma patients, a representative subset from the Prehospital Plasma during Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock (PAMPer) trial. Patients were categorized into outcome groups including Early Non-Survivors (died within 72 h; ENS; n=38), Non-Resolvers (died after 72 h or required ≥7 days of intensive care; NR; n=78), and Resolvers (survivors that required < 7 days of intensive care; R; n=34), with low Injury Severity Score (ISS) patients from the Tranexamic Acid During Prehospital Transport in Patients at Risk for Hemorrhage After Injury (STAAMP) trial as controls. The major findings include an extensive release of immune mediators and cytokine receptors at time 0h that is more pronounced in ENS and NR patients. There was a selective subset of mediators elevated at 24 and 72 h to a greater degree in NR patients, including multiple cytokines and chemokines not previously described in trauma patients. These findings were validated in a quantitative fashion using mesoscale discovery immunoassays (MSD) from an external validation cohort (VC) of samples from 58 trauma patients matched for R and NR status. This comprehensive longitudinal description of immune mediator patterns associated with trauma outcomes provides a new level of characterization of the immune response that follows severe injury.

45. A prognostic and therapeutic hallmark developed by the integrated profile of basement membrane and immune infiltrative landscape in lung adenocarcinoma.

Front Immunol

2022 Nov 30

Chen K, Liu S, Lu C

46. H3K36 methyltransferase NSD1 is essential for normal B1 and B2 cell development and germinal center formation.

Front Immunol

2022 Nov 30

Zhai S, Cao M, Zhou H

47. The top 100 most cited articles in the last two decades of atopic dermatitis: A bibliometric analysis.

Front Immunol

2022 Nov 30

Zhang L, Hou Y, Sun J

48. Gene expression analysis in endometriosis: Immunopathology insights, transcription factors and therapeutic targets.

Front Immunol

2022 Nov 30

Geng R, Huang X, Li L

BACKGROUND: Endometriosis is recognized as an estrogen-dependent inflammation disorder, estimated to affect 8%-15% of women of childbearing age. Currently, the etiology and pathogenesis of endometriosis are not completely clear. Underlying mechanism for endometriosis is still under debate and needs further exploration. The involvement of transcription factors and immune mediations may be involved in the pathophysiological process of endometriosis, but the specific mechanism remains to be explored. This study aims to investigate the underlying molecular mechanisms in endometriosis. METHODS: The gene expression profile of endometriosis was obtained from the gene expression omnibus (GEO) database. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were applied to the endometriosis GSE7305 datasets. Cibersort and MCP-counter were used to explore the immune response gene sets, immune response pathway, and immune environment. Differentially expressed genes (DEGs) were identified and screened. Common biological pathways were being investigated using the kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. Transcription factors were from The Human Transcription Factors. The least absolute shrinkage and selection operator (Lasso) model identified four differential expressions of transcription factors (AEBP1, HOXB6, KLF2, and RORB). Their diagnostic value was calculated by receiver operating characteristic (ROC) curve analysis and validated in the validation cohort (GSE11691, GSE23339). By constructing the interaction network of crucial transcription factors, weighted gene coexpression network analysis (WGCNA) was used to search for key module genes. Metascape was used for enrichment analysis of essential module genes and obtained HOXB6, KLF2. The HOXB6 and KLF2 were further verified as the only two intersection genes according to Support Vector Machine Recursive Feature Elimination (SVM-RFE) and random forest models. We constructed ceRNA (lncRNA-miRNA-mRNA) networks with four potential transcription factors. Finally, we performed molecular docking for goserelin and dienogest with four transcription factors (AEBP1, HOXB6, KLF2, and RORB) to screen potential drug targets. RESULTS: Immune and metabolic pathways were enriched in GSVA and GSEA. In single sample gene set enrichment analysis (ssGSEA), most immune infiltrating cells, immune response gene sets, and immune response pathways are differentially expressed between endometriosis and non-endometriosis. Twenty-seven transcription factors were screened from differentially expressed genes. Most of the twenty-seven transcription factors were correlated with immune infiltrating cells, immune response gene sets and immune response pathways. Furthermore, Adipocyte enhancer binding protein 1 (AEBP1), Homeobox B6 (HOXB6), Kruppel Like Factor 2 (KLF2) and RAR Related Orphan Receptor B (RORB) were selected out from twenty-seven transcription factors. ROC analysis showed that the four genes had a high diagnostic value for endometriosis. In addition, KLF2 and HOXB6 were found to play particularly important roles in multiple modules (String, WGCNA, SVM-RFE, random forest) on the gene interaction network. Using the ceRNA network, we found that NEAT1 may regulate the expressions of AEBP1, HOXB6 and RORB, while X Inactive Specific Transcript (XIST) may control the expressions of HOXB6, RORB and KLF2. Finally, we found that goserelin and dienogest may be potential drugs to regulate AEBP1, HOXB6, KLF2 and RORB through molecular docking. CONCLUSIONS: AEBP1, HOXB6, KLF2, and RORB may be potential biomarkers for endometriosis. Two of them, KLF2 and HOXB6, are critical molecules in the gene interaction network of endometriosis. Discovered by molecular docking, AEBP1, HOXB6, KLF2, and RORB are targets for goserelin and dienogest.

49. Identifying tumor antigens and immune subtypes of renal cell carcinoma for immunotherapy development.

Front Immunol

2022 Nov 3

Chen X, Zhang T, Zhai X

50. NLRP3+ macrophages aggravate inflammatory cystitis in diabetes.

Front Immunol

2022 Nov 3

Peng Y, Gao Y.

51. Moving the needle: Employing deep reinforcement learning to push the boundaries of coarse-grained vaccine models.

Front Immunol

2022 Nov 3

Faris JG, Orbidan D, Wells C

Highly mutable infectious disease pathogens (hm-IDPs) such as HIV and influenza evolve faster than the human immune system can contain them, allowing them to circumvent traditional vaccination approaches and causing over one million deaths annually. Agent-based models can be used to simulate the complex interactions that occur between immune cells and hm-IDP-like proteins (antigens) during affinity maturation-the process by which antibodies evolve. Compared to existing experimental approaches, agent-based models offer a safe, low-cost, and rapid route to study the immune response to vaccines spanning a wide range of design variables. However, the highly stochastic nature of affinity maturation and vast sequence space of hm-IDPs render brute force searches intractable for exploring all pertinent vaccine design variables and the subset of immunization protocols encompassed therein. To address this challenge, we employed deep reinforcement learning to drive a recently developed agent-based model of affinity maturation to focus sampling on immunization protocols with greater potential to improve the chosen metrics of protection, namely the broadly neutralizing antibody (bnAb) titers or fraction of bnAbs produced. Using this approach, we were able to coarse-grain a wide range of vaccine design variables and explore the relevant design space. Our work offers new testable insights into how vaccines should be formulated to maximize protective immune responses to hm-IDPs and how they can be minimally tailored to account for major sources of heterogeneity in human immune responses and various socioeconomic factors. Our results indicate that the first 3 to 5 immunizations, depending on the metric of protection, should be specially tailored to achieve a robust protective immune response, but that beyond this point further immunizations require only subtle changes in formulation to sustain a durable bnAb response.

52. Targeted drug delivery system for ovarian cancer microenvironment: Improving the effects of immunotherapy.

Front Immunol

2022 Nov 3

Peng H, He X, Wang Q.

53. Primary antibody response after influenza virus infection is first dominated by low-mutated HA-stem antibodies followed by higher-mutated HA-head antibodies.

Front Immunol

2022 Nov 3

Aartse A, Mortier D, Mooij P

54. Reduced vitamin D-induced cathelicidin production and killing of Mycobacterium tuberculosis in macrophages from a patient with a non-functional vitamin D receptor: A case report.

Front Immunol

2022 Nov 3

Al-Jaberi FAH, Crone CG, Lindenstrøm T

55. Low dose versus standard dose rituximab for the treatment of antiphospholipid syndrome: A pilot study from a tertiary medical center.

Front Immunol

2022 Nov 3

Gan Y, Zhong X, Zhao Y

56. Identification of CKS1B as a prognostic indicator and a predictive marker for immunotherapy in pancreatic cancer.

Front Immunol

2022 Nov 3

Li L, Wang J, Zhang Z

57. Immune niches orchestrated by intestinal mesenchymal stromal cells lining the crypt-villus.

Front Immunol

2022 Nov 3

Sun H, Tan J, Chen H

58. SMO mutation predicts the effect of immune checkpoint inhibitor: From NSCLC to multiple cancers.

Front Immunol

2022 Nov 3

Ji W, Niu X, Yu Y

BACKGROUND: The emergence of immune checkpoint inhibitors (ICIs) is one of the most promising breakthroughs for the treatment of multiple cancer types, but responses vary. Growing evidence points to a link between developmental signaling pathway-related genes and antitumor immunity, but the association between the genomic alterations in these genes and the response to ICIs still needs to be elucidated. METHODS: Clinical data and sequencing data from published studies and our cohort were collected to analyze the association of the mutation status of SMO with the efficacy of ICI therapy in the non-small cell lung cancer (NSCLC) cohort and the pan-cancer cohort. Furthermore, the correlation between SMO mutation and immunotherapeutic biomarkers such as immune cell infiltration, immune-related genes, and underlying signaling pathways was analyzed. Three SMO mutant plasmids were transfected into cells to explore the SMO mutation status in the context of its expression and cell growth. RESULT: In the NSCLC discovery cohort, the median progression-free survival in the SMO mutant (SMO_MUT) was longer than that in the wild type (SMO_WT) (23.0 vs. 3.8 months, adjusted p = 0.041). This finding was further confirmed in the NSCLC validation cohort (8.7 vs. 5.1 months, adjusted p = 0.013). In the pan-cancer cohort (n = 1,347), a significant overall survival advantage was observed in patients with SMO mutations [not reached (NR) vs. 18 months, adjusted p = 0.024]. In the subgroup analysis, the survival advantage of SMO_MUT against SMO_WT was prominent and consistent across genders, ages, treatment types, cancer types, and the tumor mutation burden (TMB) status (all p interaction > 0.05). In an in vitro experiment, we found that both the mutant and wild-type plasmids can promote the expression of SMO, but the mutant plasmid had lower SMO mRNA and protein levels than the wild type. In CCK-8 experiments, we found that SMO_MUT plasmids can improve the growth of Calu-1 and PC-9 cells, but this capability varied between different mutations and cells. Upon further exploration, the SMO mutation status was found to be related to a higher TMB, more neoantigen load, more DNA damage repair (DDR) mutations, higher microsatellite instability (MSI) score, and higher CD8+ T-cell infiltration. CONCLUSIONS: The SMO mutation status is an independent prognostic factor that can be used to predict better clinical outcomes of ICI treatment across multiple cancer types.

59. Activation of distinct antiviral T-cell immunity: A comparison of bi- and trispecific T-cell engager antibodies with a chimeric antigen receptor targeting HBV envelope proteins.

Front Immunol

2022 Nov 3

Debelec-Butuner B, Quitt O, Schreiber S

Despite the availability of an effective prophylactic vaccine, 820,000 people die annually of hepatitis B virus (HBV)-related liver disease according to WHO. Since current antiviral therapies do not provide a curative treatment for the 296 million HBV carriers around the globe, novel strategies to cure HBV are urgently needed. A promising approach is the redirection of T cells towards HBV-infected hepatocytes employing chimeric antigen receptors or T-cell engager antibodies. We recently described the effective redirection of T cells employing a second-generation chimeric antigen receptor directed against the envelope protein of hepatitis B virus on the surface of infected cells (S-CAR) as well as bispecific antibodies that engage CD3 or CD28 on T cells employing the identical HBV envelope protein (HBVenv) binder. In this study, we added a trispecific antibody comprising all three moieties to the tool-box. Cytotoxic and non-cytolytic antiviral activities of these bi- and trispecific T-cell engager antibodies were assessed in co-cultures of human PBMC with HBV-positive hepatoma cells, and compared to that of S-CAR-grafted T cells. Activation of T cells via the S-CAR or by either a combination of the CD3- and CD28-targeting bispecific antibodies or the trispecific antibody allowed for specific elimination of HBV-positive target cells. While S-CAR-grafted effector T cells displayed faster killing kinetics, combinatory treatment with the bispecific antibodies or single treatment with the trispecific antibody was associated with a more pronounced cytokine release. Clearance of viral antigens and elimination of the HBV persistence form, the covalently closed circular (ccc) DNA, through cytolytic as well as cytokine-mediated activity was observed in all three settings with the combination of bispecific antibodies showing the strongest non-cytolytic, cytokine-mediated antiviral effect. Taken together, we demonstrate that bi- and trispecific T-cell engager antibodies can serve as a potent, off-the-shelf alternative to S-CAR-grafted T cells to cure HBV.

60. NKB cells: A double-edged sword against inflammatory diseases.

Front Immunol

2022 Nov 3

Tandel N, Negi S, Tyagi RK.

61. Intranasal inoculation of IFN-λ resolves SARS-CoV-2 lung infection via the rapid reduction of viral burden and improvement of tissue damage.

Front Immunol

2022 Nov 29

Shin H, Kim S, Jo A

62. Combined proteomics and single cell RNA-sequencing analysis to identify biomarkers of disease diagnosis and disease exacerbation for systemic lupus erythematosus.

Front Immunol

2022 Nov 29

Li Y, Ma C, Liao S

INTRODUCTION: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease for which there is no cure. Effective diagnosis and precise assessment of disease exacerbation remains a major challenge. METHODS: We performed peripheral blood mononuclear cell (PBMC) proteomics of a discovery cohort, including patients with active SLE and inactive SLE, patients with rheumatoid arthritis (RA), and healthy controls (HC). Then, we performed a machine learning pipeline to identify biomarker combinations. The biomarker combinations were further validated using enzyme-linked immunosorbent assays (ELISAs) in another cohort. Single-cell RNA sequencing (scRNA-seq) data from active SLE, inactive SLE, and HC PBMC samples further elucidated the potential immune cellular sources of each of these PBMC biomarkers. RESULTS: Screening of the PBMC proteome identified 1023, 168, and 124 proteins that were significantly different between SLE vs. HC, SLE vs. RA, and active SLE vs. inactive SLE, respectively. The machine learning pipeline identified two biomarker combinations that accurately distinguished patients with SLE from controls and discriminated between active and inactive SLE. The validated results of ELISAs for two biomarker combinations were in line with the discovery cohort results. Among them, the six-protein combination (IFIT3, MX1, TOMM40, STAT1, STAT2, and OAS3) exhibited good performance for SLE disease diagnosis, with AUC of 0.723 and 0.815 for distinguishing SLE from HC and RA, respectively. Nine-protein combination (PHACTR2, GOT2, L-selectin, CMC4, MAP2K1, CMPK2, ECPAS, SRA1, and STAT2) showed a robust performance in assessing disease exacerbation (AUC=0.990). Further, the potential immune cellular sources of nine PBMC biomarkers, which had the consistent changes with the proteomics data, were elucidated by PBMC scRNAseq. DISCUSSION: Unbiased proteomic quantification and experimental validation of PBMC samples from two cohorts of patients with SLE were identified as biomarker combinations for diagnosis and activity monitoring. Furthermore, the immune cell subtype origin of the biomarkers in the transcript expression level was determined using PBMC scRNAseq. These findings present valuable PBMC biomarkers associated with SLE and may reveal potential therapeutic targets.

63. Three-dimensional analyses of vascular network morphology in a murine lymph node by X-ray phase-contrast tomography with a 2D Talbot array.

Front Immunol

2022 Nov 29

Schwarzenberg FL, Schütz P, Hammel JU

64. Case report: Dynamic antibody monitoring in a case of anti-recombinant human erythropoietin-mediated pure red cell aplasia with prolonged course after kidney transplantation.

Front Immunol

2022 Nov 29

Chen XM, Li H, Wu Y

65. Occurrence and role of lung megakaryocytes in infection and inflammation.

Front Immunol

2022 Nov 29

Gelon L, Fromont L, Lefrançais E.

66. Vesicle-mediated transport-related genes are prognostic predictors and are associated with tumor immunity in lung adenocarcinoma.

Front Immunol

2022 Nov 29

Qian C, Jiang Z, Zhou T

BACKGROUND: Globally, lung adenocarcinoma (LUAD) is the leading cause of cancer-related deaths. It is a progressive disorder that arises from multiple genetic and environmental factors. Dysregulated expression of vesicle-mediated transport-related genes (VMTRGs) have been reported in several cancers. However, the prognostic significance of VMTRGs in LUAD has yet to be established. METHODS: The VMTRG profiling data for 482 LUAD patients and 59 normal controls were downloaded from The Cancer Genome Altas (TCGA). Univariate Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were performed to construct and optimize the risk model. Several GEO datasets were used to validate the risk model. The roles of these genes were investigated via the Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analyses. Differences in immune cell infiltrations between risk groups were evaluated using five algorithms. "pRRophetic" was used to investigate anti-cancer drug sensitivities in two groups. Expression of these five genes in LUAD samples and adjacent normal tissues were evaluated by qRT-PCR. Colony formation and wound healing assays were performed to assess the significance of CNIH1 and AP3S1 in LUAD cells. RESULTS: We identified 85 prognosis-associated VMTRGs that could be constructed a risk model for LUAD patients, indicating their potential importance in LUAD development. The risk model including the five VMTRGs (CNIH1, KIF20A, GALNT2, GRIA1, and AP3S1) was associated with clinical outcomes. Tumor stage and risk score were found to be independent prognostic factors for LUAD patients. The five VMTRGs were also correlated with activation of the Notch and p53 signaling pathways. The risk model was significantly associated with immune responses and with high-level expression of immune checkpoints. High-risk group patients were more sensitive to several chemotherapeutic drugs and Lapatinib. Furthermore, CNIH1 and AP3S1 promoted LUAD cell growth and migration in vitro. CONCLUSION: We constructed a VMTRG-based risk model for effective prediction of prognostic outcomes for LUAD patients. The risk model was associated with immune infiltration levels. These five hub genes are potential targets for immune therapy combined with chemotherapy in LUAD.

67. Editorial: Non-coding RNA in immunotherapies and immune regulation.

Front Immunol

2022 Nov 29

Kaeffer B, Chen C, Louveau A.

68. Analyzing the immunogenicity of bivalent booster vaccinations in healthcare workers: The SWITCH ON trial protocol.

Front Immunol

2022 Nov 29

Tan NH, Sablerolles RSG, Rietdijk WJR

69. Insights into prognosis and immune infiltration of cuproptosis-related genes in breast cancer.

Front Immunol

2022 Nov 28

Huang T, Liu Y, Li J

70. The atypical chemokine receptor-2 fine-tunes the immune response in herpes stromal keratitis.

Front Immunol

2022 Nov 28

Yu T, Schuette F, Christofi M

71. Vanadyl sulfate-enhanced oncolytic virus immunotherapy mediates the antitumor immune response by upregulating the secretion of pro-inflammatory cytokines and chemokines.

Front Immunol

2022 Nov 28

Alluqmani N, Jirovec A, Taha Z

72. Altered dental plaque microbiota correlated with salivary inflammation in female methamphetamine users.

Front Immunol

2022 Nov 28

Deng Z, Guo K, Cao F

Poor oral health is the most immediate and overlooked hazard of methamphetamine abuse in humans. Previous studies have reported methamphetamine-associated alterations in saliva microbiota, but the cause of methamphetamine-induced alterations in the oral microenvironment remains unclear. The present study aimed to investigate the alterations in dental plaque microbiota in methamphetamine users, and to explore their relationship with local immune inflammation in the oral cavity. This may provide new ideas on the development of methamphetamine-related oral microenvironment changes. Questionnaires and samples were obtained from 30 female methamphetamine users and 15 sex- and age-matched healthy controls. Microbial profiles of supragingival dental plaque were analyzed using 16S rRNA gene sequencing. Inflammatory factors in saliva were measured using enzyme-linked immunosorbent assay. Methamphetamine users had worse oral self-evaluation. Compared with healthy controls, methamphetamine users showed no differences in oral dental plaque microbial diversity but exhibited differences in the relative abundance of several microbial taxa. At the phylum level, a higher abundance of Proteobacteria and a lower abundance of Firmicutes were detected in methamphetamine users. Moreover, function prediction using the MetaCyc database showed that 33 pathways were significantly upregulated in methamphetamine users; Only the glycolytic (Pyrococcus) pathway was enriched in the C group. Importantly, salivary inflammatory factors showed complex significant associations with bacterial genera in methamphetamine users. Specifically, the genus Neisseria was positively correlated with IL-17 levels in saliva, and both were high in methamphetamine users. In contrast, the genus Streptococcus, with a lower abundance, was positively correlated with lower IL-10 levels. Overall, This study is the first to provide evidence for a link between altered dental plaque microbiota and salivary inflammation in methamphetamine users. Further elucidation of the interactions between methamphetamine use and oral microenvironment would be beneficial for appropriate interventions to improve oral health.

73. Assessing the efficacy of immunotherapy in lung squamous carcinoma using artificial intelligence neural network.

Front Immunol

2022 Nov 28

Li S, Li W, Ma T

74. Association of COVID-19 mortality with serum selenium, zinc and copper: Six observational studies across Europe.

Front Immunol

2022 Nov 28

Demircan K, Chillon TS, Bracken T

75. AKR1B8 deficiency drives severe DSS-induced acute colitis through invasion of luminal bacteria and activation of innate immunity.

Front Immunol

2022 Nov 28

Deng Q, Yao Y, Yang J

BACKGROUND: Dysfunction of intestinal epithelial cells (IECs) promotes inflammatory bowel disease (IBD) and associated colorectal cancer (CRC). AKR1B8 deficiency impairs the IEC barrier function, leading to susceptibility to chronic colitis induced by dextran sulfate sodium (DSS), yet it remains unclear how acute colitic response is in AKR1B8 deficient mice. METHODS: AKR1B8 knockout (KO) and littermate wild type mice were exposed to oral 1.5% DSS in drinking water for 6 days. Disease activity index and histopathological inflammation scores by H&E staining were calculated for colitic severity; permeability was assessed by fluorescein isothiocyanate dextran (FITC-Dextran) probes and bacterial invasion and transmission were detected by in situ hybridization in mucosa or by culture in blood agar plates. Immunofluorescent staining and flow cytometry were applied for immune cell quantification. Toll-like receptor 4 (TLR4) and target gene expression was analyzed by Western blotting and qRT-PCR. RESULTS: AKR1B8 KO mice developed severe acute colitis at a low dose (1.5%) of DSS in drinking water compared to wild type controls. In AKR1B8 KO mice, FITC-dextran was penetrated easily and luminal bacteria invaded to the surface of IEC layer on day 3, and excessive bacteria translocated into the colonic mucosa, mesenteric lymph nodes (MLNs) and liver on day 6, which was much mild in wild type mice. Hyper-infiltration of neutrophils and basophils occurred in AKR1B8 KO mice, and monocytes in spleen and macrophages in colonic mucosa increased markedly compared to wild type mice. TLR4 signaling in colonic epithelial cells of AKR1B8 KO mice was activated to promote great IL-1β and IL-6 expression compared to wild type mice. CONCLUSIONS: AKR1B8 deficiency in IECs drives severe acute colitis induced by DSS at a low dose through activation of the innate immunity, being a novel pathogenic factor of colitis.

76. The immune response to lumpy skin disease virus in cattle is influenced by inoculation route.

Front Immunol

2022 Nov 28

Fay PC, Wijesiriwardana N, Munyanduki H

77. Developmental endothelial locus-1 in cardiovascular and metabolic diseases: A promising biomarker and therapeutic target.

Front Immunol

2022 Nov 28

Zhao M, Zheng Z, Li C

78. Baseline immune signature score of Tregs × HLA-DR(+)CD4(+) T cells × PD1(+)CD8(+) T cells predicts outcome to immunotherapy in cancer patients.

Front Immunol

2022 Nov 28

Mispelbaum R, Hattenhauer ST, Held SAE

BACKGROUND: The use of immunotherapy (IT) is rapidly increasing across different tumor entities. PD-L1 expression is primarily used for therapy evaluation. The disadvantages of PD-L1 status are spatial and temporal heterogeneity as well as tumor type-dependent variation of predictive value. To optimize patient selection for IT, new prediction markers for therapy success are needed. Based on the systemic efficacy of IT, we dissected the immune signature of peripheral blood as an easily accessible predictive biomarker for therapeutic success. METHODS: We conducted a retrospective clinical study of 62 cancer patients treated with IT. We assessed peripheral immune cell counts before the start of IT via flow cytometry. The predictive value for therapy response of developed immune signature scores was tested by ROC curve analyses and scores were correlated with time to progression (TTP). RESULTS: High score values of "Tregs ÷ (CD4+/CD8+ ratio)" (Score A) and high score values of "Tregs × HLA-DR+CD4+ T cells × PD1+CD8+ T cells" (Score B) significantly correlated with response at first staging (p = 0.001; p < 0.001). At the optimal cutoff point, Score A correctly predicted 79.1% and Score B correctly predicted 89.3% of the staging results (sensitivity: 86.2%, 90.0%; specificity: 64.3%, 87.5%). A high Score A and Score B statistically correlated with prolonged median TTP (6.13 vs. 2.17 months, p = 0.025; 6.43 vs. 1.83 months, p = 0.016). Cox regression analyses for TTP showed a risk reduction of 55.7% (HR = 0.44, p = 0.029) for Score A and an adjusted risk reduction of 73.2% (HR = 0.27, p = 0.016) for Score B. CONCLUSION: The two identified immune signature scores showed high predictive value for therapy response as well as for prolonged TTP in a pan-cancer patient population. Our scores are easy to determine by using peripheral blood and flow cytometry, apply to different cancer entities, and allow an outcome prediction before the start of IT.

79. Regulation and directed inhibition of ECP production by human neutrophils.

Front Immunol

2022 Nov 28

Vega-Rioja A, Chacón P, Fernández-Delgado L

80. Corrigendum: DCBLD1 Overexpression is associated with a poor prognosis in head and neck squamous cell carcinoma.

Front Immunol

2022 Nov 25

Fu LL, Yan M, Ma MX

81. Comprehensive analysis of anoikis-related long non-coding RNA immune infiltration in patients with bladder cancer and immunotherapy.

Front Immunol

2022 Nov 25

Zhang YY, Li XW, Li XD

BACKGROUND: Anoikis is a form of programmed cell death or programmed cell death(PCD) for short. Studies suggest that anoikis involves in the decisive steps of tumor progression and cancer cell metastasis and spread, but what part it plays in bladder cancer remains unclear. We sought to screen for anoikis-correlated long non-coding RNA (lncRNA) so that we can build a risk model to understand its ability to predict bladder cancer prognosis and the immune landscape. METHODS: We screened seven anoikis-related lncRNAs (arlncRNAs) from The Cancer Genome Atlas (TCGA) and designed a risk model. It was validated through ROC curves and clinicopathological correlation analysis, and demonstrated to be an independent factor of prognosis prediction by uni- and multi-COX regression. In the meantime, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, immune infiltration, and half-maximal inhibitory concentration prediction (IC50) were implemented with the model. Moreover, we divided bladder cancer patients into three subtypes by consensus clustering analysis to further study the differences in prognosis, immune infiltration level, immune checkpoints, and drug susceptibility. RESULT: We designed a risk model of seven arlncRNAs, and proved its accuracy using ROC curves. COX regression indicated that the model might be an independent prediction factor of bladder cancer prognosis. KEGG enrichment analysis showed it was enriched in tumors and immune-related pathways among the people at high risk. Immune correlation analysis and drug susceptibility results indicated that it had higher immune infiltration and might have a better immunotherapy efficacy for high-risk groups. Of the three subtypes classified by consensus clustering analysis, cluster 3 revealed a positive prognosis, and cluster 2 showed the highest level of immune infiltration and was sensitive to most chemistries. This is helpful for us to discover more precise immunotherapy for bladder cancer patients. CONCLUSION: In a nutshell, we found seven arlncRNAs and built a risk model that can identify different bladder cancer subtypes and predict the prognosis of bladder cancer patients. Immune-related and drug sensitivity researches demonstrate it can provide individual therapeutic schedule with greater precision for bladder cancer patients.

82. Immunogenomic correlates of immune-related adverse events for anti-programmed cell death 1 therapy.

Front Immunol

2022 Nov 25

Zhang L, Shi Y, Han X.

Despite impressive antitumor efficacy of programmed cell death 1 (PD-1) inhibitors, this inhibition can induce mild to severe autoimmune toxicities, termed immune-related adverse events (irAEs). Yet, predictive pretreatment biomarkers for irAEs development across cancer types remain elusive. We first assessed cellular and molecular factors. To determine factors predicting the risk of irAEs for anti-PD-1 immunotherapy across multiple cancer types, an integrative analysis of cellular and molecular factors from 9104 patients across 21 cancer types and 4865522 postmarketing adverse event reports retrieved from adverse event reporting system was then performed. Accuracy of predictions was quantified as Pearson correlation coefficient determined using leave-one-out cross-validation. Independent validation sets included small cell lung cancer and melanoma cohorts. Out of 4865522 eligible adverse events reports, 10412 cases received anti-PD-1 monotherapy, of which, 2997 (28.78%) exhibited at least one irAE. Among established immunogenomic factors, dendritic cells (DC) abundance showed the strongest correlation with irAEs risk, followed by tumor mutational burden (TMB). Further predictive accuracy was achieved by DC and TMB in combination with CD4+ naive T-cells abundance, and then validated in the small cell lung cancer cohort. Additionally, global screening of multiomics data identified 11 novel predictors of irAEs. Of these, IRF4 showed the highest correlation. Best predictive performance was observed in the IRF4 - TCL1A - SHC-pY317 trivariate model. Associations of IRF4 and TCL1A expression with irAEs development were verified in the melanoma cohort receiving immune checkpoint inhibitors. Collectively, pretreatment cellular and molecular irAEs-associated features as well as their combinations are identified regardless of cancer types. These findings may deepen our knowledge of irAEs pathogenesis and, ultimately, aid in early detection of high-risk patients and management of irAEs.

83. Lactate regulators contribute to tumor microenvironment and predict prognosis in lung adenocarcinoma.

Front Immunol

2022 Nov 25

Shang S, Wang MZ, Xing Z

BACKGROUND: Lactic acid, as a product of glycolysis, increases tumor cell migration and the invasion of tumor cells in the tumor microenvironment. Besides this, lactic acid promotes the expression of programmed death-1 expression (PD-1) in regulatory T cells, which could cause the failure of PD-1 blockade therapy. However, the implications of lactic acid in the tumor microenvironment of lung adenocarcinoma (LUAD) remain largely unclear. METHODS: We performed unsupervised consensus clustering to identify lactic-associated subtypes using expression profile of lactate regulators in LUAD. Differentially expressed genes (DEGs) associated with lactic-associated subtypes was used to construct lactate signature (LaSig) using LASSO regression algorithm. Immune infiltration analysis was conducted by ESTIMATER and drug sensitivity was estimated by R package called "pRRophetic". The difference between two groups was calculated using Wilcox rank sum test and correlation analysis was calculated using Pearson correlation coefficient. RESULTS: In this study, we evaluated DNA methylation and the mutation frequency of lactate regulators and found lactate regulators showed low mutation frequency in the TCGA-LUAD cohort, except TP53. At the RNA level, the expression level of lactate regulators was significantly associated with the immune cell component. In particular, expression of LDHA was positively correlated with CD4 T cell, CD8 T cell, M1 macrophages, and the enrichment score of multiple immune pathways. Two clusters were defined using the gene expression level of lactate regulators, and LDHA was significantly upregulated in cluster 1 with poor overall survival. A lactate signature (LaSig) had a robust performance in predicting the survival rate and immunotherapy response of LUAD patients. Moreover, patients in the high LaSig group may be more likely to benefit from these drugs (Cisplatin, Erlotinib, Gemcitabine, and Vinblastine) than those in the low LaSig group. CONCLUSION: In summary, our study explores the role of lactate regulators in guiding the clinical treatment of lung adenocarcinoma and provides additional help to supplement traditional molecular subtypes.

84. Characterization of intrahepatic B cells in acute-on-chronic liver failure.

Front Immunol

2022 Nov 25

Zhao Y, He W, Wang C

BACKGROUND AND OBJECTIVES: Acute on chronic liver failure (ACLF) is characterized by the immunologic dissonance during the prolonged pathogenic development. Both abnormal innate immune response and adaptive T-cell response have been reported in patients with ACLF; however, less is known regarding B cells in ACLF pathogenesis. Previous reports were only based on immunophenotyping of peripheral blood samples. Here, we aim to dissect liver-infiltrating B-cell subpopulation in ACLF. METHODS: Paired liver perfusate and peripheral blood were freshly collected from healthy living donors and recipients during liver transplantation. Liver tissues were obtained from patients with ACLF, cirrhosis, and healthy controls. Flow cytometry was used to characterize the phenotypic and functional alterations in intrahepatic and circulating B-cell populations from ACLF, cirrhosis, and healthy controls. The expression of CD19+ and CD138+ on liver tissues was examined by immunohistochemistry staining. RESULTS: In this study, we first deciphered the intrahepatic B cells subsets of patients with ACLF. We found that the ACLF liver harbored reduced fraction of naïve B cells and elevated percentage of CD27+CD21- activated memory B cells (AM), CD27-CD21- atypical memory B cells (atMBC), CD27+IgD-IgM+(IgM+ memory B cells), and CD27+CD38++ plasma cells than cirrhosis and healthy controls. Moreover, these B subpopulations demonstrated enhanced activation and altered effector functions. Specifically, the ACLF liver was abundant in atMBC expressing higher CD11c and lower CD80 molecule, which was significantly correlated to alanine aminotransferase and aspartate aminotransferase. In addition, we found that intrahepatic CD27+CD38++plasma cells were preferentially accumulated in ACLF, which expressed more CD273 (PD-L2) and secreted higher granzyme B and IL-10. Finally, the enriched hepatic plasma B cells were in positive association with disease severity indices including alkaline phosphatase and gamma-glutamyl transferase. CONCLUSIONS: In this pilot study, we showed an intrahepatic B-cell landscape shaped by the ACLF liver environment, which was distinct from paired circulating B-cell subsets. The phenotypic and functional perturbation in atMBC and plasma cells highlighted the unique properties of infiltrating B cells during ACLF progression, thereby denoting the potential of B-cell intervention in ACLF therapy.

85. Development of a polyamine gene expression score for predicting prognosis and treatment response in clear cell renal cell carcinoma.

Front Immunol

2022 Nov 25

Chen M, Nie Z, Huang D

BACKGROUNDS: Polyamine metabolism (PM) is closely related to the tumor microenvironment (TME) and is involved in antitumor immunity. Clear cell renal cell carcinoma (ccRCC) not only has high immunogenicity but also has significant metabolic changes. However, the role of PM in the immune microenvironment of ccRCC remains unclear. This study aimed to reveal the prognostic value of PM-related genes (PMRGs) expression in ccRCC and their correlation with the TME. METHODS: The expression levels PMRGs in different cells were characterized with single-cell sequencing analysis. The PMRG expression pattern of 777 ccRCC patients was evaluated based on PMRGs. Unsupervised clustering analysis was used in identifying PMRG expression subtypes, and Lasso regression analysis was used in developing polyamine gene expression score (PGES), which was validated in external and internal data sets. The predictive value of PGES for immunotherapy was validated in the IMvigor210 cohort. Multiple algorithms were used in analyzing the correlation between PGES and immune cells. The sensitivity of PGES to chemotherapeutic drugs was analyzed with the "pRRophetic" package. We validated the genes that develop PGES in tissue samples. Finally, weighted gene co-expression network analysis was used in identifying the key PMRGs closely related to ccRCC, and cell function experiments were carried out. RESULTS: PMRGs were abundantly expressed on tumor cells, and PMRG expression was active in CD8+ T cells and fibroblasts. We identified three PMRG expression subtypes. Cancer and immune related pathways were active in PMRG expression cluster A, which had better prognosis. PGES exhibited excellent predictive value. The high-PGES group was characterized by high immune cell infiltration, high expression of T cell depletion markers, high tumor mutation burden and tumor immune dysfunction and exclusion, was insensitive to immunotherapy but sensitive to sunitinib, temsirolimus, and rapamycin, and had poor prognosis. Spermidine synthetase (SRM) has been identified as a key gene and is highly expressed in ccRCC at RNA and protein levels. SRM knockdown can inhibit ccRCC cell proliferation, migration, and invasion. CONCLUSIONS: We revealed the biological characteristics of PMRG expression subtypes and developed PGES to accurately predict the prognosis of patients and response to immunotherapy.

86. Rap1b-loss increases neutrophil lactate dehydrogenase activity to enhance neutrophil migration and acute inflammation in vivo.

Front Immunol

2022 Nov 25

Chowdhury CS, Wareham E, Xu J

87. Sustained viral response and relapse after discontinuation of oral antiviral drugs in HBeAg-positive patients with chronic hepatitis B infection.

Front Immunol

2022 Nov 25

Sun F, Li Z, Hu L

OBJECTIVE: To investigate the sustained virological response and relapse in chronic hepatitis B (CHB) patients with hepatitis B e antigen (HBeAg) positive after stopping oral antiviral drugs, and to monitor the disease progression and the incidence of adverse events such as liver cirrhosis and hepatocellular carcinoma. METHODS: This is a prospective observational study. Patients who continued nucleos(t)ide analogue (NA) treatment after achieving HBeAg seroconversion for more than 3 years were enrolled. After signing the informed consent form, patients stopped NA treatment and received follow-up. During the follow-up, the antiviral treatment information of the patients was collected, and the follow-up observation was carried out every 3 months since the enrollment. We monitored the virological indexes, liver and kidney function, serology and liver imaging during follow-up. The purpose of this study was to explore the sustained virological response rate, HBV DNA recurrence rate, clinical relapse rate and the related factors after drug withdrawal. RESULTS: A total of 82 patients were enrolled, including 42 males (51.22%) and 40 females (48.78%), with a median age of 34.00 (31.00, 37.25) years. All enrolled patients were followed up for 1 year. At the end of the follow-up, 36.59% (30/82) of patients had sustained virological response, 63.41% (52/82) of patients had HBV DNA reactivation, 17.07% (14/82) of patients had clinical relapse, and 10.98% (9/82) of patients had HBeAg reversion. During the follow-up, there were no adverse events such as liver cirrhosis and hepatocellular carcinoma. The median level of hepatitis B surface antigen (HBsAg) in patients with sustained virological response was lower than that in patients with HBV DNA reactivation (2.92 vs.3.18 log10IU/ml, Z=-1.492/P=0.136), and the median level of baseline HBsAg in patients with HBV DNA reactivation was lower than that in patients with clinical relapse (3.01 vs.3.45 log10IU/mL, Z=-1.795/P=0.073), but the difference was not significant. There was no significant statistical difference between patients with sustained virological response and HBV DNA reactivation of the median total treatment time [69.50 (56.25, 86.00) vs.62.50 (44.00, 88.50) months, Z=-0.689/P=0.491], and the consolidation treatment time [41.50 (36.75, 54.75) vs.40.50 (36.00, 53.75) months, Z=-0.419/P=0.675]. CONCLUSION: The sustained virological response rate of HBeAg positive CHB patients after stopping oral antiviral treatment is lower, and it is more common in patients with lower HBsAg levels. Patients still need to be closely monitored after stopping NA therapy.

88. Dysregulation of iron metabolism modulators in virologically suppressed HIV-infected patients.

Front Immunol

2022 Nov 25

Garrido-Rodríguez V, Álvarez-Ríos AI, Olivas-Martínez I

BACKGROUND: Iron metabolism plays an essential role in cellular functions. Since virologically suppressed chronic HIV-infected subjects under effective antiretroviral treatment (ART) exhibit a persistent immune dysfunction that leads to comorbidities, iron homeostasis may be relevant in this context. We aimed to explore iron metabolism in virologically suppressed chronic HIV infected subjects under a successful ART. METHODS: In this retrospective study, traditional iron metabolism biomarkers (total iron, ferritin, transferrin, and transferrin saturation index), as well as soluble transferrin receptor (sTfR), hepcidin, and inflammatory markers were determined in virologically suppressed chronic HIV-infected subjects under at least 2 years of ART (HIV) who also had >350 CD4-T-cells/mm3 (N=92) from Spain. As controls, we collected non-HIV age-matched healthy donors (Young, N=25) and elderly subjects (>65 years old; Elderly; N=25). Additionally, an external group of non-HIV patients with ferritin<50 ng/mL diagnosed with absolute iron deficiency (Ferropenic group; N=84) was included. Comparisons between groups were performed using Kruskal-Wallis or Mann-Whitney U-tests, while associations between variables were explored by Spearman's rho correlation coefficient. RESULTS: We selected samples from HIV-infected subjects (aged 42[34-47], 95% males), young age-matched (aged 40[30-58], 60% males), and elderly controls (aged 82[78-88], 100% males). Compared to both healthy (Young and Elderly) groups, HIV exhibited decreased iron, transferrin saturation, and sTfR, and increased ferritin, but similar hepcidin levels. Notably, associations between sTfR and iron (Young, r=-0.587, p=0.002; Elderly, r=-0.496, p=0.012) or transferrin saturation index (Young, r=-0.581, p=0.002; Elderly, r=-0.489, p=0.013) were negative in both controls while positive in HIV (r=0.464, p<0.0001 and r=0.421, p<0.0001, respectively). Moreover, the expected negative correlation between hepcidin and sTfR, observed in controls (Young, r=-0.533, p=0.006; Elderly, r=-0.473, p=0.017), was absent in HIV (r=0.082; p=0.438). Interestingly, the HIV inflammatory profile differed from the Elderly one, who despite their inflammaging-related profile, succeed in maintaining these associations. Furthermore, subjects from the ferropenic group (aged 42[32-51], 5% males), showing significantly lower levels of hepcidin and higher sTfR, as expected, reflected similar correlations as those Young and Elderly, in contrast to HIV. CONCLUSIONS: Virologically suppressed chronic HIV-infected patients under successful ART exhibit altered levels of iron metabolism modulators suggesting a complex functional iron deficiency.

89. Autoimmune hepatitis after COVID-19 vaccination.

Front Immunol

2022 Nov 25

Zheng H, Zhang T, Xu Y

90. Criteria for identifying potentially resectable patients with initially oncologically unresectable hepatocellular carcinoma before treatment with lenvatinib plus an anti-PD-1 antibody.

Front Immunol

2022 Nov 25

Xu B, Zhu XD, Shen YH

BACKGROUND: Conversion therapy is feasible in patients with oncologically unresectable hepatocellular carcinoma (HCC). However, it is challenging to prospectively identify patients who are more likely to achieve successful conversion before initiating systemic therapy, either alone or combined with locoregional therapy. METHODS: Criteria for identifying potentially resectable patients with initially oncologically unresectable HCC before treatment with lenvatinib plus an anti-PD-1 antibody were proposed based on real-world evidence. Multivariate Firth logistic regression was used to validate the proposed criteria in a retrospective cohort of consecutive patients with advanced HCC, who received combination therapy with lenvatinib plus an anti-PD-1 antibody between September 2018 and September 2021. RESULTS: The proposed criteria were as follows: (1) Eastern Cooperative Oncology Group performance status of 0 or 1; (2) Child-Pugh class A; (3) intrahepatic tumors confined to one lobe (left, right, or middle lobe), or present in one lobe alongside a single tumor with diameter ≤5 cm or up to three tumors each with diameter ≤3 cm in the remaining lobes, with R0 resection achievable by hemihepatectomy, alone or combined with locoregional therapy to the remaining lobes during surgery; and (4) no portal vein tumor thrombus involving the contralateral liver lobe or reaching the superior mesenteric vein, no hepatic vein tumor thrombus involving more than two major hepatic vein branches on the tumor side, and no tumor thrombus of the inferior vena cava reaching the atrium. Firth logistic regression confirmed the criteria were an independent predictor of surgery following conversion therapy with lenvatinib plus an anti-PD-1 antibody. CONCLUSIONS: This study proposed and validated criteria for identifying patients with initially oncologically unresectable HCC who are potentially resectable when treated with combination therapy with lenvatinib plus an anti-PD-1 antibody. The proposed criteria could help standardize conversion therapy studies in advanced HCC.

91. Corrigendum: IgG anti-spike antibodies and surrogate neutralizing antibody levels decline faster 3 to 10 months after BNT162b2 vaccination than after SARS-CoV-2 infection in healthcare workers.

Front Immunol

2022 Nov 25

Decru B, Van Elslande J, Steels S

92. Caspase-8 activation in neutrophils facilitates autoimmune kidney vasculitis through regulating CD4(+) effector memory T cells.

Front Immunol

2022 Nov 25

Hu J, Huang Z, Yu M

93. PD-L1: Biological mechanism, function, and immunotherapy in gastric cancer.

Front Immunol

2022 Nov 24

Zhang Y, Yang Y, Chen Y

94. Dissecting the impact of molecular T-cell HLA mismatches in kidney transplant failure: A retrospective cohort study.

Front Immunol

2022 Nov 24

Lemieux W, Fleischer D, Yang AY

INTRODUCTION: Kidney transplantation is the optimal treatment in end-stage kidney disease, but de-novo donor specific antibody development continues to negatively impact patients undergoing kidney transplantation. One of the recent advances in solid organ transplantation has been the definition of molecular mismatching between donors and recipients' Human Leukocyte Antigens (HLA). While not fully integrated in standard clinical care, cumulative molecular mismatch at the level of eplets (EMM) as well as the PIRCHE-II score have shown promise in predicting transplant outcomes. In this manuscript, we sought to study whether certain T-cell molecular mismatches (TcEMM) were highly predictive of death-censored graft failure (DCGF). METHODS: We studied a retrospective cohort of kidney donor:recipient pairs from the Scientific Registry of Transplant Recipients (2000-2015). Allele level HLA-A, B, C, DRB1 and DQB1 types were imputed from serologic types using the NMDP algorithm. TcEMMs were then estimated using the PIRCHE-II algorithm. Multivariable Accelerated Failure Time (AFT) models assessed the association between each TcEMM and DCGF. To discriminate between TcEMMs most predictive of DCGF, we fit multivariable Lasso penalized regression models. We identified co-expressed TcEMMs using weighted correlation network analysis (WGCNA). Finally, we conducted sensitivity analyses to address PIRCHE and IMGT/HLA version updates. RESULTS: A total of 118,309 donor:recipient pairs meeting the eligibility criteria were studied. When applying the PIRCHE-II algorithm, we identified 1,935 distinct TcEMMs at the population level. A total of 218 of the observed TcEMM were independently associated with DCGF by AFT models. The Lasso penalized regression model with post selection inference identified a smaller subset of 86 TcEMMs (56 and 30 TcEMM derived from HLA Class I and II, respectively) to be highly predictive of DCGF. Of the observed TcEMM, 38.14% appeared as profiles of highly co-expressed TcEMMs. In addition, sensitivity analyses identified that the selected TcEMM were congruent across IMGT/HLA versions. CONCLUSION: In this study, we identified subsets of TcEMMs highly predictive of DCGF and profiles of co-expressed mismatches. Experimental verification of these TcEMMs determining immune responses and how they may interact with EMM as predictors of transplant outcomes would justify their consideration in organ allocation schemes and for modifying immunosuppression regimens.

95. Zanubrutinib plus salvage chemotherapy for relapsed or refractory diffuse large B-cell lymphoma.

Front Immunol

2022 Nov 24

Yuan X, Li X, Huang Y

INTRODUCTION: Relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) has poor clinical outcomes when treated with conventional salvage chemotherapy. Monotherapy using zanubrutinib, a selective Bruton's tyrosine kinase (BTK) inhibitor, has achieved modest antitumor effect in R/R DLBCL. Here we aimed to evaluate the efficacy and safety of zanubrutinib plus salvage chemotherapy in R/R DLBCL patients. METHODS: We retrospectively reviewed R/R DLBCL patients who were administered with zanubrutinib plus salvage chemotherapy in our center between January, 2019 and December, 2021. Targeted panel sequencing of 11 lymphoma-related genes was performed on 8 patients with poor responses to zanubrutinib-based chemotherapy. RESULTS: 27 R/R DLBCL patients were enrolled. Median age at this study was 59 years (range, 15-72). The best overall response rate (ORR) was 74.1% and complete remission rate was 33.3%. With a median follow-up of 11 months (range, 1-17), the median progression-free survival (PFS) was 8.1 months, and the overall survival (OS) was not achieved. The most common grade-3/4 adverse events were neutropenia (70.4%), thrombocytopenia (66.7%), and febrile neutropenia (33.3%). In multivariate analysis, early treatment and overall response after chemotherapy were independent favorable prognostic factors for PFS. Overall response after chemotherapy was an independent favorable factor for OS. Among the 8 patients with poor response to zanubrutinib-based treatment, the majority of patients had NOTCH2 mutations (n=8, 100%) and TP53 mutations (n=7, 87.5%). However, these patients achieved an ORR of 75% at 3 months after CD19-CAR-T cell therapy (including 4 cases of complete remission and 2 cases of partial remission). With a median follow-up of 9 months from CAR-T cell infusion (range, 1-16 months), the median PFS was 14.5 months, and the median OS was not reached. CONCLUSION: With high efficacy and manageable tolerability, zanubrutinib plus salvage chemotherapy may be a potential treatment option for R/R DLBCL. CAR-T cell therapy may be a priority strategy for these poor responders to BTKi-based treatment.

96. The impact of soluble HLA-G in IVF/ICSI embryo culture medium on implantation success.

Front Immunol

2022 Nov 24

Radwan P, Tarnowska A, Piekarska K

97. Acircadian rhythm-related gene signature for predicting survival and drug response in HNSC.

Front Immunol

2022 Nov 24

Zhang C, Dang D, Wang H

98. The dual role of the CD95 and CD95L signaling pathway in glioblastoma.

Front Immunol

2022 Nov 24

Zhang Y, Jin T, Dou Z

99. Impact of dietary vitamin D on immunoregulation and disease pathology in lupus-prone NZB/W F1 mice.

Front Immunol

2022 Nov 24

Kraemer AN, Schäfer AL, Sprenger DTL

100. A pregnancy hormone-cell death link promotes enhanced lupus-specific immunological effects.

Front Immunol

2022 Nov 24

Sachdeva R, Pal R.

Women of reproductive age demonstrate an increased incidence of systemic lupus erythematosus, and reproductive hormones have been implicated in disease progression. Additionally, pregnancy can be associated with disease "flares", the reasons for which remain obscure. While apoptotic bodies are believed to provide an autoantigenic trigger in lupus, whether autoantigenic constituents vary with varying cellular insults, and whether such variations can be immunologically consequential in the context of pregnancy, remains unknown. As assessed by antigenicity and mass spectrometry, apoptotic bodies elicited by different drugs demonstrated the differential presence of lupus-associated autoantigens, and varied in the ability to elicit lupus-associated cytokines from lupus splenocytes and alter the phenotype of lupus B cells. Immunization of tamoxifen-induced apoptotic bodies in lupus-prone mice generated higher humoral autoreactive responses than did immunization with cisplatin-induced apoptotic bodies, and both apoptotic bodies were poorly immunogenic in healthy mice. Incubation of lupus splenocytes (but not healthy splenocytes) with the pregnancy hormone human chorionic gonadotropin (hCG) along with tamoxifen-induced apoptotic bodies (but not cisplatin-induced apoptotic bodies) induced increases in the secretion of lupus-associated cytokines and in the up-modulation of B cell phenotypic markers. In addition, levels of secreted autoantibodies (including of specificities linked to lupus pathogenesis) were enhanced. These events were associated with the heightened phosphorylation of several signaling intermediates. Observations suggest that hCG is a potential disease-promoting co-stimulant in a lupus-milieu; when combined with specific apoptotic bodies, it enhances the intensity of multiple lupus-associated events. These findings deepen mechanistic insight into the hormone's links with autoreactive responses in lupus-prone mice and humans.

101. Profiling the B cell immune response elicited by vaccination against the respiratory virus SARS-CoV-2.

Front Immunol

2022 Nov 24

Pettini E, Medaglini D, Ciabattini A.

102. Cell atlas of the immune microenvironment in gastrointestinal cancers: Dendritic cells and beyond.

Front Immunol

2022 Nov 24

Wang Y, Yang T, Liang H

103. Weaning stress and intestinal health of piglets: A review.

Front Immunol

2022 Nov 24

Tang X, Xiong K, Fang R

104. Corrigendum: Lymphatic reconstruction in kidney allograft aggravates chronic rejection by promoting alloantigen presentation.

Front Immunol

2022 Nov 24

Lin J, Chen Y, Zhu H

105. Determining distinct roles of IL-1α through generation of an IL-1α knockout mouse with no defect in IL-1β expression.

Front Immunol

2022 Nov 24

Malireddi RKS, Bynigeri RR, Kancharana B

106. Evaluation of the ability of fatty acid metabolism signature to predict response to neoadjuvant chemoradiotherapy and prognosis of patients with locally advanced rectal cancer.

Front Immunol

2022 Nov 24

Zhou H, Chen Y, Xiao Y

107. Inducing ferroptosis has the potential to overcome therapy resistance in breast cancer.

Front Immunol

2022 Nov 24

Qi X, Wan Z, Jiang B

108. A one-year unisexual Schistosoma mansoni infection causes pathologic organ alterations and persistent non-polarized T cell-mediated inflammation in mice.

Front Immunol

2022 Nov 24

Sombetzki M, Reinholdt C, Winkelmann F

109. Sex bias in lymphocytes: Implications for autoimmune diseases.

Front Immunol

2022 Nov 24

Dodd KC, Menon M.

110. Plasma adsorption in refractory chronic gouty arthritis flare: A case report.

Front Immunol

2022 Nov 24

Lei Y, Cui TJ, Wang XH

BACKGROUND: Along with uric acid, which is the primary driving factor of gout, downstream inflammatory mediators have been shown to be involved in the pathogenesis of gouty arthritis flares. Extracorporeal haemadsorption is an emerging technology for the treatment of dysregulated inflammatory states by effectively removing cytokines from the bloodstream. Whether haemadsorption was effective in refractory gout flares has not been reported in the literature. CASE SUMMARY: We report the case of a 52-year-old male who presented with refractory gouty arthropathy for 30 years. His uric acid levels were poorly controlled due to poor diet and treatment compliance. Tophi were found to have precipitated in multiple joints and subcutaneous tissue. In the last 2 years, his incidents of gouty flares had become more frequent, and resistant to the medications, including colchicine, allopurinol, febuxostat, glucocorticoids, and NSAID analgesics. He had experienced a triad of chills, high fever and arthritis for the past 2 weeks. Therefore, he took 2 mg colchicine twice daily for 2 weeks with no improvement in his pain. Proinflammatory cytokines, such as interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α), were found to be remarkably elevated. Given that conventional treatment was unsuccessful, we tried to employ plasma adsorption (PA) to remove inflammatory cytokines. After 4 sessions, symptoms, such as fever, joint swelling and pain, were greatly improved. Meanwhile, the levels of proinflammatory factors such as IL-6 and TNF-α were found to be decreased, while the anti-inflammatory factor IL-10 remained the same during the course. He was followed up for 8 months and arthritis have flared up twice in response to a high-purine diet. CONCLUSION: Our study suggests that plasma adsorption (PA) may be a promising and feasible treatment for refractory gout when conventional treatments are unsatisfactory or contraindicated. However, more clinical trials are needed to verify the efficacy and safety of the treatment. CORE TIP: Chronic gouty arthritis flares are refractory to conventional treatment, such as uric acid-lowering drugs and NSAID analgesics. Due to the involvement of inflammatory cytokines, plasma adsorption was employed to alleviate flares by removing inflammatory mediators. Herein, we report a 52-year-old male who presented with refractory gouty arthropathy for 30 years, manifested with a triad of chills, high fever and arthritis. He underwent several sessions of plasma adsorption, and his symptoms soon improved, along with a drop in inflammatory mediators. We conclude that plasma adsorption may be a promising and feasible treatment for refractory gout when conventional treatments are unsatisfactory or contraindicated.

111. The role of the intestinal microbiome in antiphospholipid syndrome.

Front Immunol

2022 Nov 24

van Mourik DJM, Salet DM, Middeldorp S

112. Glucocorticoid receptor hypersensitivity enhances inflammatory signaling and inhibits cell cycle progression in porcine PBMCs.

Front Immunol

2022 Nov 24

Li Z, Hadlich F, Wimmers K

113. Type I interferon subtypes differentially activate the anti-leukaemic function of natural killer cells.

Front Immunol

2022 Nov 24

Barnes SA, Audsley KM, Newnes HV

114. Case report: Optimized ruxolitinib-based therapy in an infant with familial hemophagocytic lymphohistiocytosis type 3.

Front Immunol

2022 Nov 23

Niizato D, Isoda T, Mitsuiki N

115. Type 1 interferon suppresses expression and glucocorticoid induction of glucocorticoid-induced leucine zipper (GILZ).

Front Immunol

2022 Nov 23

Dankers W, Northcott M, Bennett T

116. Chitosan particle stabilized Pickering emulsion/interleukin-12 adjuvant system for Pgp3 subunit vaccine elicits immune protection against genital chlamydial infection in mice.

Front Immunol

2022 Nov 23

Shu M, Zhao L, Shi K

117. Editorial: Innate lymphocytes in tumor surveillance.

Front Immunol

2022 Nov 23

Fritz JH, Stoiber D.

118. Standardization of neutrophil CD64 and monocyte HLA-DR measurement and its application in immune monitoring in kidney transplantation.

Front Immunol

2022 Nov 23

Peng B, Yang M, Zhuang Q

BACKGROUND: Infections cause high mortality in kidney transplant recipients (KTRs). The expressions of neutrophil CD64 (nCD64) and monocyte HLA-DR (mHLA-DR) provide direct evidence of immune status and can be used to evaluate the severity of infection. However, the intensities of nCD64 and mHLA-DR detected by flow cytometry (FCM) are commonly measured by mean fluorescence intensities (MFIs), which are relative values, thus limiting their application. We aimed to standardize nCD64 and mHLA-DR expression using molecules of equivalent soluble fluorochrome (MESF) and to explore their role in immune monitoring for KTRs with infection. METHODS: The study included 50 KTRs diagnosed with infection, 65 immunologically stable KTRs and 26 healthy controls. The blood samples were collected and measured simultaneously by four FCM protocols at different flow cytometers. The MFIs of nCD64 and mHLA-DR were converted into MESF by Phycoerythrin (PE) Fluorescence Quantitation Kit. The intraclass correlation coefficients (ICCs) and the Bland-Altman plots were used to evaluate the reliability between the four FCM protocols. MESFs of nCD64 and mHLA-DR, nCD64 index and sepsis index (SI) with the TBNK panel were used to evaluate the immune status. Comparisons among multiple groups were performed with ANOVA one-way analysis. Receiver operating characteristics (ROC) curve analysis was performed to diagnose infection or sepsis. Univariate and multivariate logistic analysis examined associations of the immune status with infection. RESULTS: MESFs of nCD64 and mHLA-DR measured by four protocols had excellent reliability (ICCs 0.993 and 0.957, respectively). The nCD64, CD64 index and SI in infection group were significantly higher than those of stable KTRs group. Patients with sepsis had lower mHLA-DR but higher SI than non-sepsis patients. ROC analysis indicated that nCD64 had the highest area under the curve (AUC) for infection, and that mHLA-DR had the highest AUC for sepsis. Logistic analysis indicated that nCD64 > 3089 and B cells counts were independent risk factors for infection. CONCLUSION: The standardization of nCD64 and mHLA-DR made it available for widespread application. MESFs of nCD64 and mHLA-DR had good diagnostic performance on infection and sepsis, respectively, which could be promising indicators for immune status of KTRs and contributed to individualized treatment.

119. An EGFR L858R mutation identified in 1862 Chinese NSCLC patients can be a promising neoantigen vaccine therapeutic strategy.

Front Immunol

2022 Nov 23

Lin J, Liu J, Hao SG

BACKGROUND: This study aimed to develop a vaccine that targets mutation-derived neoantigen in Chinese non-small-cell lung cancer (NSCLC). METHODS: A cohort of 1862 Chinese NSCLC patients who underwent targeted sequencing with a 1021-gene panel was investigated. HLA typing was done using OptiType v1.0 and neoantigens were predicted by netMHCpan v4.0. HLA LOH was inferred using the lohhla algorithm and TMB were quantified by counting the total number of non-synonymous ones based on our panel data. CIBERSORT was utilized to estimate the TME in different EGFR mutant subtype by using TCGA data. RESULTS: HLA-A*11:01(42.59%) was the top one allele and HLA-A*33:03(12.94%) ranked 12th. EGFR L858R (22.61%) was the most prevalent gene variant. The binding affinity (IC50 MT = 22.9 nM) and shared frequency (2.93%) of EGFR L858R in combination with HLA-A*33:03 were optimal. In a subsequent further analysis on immunological features of EGFR mutant subtypes, 63.1% HLA loss of heterozygosity LOH (HLA LOH) and 0.37% (7 of 1862) B2M aberrations were found in our population, both had no significant association with EGFR mutant subtypes suggesting that the process of antigen presentation involved HLA LOH and B2M mechanisms in EGFR L858R is working. Tumor mutation burden (TMB) was investigated by utilizing our panel and showed that EGFR L858R had the lowest TMB compared with other EGFR mutant subtypes. In addition, analysis of 22 immune cell types from The Cancer Genome Atlas (TCGA) data showed EGFR L858R was correlated with low level of CD8 T cells, activated CD4 memory T cells and elevated level of macrophage M2 suggesting an inhibited tumor microenvironment (TME). CONCLUSION: Our study identified that EGFR L858R neoantigen had the potential to generate cancer vaccines in NSCLC patients with HLA A*33:03. The neoantigen-based vaccines may become an effective salvage regimen for EGFR L858R subgroup after targeted therapy or immune checkpoint inhibitors (ICIs) failure.

120. Human endogenous retroviruses and the inflammatory response: A vicious circle associated with health and illness.

Front Immunol

2022 Nov 23

Rangel SC, da Silva MD, da Silva AL

121. Characterization of immune microenvironment infiltration and m(6)A regulator-mediated RNA methylation modification patterns in osteoarthritis.

Front Immunol

2022 Nov 23

Ouyang Y, Tu Y, Chen S

122. Editorial: Clinical management, pathogenesis and biomarkers of cardiovascular disease associated with systemic autoimmune disorders.

Front Immunol

2022 Nov 23

Perez-Sanchez C, Pineda-Torra I, Lopez-Pedrera C.

123. Nasal administration of anti-CD3 monoclonal antibody modulates effector CD8+ T cell function and induces a regulatory response in T cells in human subjects.

Front Immunol

2022 Nov 23

Chitnis T, Kaskow BJ, Case J

BACKGROUND: Parenteral anti-CD3 Mab (OKT3) has been used to treat transplant rejection and parental administration of a humanized anti-CD3 Mab (Teplizumab) showed positive effects in diabetes. Nasal administration of anti-CD3 Mab has not been carried out in humans. Nasal anti-CD3 Mab suppresses autoimmune diseases and central nervous system (CNS) inflammation in animal models. We investigated the safety and immune effects of a fully humanized, previously uncharacterized nasal anti-CD3 Mab (Foralumab) in humans and its in vitro stimulatory properties. METHODS: In vitro, Foralumab were compared to UCHT1 anti-human CD3 mAb. For human administration, 27 healthy volunteers (9 per group) received nasal Foralumab or placebo at a dose of 10ug, 50ug, or 250ug daily for 5 days. Safety was assessed and immune parameters measured on day 1 (pre-treatment), 7, 14, and 30 by FACS and by scRNAseq. RESULTS: In vitro, Foralumab preferentially induced CD8+ T cell stimulation, reduced CD4+ T cell proliferation and lowered expression of IFNg, IL-17 and TNFa. Foralumab induced LAP, TIGIT, and KLRG1 immune checkpoint molecules on CD8+ and CD4+ T cells in a mechanism independent of CD8 T cells. In vivo, nasal Foralumab did not modulate CD3 from the T cell surface at any dose. Immune effects were primarily observed at the 50ug dose and consisted of reduction of CD8+ effector memory cells, an increase in naive CD8+ and CD4+ T cells, and reduced CD8+ T cell granzyme B and perforin expression. Differentially expressed genes observed by scRNAseq in CD8+ and CD4+ populations promoted survival and were anti-inflammatory. In the CD8+ TEMRA population there was induction of TIGIT, TGFB1 and KIR3DL2, indicative of a regulatory phenotype. In the memory CD4+ population, there was induction of CTLA4, KLRG1, and TGFB whereas there was an induction of TGF-B1 in naïve CD4+ T cells. In monocytes, there was induction of genes (HLA-DP, HLA-DQ) that promote a less inflammatory immune response. No side effects were observed, and no subjects developed human anti-mouse antibodies. CONCLUSION: These findings demonstrate that nasal Foralumab is safe and immunologically active in humans and presents a new avenue for the treatment of autoimmune and CNS diseases.

124. Hemoglobin induces inflammation through NF-kB signaling pathway and causes cell oxidative damage in grass carp (Ctenopharyngodon idella).

Front Immunol

2022 Nov 23

Tang Y, Yang S, Yao M

125. Advanced primary vaginal squamous cell carcinoma: A case report and literature review.

Front Immunol

2022 Nov 22

Shen Y, Meng X, Wang L

126. Inflamed adipose tissue: A culprit underlying obesity and heart failure with preserved ejection fraction.

Front Immunol

2022 Nov 22

Li C, Qin D, Hu J

127. Identification of immune-related features involved in Duchenne muscular dystrophy: A bidirectional transcriptome and proteome-driven analysis.

Front Immunol

2022 Nov 22

Wu X, Dong N, Yu L

128. Corrigendum: A potential bioelectromagnetic method to slow down the progression and prevent the development of ultimate pulmonary fibrosis by COVID-19.

Front Immunol

2022 Nov 22

Masaud SM, Szasz O, Szasz AM

129. N6-methyladenosine regulators-related immune genes enable predict graft loss and discriminate T-cell mediate rejection in kidney transplantation biopsies for cause.

Front Immunol

2022 Nov 22

Pang Q, Chen H, Wu H

130. Corrigendum: Anti-HIV-1 nanobody-IgG1 constructs with improved neutralization potency and the ability to mediate Fc effector functions.

Front Immunol

2022 Nov 22

Schriek AI, van Haaren MM, Poniman M

131. The osteoblast secretome in Staphylococcus aureus osteomyelitis.

Front Immunol

2022 Nov 22

Granata V, Possetti V, Parente R

132. IL-17A and TNF-α inhibitors induce multiple molecular changes in psoriasis.

Front Immunol

2022 Nov 22

Dong Q, Li D, Xie BB

133. Are homeostatic mechanisms aiding the reconstitution of the T-cell pool during lymphopenia in humans?

Front Immunol

2022 Nov 22

Baliu-Piqué M, Tesselaar K, Borghans JAM.

134. A novel signature based on CeRNA and immune status predicts prognostic risk and drug sensitivity in gastric cancer patients.

Front Immunol

2022 Nov 22

Cao W, Zhou W, Li M

BACKGROUND: At present, there is increasing evidence that both competitive endogenous RNAs (ceRNAs) and immune status in the tumor microenvironment (TME) can affect the progression of gastric cancer (GC), and are closely related to the prognosis of patients. However, few studies have linked the two to jointly determine the prognosis of patients with GC. This study aimed to develop a combined prognostic model based on ceRNAs and immune biomarkers. METHODS: First, the gene expression profiles and clinical information were downloaded from TCGA and GEO databases. Then two ceRNA networks were constructed on the basis of circRNA. Afterwards, the key genes were screened by univariate Cox regression analysis and Lasso regression analysis, and the ceRNA-related prognostic model was constructed by multivariate Cox regression analysis. Next, CIBERSORT and ESTIMATE algorithms were utilized to obtain the immune cell infiltration abundance and stromal/immune score in TME. Furthermore, the correlation between ceRNAs and immunity was found out through co-expression analysis, and another immune-related prognosis model was established. Finally, combining these two models, a comprehensive prognostic model was built and visualized with a nomogram. RESULTS: The (circRNA, lncRNA)-miRNA-mRNA regulatory network of GC was constructed. The predictive power of ceRNA-related and immune-related prognosis models was moderate. Co-expression analysis showed that the ceRNA network was correlated with immunity. The integrated model of combined ceRNAs and immunity in the TCGA training set, the AUC values of 1, 3, and 5-year survival rates were 0.78, 0.76, and 0.78, respectively; in the independent external validation set GSE62254, they were 0.81, 0.79, and 0.78 respectively; in GSE15459, they were 0.84, 0.88 and 0.89 respectively. Besides, the prognostic score of the comprehensive model can predict chemotherapeutic drug resistance. Moreover, we found that plasma variant translocation 1 (PVT1) and infiltrating immune cells (mast cells) are worthy of further investigation as independent prognostic factors. CONCLUSIONS: Two ceRNA regulatory networks were constructed based on circRNA. At the same time, a comprehensive prognosis model was established, which has a high clinical significance for prognosis prediction and chemotherapy drug selection of GC patients.

135. Immune and non-immune cell subtypes identify novel targets for prognostic and therapeutic strategy: A study based on intratumoral heterogenicity analysis of multicenter scRNA-seq datasets in lung adenocarcinoma.

Front Immunol

2022 Nov 22

Fan T, Lu J, Niu D

136. The mechanisms underlying the immune control of Zika virus infection at the maternal-fetal interface.

Front Immunol

2022 Nov 22

Espino A, Gouilly J, Chen Q

137. Multiplexed engineering and precision gene editing in cellular immunotherapy.

Front Immunol

2022 Nov 22

Biederstädt A, Manzar GS, Daher M.

The advent of cellular immunotherapy in the clinic has entirely redrawn the treatment landscape for a growing number of human cancers. Genetically reprogrammed immune cells, including chimeric antigen receptor (CAR)-modified immune effector cells as well as T cell receptor (TCR) therapy, have demonstrated remarkable responses across different hard-to-treat patient populations. While these novel treatment options have had tremendous success in providing long-term remissions for a considerable fraction of treated patients, a number of challenges remain. Limited in vivo persistence and functional exhaustion of infused immune cells as well as tumor immune escape and on-target off-tumor toxicities are just some examples of the challenges which restrain the potency of today's genetically engineered cell products. Multiple engineering strategies are being explored to tackle these challenges.The advent of multiplexed precision genome editing has in recent years provided a flexible and highly modular toolkit to specifically address some of these challenges by targeted genetic interventions. This class of next-generation cellular therapeutics aims to endow engineered immune cells with enhanced functionality and shield them from immunosuppressive cues arising from intrinsic immune checkpoints as well as the hostile tumor microenvironment (TME). Previous efforts to introduce additional genetic modifications into immune cells have in large parts focused on nuclease-based tools like the CRISPR/Cas9 system or TALEN. However, nuclease-inactive platforms including base and prime editors have recently emerged and promise a potentially safer route to rewriting genetic sequences and introducing large segments of transgenic DNA without inducing double-strand breaks (DSBs). In this review, we discuss how these two exciting and emerging fields-cellular immunotherapy and precision genome editing-have co-evolved to enable a dramatic expansion in the possibilities to engineer personalized anti-cancer treatments. We will lay out how various engineering strategies in addition to nuclease-dependent and nuclease-inactive precision genome editing toolkits are increasingly being applied to overcome today's limitations to build more potent cellular therapeutics. We will reflect on how novel information-rich unbiased discovery approaches are continuously deepening our understanding of fundamental mechanisms governing tumor biology. We will conclude with a perspective of how multiplexed-engineered and gene edited cell products may upend today's treatment paradigms as they evolve into the next generation of more potent cellular immunotherapies.

138. Exploring the association between Th17 pathway gene polymorphisms and pulmonary tuberculosis.

Front Immunol

2022 Nov 21

Li HM, Wang LJ, Huang Q

139. Immunomodulatory regulator blockade in a viral exacerbation model of severe asthma.

Front Immunol

2022 Nov 21

Nicholas B, Lee HH, Guo J

140. Integrated analysis of multiple microarray studies to establish differential diagnostic models of Crohn's disease and ulcerative colitis based on a metalloproteinase-associated module.

Front Immunol

2022 Nov 21

Deng J, Zhao N, Lv LP

BACKGROUND: The ulcerative colitis (UC) and Crohn's disease (CD) subtypes of inflammatory bowel disease (IBD) are autoimmune diseases influenced by multiple complex factors. The clinical treatment strategies for UC and CD often differ, indicating the importance of improving their discrimination. METHODS: Two methods, robust rank aggregation (RRA) analysis and merging and intersection, were applied to integrate data from multiple IBD cohorts, and the identified differentially expressed genes (DEGs) were used to establish a protein-protein interaction (PPI) network. Molecular complex detection (MCODE) was used to identify important gene sets. Two differential diagnostic models to distinguish CD and UC were established via a least absolute shrinkage and selection operator (LASSO) logistic regression, and model evaluation was performed in both the training and testing groups, including receiver operating characteristic (ROC) curves, calibration plots and decision curve analysis (DCA). The potential value of MMP-associated genes was further verified using different IBD cohorts and clinical samples. RESULTS: Four datasets (GSE75214, GSE10616, GSE36807, and GSE9686) were included in the analysis. Both data integration methods indicated that the activation of the MMP-associated module was significantly elevated in UC. Two LASSO models based on continuous variable (Model_1) and binary variable (Model_2) MMP-associated genes were established to discriminate CD and UC. The results showed that Model_1 exhibited good discrimination in the training and testing groups. The calibration analysis and DCA showed that Model_1 exhibited good performance in the training group but failed in the testing group. Model_2 exhibited good discrimination, calibration and DCA results in the training and testing groups and exhibited greater diagnostic value. The effects of Model_1 and Model_2 were further verified in a new IBD cohort of GSE179285. The MMP genes exhibited high value as biomarkers for the discrimination of IBD patients using published cohort and immunohistochemistry (IHC) staining data. The MMP-associated gene levels were statistically significantly positively correlated with the levels of the differentially expressed cell types, indicating their potential value in differential diagnosis. The single-cell analysis confirmed that the expression of ANXA1 in UC was higher than that in CD. CONCLUSION: MMP-associated modules are the main differential gene sets between CD and UC. The established Model_2 overcomes batch differences and has good clinical applicability. Subsequent in-depth research investigating how MMPs are involved in the development of different IBD subtypes is necessary.

141. Human gut microbiota-reactive DP8α regulatory T cells, signature and related emerging functions.

Front Immunol

2022 Nov 21

Jotereau F, Alameddine J, Teusan R

In mice, microbiota-induced Tregs both maintain intestinal homeostasis and provide resistance to immuno-pathologies in the adult. Identifying their human functional counterpart therefore represents an important goal. We discovered, in the human colonic lamina propria and blood, a FoxP3-negative IL-10-secreting Treg subset, which co-expresses CD4 and CD8α (hence named DP8α) and displays a TCR-reactivity against Faecalibacterium prausnitzii, indicating a role for this symbiotic bacterium in their induction. Moreover, supporting their role in intestinal homeostasis, we previously reported both their drastic decrease in IBD patients and their protective role in vivo against intestinal inflammation, in mice. Here, we aimed at identifying the genomic, phenotypic and functional signatures of these microbiota-induced Tregs, towards delineating their physiological role(s) and clinical potential. Human F. prausnitzii-reactive DP8α Treg clones were derived from both the colonic lamina propria and blood. RNA-sequencing, flow cytometry and functional assays were performed to characterize their response upon activation and compare them to donor- and tissue-matched FoxP3+ Treg clones. DP8α Tregs exhibited a unique mixed Tr1-like/cytotoxic CD4+ T cell-profile and shared the RORγt and MAF master genes with mouse gut microbiota-induced FoxP3+ Tregs. We revealed their potent cytotoxic, chemotactic and IgA-promoting abilities, which were confirmed using in vitro assays. Therefore, besides their induction by a Clostridium bacterium, DP8α Tregs also partake master genes with mouse microbiota-induced Tregs. The present identification of their complete signature and novel functional properties, should be key in delineating the in vivo roles and therapeutic applications of these unique human microbiota-induced Tregs through their study in pathological contexts, particularly in inflammatory bowel diseases.

142. Ferroptosis increases obesity: Crosstalk between adipocytes and the neuroimmune system.

Front Immunol

2022 Nov 21

Zhang S, Sun Z, Jiang X

143. Early vascular endothelial complications after hematopoietic cell transplantation: Role of the endotheliopathy in biomarkers and target therapies development.

Front Immunol

2022 Nov 21

Moreno-Castaño AB, Salas MQ, Palomo M

144. Functional molecular expression of nature killer cells correlated to HBsAg clearance in HBeAg-positive chronic hepatitis B patients during PEG-IFN α-2a therapy.

Front Immunol

2022 Nov 21

Cao W, Lu H, Zhang L

OBJECTIVE: To explore whether the frequencies and functional molecules expression of Natural Killer cells (NK cells) are related to hepatitis B surface antigen (HBsAg) disappearance in hepatitis B e envelope antigen (HBeAg)-positive patients with chronic hepatitis B (CHB) throughout peginterferon alpha-2a (PEG-IFN α-2a) treatment. METHODS: In this prospective research, HBeAg-positive patients with CHB received PEG-IFN α-2a treatment, completing 4-year follow-up. After PEG-IFN α-2a treatment, undetectable HBV DNA, HBsAg loss, and HBeAg disappearance were defined as functional cure. Proportions of NK, CD56dim, CD56bright, NKp46+, NKp46dim, NKp46high, and interferon alpha receptor 2 (IFNAR2)+ NK cells, and the mean fluorescence intensity (MFI) of NK cell surface receptors IFNAR2 and NKp46 were detected. RESULTS: 66 patients were enrolled into the study in which 17 patients obtained functional cure. At baseline, hepatitis B virus desoxyribose nucleic acid (HBV DNA) titer in patients with functional cure was remarkably lower than that in Non-functional cure group. Compared with baseline, HBV DNA levels, HBsAg levels, and HBeAg levels significantly declined at week 12 and 24 of therapy in patients with functional cure. At baseline, the negative correlation between CD56bright NK% and HBV DNA and the negative correlation between CD56dim NK% and HBV DNA was showed; CD56bright NK% and IFNAR2 MFI in patients with functional cure were remarkably higher than those in patients without functional cure. After therapy, CD56bright NK% and NKp46high NK% in patients with functional cure were higher than those in patients without functional cure. In Functional cure group, after 24 weeks of treatment NK%, CD56bright NK%, IFNAR2 MFI weakly increased, and NKp46high NK% and NKp46 MFI significantly increased, meanwhile, CD56dim NK% and NKp46dim NK% decreased. Only NKp46 MFI increased after therapy in patients without functional cure. CONCLUSION: The lower HBV DNA load and the higher CD56bright NK% before therapy, and the higher the post-treatment CD56bright NK%, IFNAR2 MFI, NKp46high NK%, the easier to achieve functional cure.

145. Research progress on unique paratope structure, antigen binding modes, and systematic mutagenesis strategies of single-domain antibodies.

Front Immunol

2022 Nov 21

Liu C, Lin H, Cao L

146. Screening the immune-related circRNAs and genes in mice of spinal cord injury by RNA sequencing.

Front Immunol

2022 Nov 21

Li Y, Wang B, Sun W

147. The role of YAP1 in survival prediction, immune modulation, and drug response: A pan-cancer perspective.

Front Immunol

2022 Nov 21

Hu X, Zhang Y, Yu H

INTRODUCTION: Dysregulation of the Hippo signaling pathway has been implicated in multiple pathologies, including cancer, and YAP1 is the major effector of the pathway. In this study, we assessed the role of YAP1 in prognostic value, immunomodulation, and drug response from a pan-cancer perspective. METHODS: We compared YAP1 expression between normal and cancerous tissues and among different pathologic stages survival analysis and gene set enrichment analysis were performed. Additionally, we performed correlation analyses of YAP1 expression with RNA modification-related gene expression, tumor mutation burden (TMB), microsatellite instability (MSI), immune checkpoint regulator expression, and infiltration of immune cells. Correlations between YAP1 expression and IC50s (half-maximal inhibitory concentrations) of drugs in the CellMiner database were calculated. RESULTS: We found that YAP1 was aberrantly expressed in various cancer types and regulated by its DNA methylation and post-transcriptional modifications, particularly m6A methylation. High expression of YAP1 was associated with poor survival outcomes in ACC, BLCA, LGG, LUAD, and PAAD. YAP1 expression was negatively correlated with the infiltration of CD8+ T lymphocytes, CD4+ Th1 cells, T follicular helper cells, NKT cells, and activated NK cells, and positively correlated with the infiltration of myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs) in pan-cancer. Higher YAP1 expression showed upregulation of TGF-β signaling, Hedgehog signaling, and KRAS signaling. IC50s of FDA-approved chemotherapeutic drugs capable of inhibiting DNA synthesis, including teniposide, dacarbazine, and doxorubicin, as well as inhibitors of hypoxia-inducible factor, MCL-1, ribonucleotide reductase, and FASN in clinical trials were negatively correlated with YAP1 expression. DISCUSSION: In conclusion, YAP1 is aberrantly expressed in various cancer types and regulated by its DNA methylation and post-transcriptional modifications. High expression of YAP1 is associated with poor survival outcomes in certain cancer types. YAP1 may promote tumor progression through immunosuppression, particularly by suppressing the infiltration of CD8+ T lymphocytes, CD4+ Th1 cells, T follicular helper cells, NKT cells, and activated NK cells, as well as recruiting MDSCs and CAFs in pan-cancer. The tumor-promoting activity of YAP1 is attributed to the activation of TGF-β, Hedgehog, and KRAS signaling pathways. AZD2858 and varlitinib might be effective in cancer patients with high YAP1 expression.

148. Editorial: The innate immune system in rheumatoid arthritis.

Front Immunol

2022 Nov 21

Chen Z, Leceta J, Abdul-Sater AA

149. Identification of a claudin-low subtype in clear cell renal cell carcinoma with implications for the evaluation of clinical outcomes and treatment efficacy.

Front Immunol

2022 Nov 21

Zhang C, Li Y, Qian J

BACKGROUND: In bladder and breast cancer, the claudin-low subtype is widely identified, revealing a distinct tumor microenvironment (TME) and immunological feature. Although we have previously identified individual claudin members as prognostic biomarkers in clear cell renal cell carcinoma (ccRCC), the existence of an intrinsic claudin-low subtype and its interplay with TME and clinical outcomes remains unclear. METHODS: Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA)- kidney clear cell carcinoma (KIRC) cohort and E-MTAB-1980 were derived as the training and validation cohorts, respectively. In addition, GSE40435, GSE53757, International Cancer Genome Consortium (ICGC) datasets, and RNA-sequencing data from local ccRCC patients were utilized as validation cohorts for claudin clustering based on silhouette scores. Using weighted correlation network analysis (WGCNA) and multiple machine learning algorithms, including least absolute shrinkage and selection operator (LASSO), CoxBoost, and random forest, we constructed a claudin-TME related (CTR) risk signature. Furthermore, the CTR associated genomic characteristics, immunity, and treatment sensitivity were evaluated. RESULTS: A claudin-low phenotype was identified and associated with an inferior survival and distinct TME and cancer immunity characteristics. Based on its interaction with TME, a risk signature was developed with robust prognostic prediction accuracy. Moreover, we found its association with a claudin-low, stem-like phenotype and advanced clinicopathological features. Intriguingly, it was also effective in kidney chromophobe and renal papillary cell carcinoma. The high CTR group exhibited genomic characteristics similar to those of claudin-low phenotype, including increased chromosomal instability (such as deletions at 9p) and risk genomic alterations (especially BAP1 and SETD2). In addition, a higher abundance of CD8 T cells and overexpression of immune checkpoints, such as LAG3, CTLA4 and PDCD1, were identified in the high CTR group. Notably, ccRCC patients with high CTR were potentially more sensitive to immune checkpoint inhibitors; their counterparts could have more clinical benefits when treated with antiangiogenic drugs, mTOR, or HIF inhibitors. CONCLUSION: We comprehensively evaluated the expression features of claudin genes and identified a claudin-low phenotype in ccRCC. In addition, its related signature could robustly predict the prognosis and provide guide for personalizing management strategies.

150. Preparing for the next pandemic: Simulation-based deep reinforcement learning to discover and test multimodal control of systemic inflammation using repurposed immunomodulatory agents.

Front Immunol

2022 Nov 21

Cockrell C, Larie D, An G.

BACKGROUND: Preparation to address the critical gap in a future pandemic between non-pharmacological measures and the deployment of new drugs/vaccines requires addressing two factors: 1) finding virus/pathogen-agnostic pathophysiological targets to mitigate disease severity and 2) finding a more rational approach to repurposing existing drugs. It is increasingly recognized that acute viral disease severity is heavily driven by the immune response to the infection ("cytokine storm" or "cytokine release syndrome"). There exist numerous clinically available biologics that suppress various pro-inflammatory cytokines/mediators, but it is extremely difficult to identify clinically effective treatment regimens with these agents. We propose that this is a complex control problem that resists standard methods of developing treatment regimens and accomplishing this goal requires the application of simulation-based, model-free deep reinforcement learning (DRL) in a fashion akin to training successful game-playing artificial intelligences (AIs). This proof-of-concept study determines if simulated sepsis (e.g. infection-driven cytokine storm) can be controlled in the absence of effective antimicrobial agents by targeting cytokines for which FDA-approved biologics currently exist. METHODS: We use a previously validated agent-based model, the Innate Immune Response Agent-based Model (IIRABM), for control discovery using DRL. DRL training used a Deep Deterministic Policy Gradient (DDPG) approach with a clinically plausible control interval of 6 hours with manipulation of six cytokines for which there are existing drugs: Tumor Necrosis Factor (TNF), Interleukin-1 (IL-1), Interleukin-4 (IL-4), Interleukin-8 (IL-8), Interleukin-12 (IL-12) and Interferon-γ(IFNg). RESULTS: DRL trained an AI policy that could improve outcomes from a baseline Recovered Rate of 61% to one with a Recovered Rate of 90% over ~21 days simulated time. This DRL policy was then tested on four different parameterizations not seen in training representing a range of host and microbe characteristics, demonstrating a range of improvement in Recovered Rate by +33% to +56. DISCUSSION: The current proof-of-concept study demonstrates that significant disease severity mitigation can potentially be accomplished with existing anti-mediator drugs, but only through a multi-modal, adaptive treatment policy requiring implementation with an AI. While the actual clinical implementation of this approach is a projection for the future, the current goal of this work is to inspire the development of a research ecosystem that marries what is needed to improve the simulation models with the development of the sensing/assay technologies to collect the data needed to iteratively refine those models.

151. Epigenetic-related gene mutations serve as potential biomarkers for immune checkpoint inhibitors in microsatellite-stable colorectal cancer.

Front Immunol

2022 Nov 21

Liu C, Xiao H, Cui L

152. Description of CRISPR-Cas9 development and its prospects in human papillomavirus-driven cancer treatment.

Front Immunol

2022 Nov 21

Wei Y, Zhao Z, Ma X.

153. The role of Angiogenesis and remodeling (AR) associated signature for predicting prognosis and clinical outcome of immunotherapy in pan-cancer.

Front Immunol

2022 Nov 21

Sun X, Zhang Z, Wang Z

BACKGROUND: Angiogenesis and remodeling (AR) is necessary for the growth and metastasis of cancers. Although AR related genes involved in this process are reported, the correlation between AR and clinical outcome, immune cell infiltration, and immunotherapy is still unknown in diverse cancers. This study aimed to investigate the role of AR in the tumor immune microenvironment (TIME) in pan-cancer, and explore its values in prognostic prediction and therapeutic responses. METHODS: Firstly, AR genes (including angiogenesis genes and blood vessel remodeling genes) are collected from MsigDB database. The differential expression, and prognostic value of AR genes were studied in 33 tumor types based on TCGA and GTEx data. The AR score of each sample was calculated using the "ssGSEA" function of R package "GSVA" in pan-cancer. The correlation of the AR score with TIME index, such as the amount of stromal and immune components and the immune cell infiltration, was evaluated via integrating multiple computational methods. And we also utilized IMvigor210 and GSE78220 data to explore the prediction value of the AR score on the immunotherapy response. RESULTS: Significant differences in AR gene expression between tumors and adjacent normal tissues were found in most cancer types. The AR score varied depending on the types of tumors, and high score was related to worse survival in various tumors, such as pancreatic and stomach adenocarcinoma and so on. Moreover, the AR score was further explored to be positively correlated with proportions and pathways of immune and stromal in TIME. And the AR score was positively correlated with immunosuppressive cells, including TAMs and iTregs, while negatively with CD8+ T cells. Further analysis revealed that patients with high AR had worse therapy efficacy and survival status in bladder cancer and melanomas. CONCLUSIONS: Our systematic analysis revealed that AR is closely associated TIME, and prognosis, and clinical characteristics in multiple cancers. Targeting AR genes may activate immune microenvironment and increase the efficacy of immunotherapy.

154. Cholesterol: An important actor on the cancer immune scene.

Front Immunol

2022 Nov 21

Halimi H, Farjadian S.

155. Targeting multiple myeloma with nanobody-based heavy chain antibodies, bispecific killer cell engagers, chimeric antigen receptors, and nanobody-displaying AAV vectors.

Front Immunol

2022 Nov 2

Hambach J, Mann AM, Bannas P

156. Oocytes could rearrange immunoglobulin production to survive over adverse environmental stimuli.

Front Immunol

2022 Nov 2

Wang Y, Luo FQ, He YH

157. Untargeted metabolomics identified kynurenine as a predictive prognostic biomarker in acute myocardial infarction.

Front Immunol

2022 Nov 2

Zhang X, Cai Y, Su X

OBJECTIVE: The occurrence of cardiovascular adverse events in the first year after ST-acute myocardial infarction (STEMI) remains high; therefore, identification of patients with poor prognosis is essential for early intervention. This study aimed to evaluate the prognostic value of metabolomics-based biomarkers in STEMI patients and explore their functional mechanisms. METHODS: Metabolite profiling was performed using nuclear magnetic resonance. The plasma concentration of Kynurenine (Kyn) was measured using ultraperformance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry. Major adverse cardiac and cerebral events were assessed for 1 year. A functional metabolomics strategy was proposed for investigating the role of Kyn in both vitro and vivo models. RESULTS: The adjusted hazard ratios in STEMI patients for Kyn in the 4th quartile 7.12(5.71-10.82) was significantly higher than that in the 3rd quartile 3.03(2.62-3.74), 2nd quartile 1.86(1.70-2.03), and 1st quartile 1.20(0.93-1.39).The incidence of MACCE was significantly different among Kyn quartiles and the highest incidence of MACCE was observed in the 4th quartile when compared with the 1st quartile (9.84% vs.2.85%, P<0.001).Immunofluorescence staining indicated that indoleamine-pyrrole 2,3-dioxygenase (IDO1) was located in the CD68 positive staining area of thrombi from STEMI patients and Kyn was induced in the early phase after myocardial infarction. Kyn could trigger inflammation and oxidative stress of macrophage cells by activation of the Sirt3-acSOD2/IL-1β signaling pathway in vitro. CONCLUSIONS: Plasma Kyn levels were positively associated with the occurrence of STEMI. Kyn could induce macrophage cells inflammation and oxidative stress by activating the Sirt3-acSOD2/IL-1β pathway following myocardial ischemia injury. Kyn could be a robust biomarker for STEMI prognosis and reduction of Kyn could be beneficial in STEMI patients.

158. Implications of m6A-associated snRNAs in the prognosis and immunotherapeutic responses of hepatocellular carcinoma.

Front Immunol

2022 Nov 2

Zhang C, Zhang W, Shui Y

BACKGROUND: Hepatocellular carcinoma (HCC) is the most prevalent pathological type of liver cancer worldwide with high mortality and poor prognosis. N6-methyladenosine (m6A) can modify RNAs such as mRNA, lncRNA, miRNA, and tRNA, thereby playing a critical role in the pathogenesis of HCC. However, the role of m6A-associated small nuclear RNA (snRNA) in the prognostic value and immunotherapeutic response in HCC remains unclear. MATERIALS AND METHODS: In this study, snRNA expression data, gene mutation data, and clinical data of HCC patients were acquired from The Cancer Genome Atlas (TCGA) database. We used the least absolute shrinkage and selection operator (LASSO) Cox regression analysis to identify significant prognostic m6A-associated snRNAs, and then developed a multivariate Cox model based on the selected snRNAs. HCC patients were split into low- and high-risk groups based on the median risk score. We subsequently performed Kaplan-Meier curve analysis to estimate overall survival (OS) by clinicopathological characteristics and tumor mutational burden (TMB) status in low- and high-risk HCC patients. Finally, we compared the immunotherapeutic response as represented by tumor immune dysfunction and exclusion (TIDE) scores between the two risk groups. RESULTS: Eight m6A-associated snRNAs were selected as independent predictors to develop the risk model. Our results revealed that the OS of HCC patients in the high-risk group was significantly worse than that in the low-risk group on clinicopathologic characteristics, including age (≤65 years and >65 years), gender (male), grade (G I-II and G III-IV) and TNM staging (Stage I-II and Stage III-IV). In addition, the OS of low-TMB and low-risk group was longer than that of high-TMB and high-risk group. The TIDE score indicated that HCC patients in the high-risk group were more susceptible to immunotherapy. CONCLUSION: Our study suggests that m6A-associated snRNAs may be useful biomarkers for the prognosis of HCC and that m6A-associated snRNA models can predict the effect of immunotherapy in HCC patients.

159. Alzheimer's disease alters the transcriptomic profile of natural killer cells at single-cell resolution.

Front Immunol

2022 Nov 2

Qi C, Liu F, Zhang W

160. Tumor-derived extracellular vesicles modulate innate immune responses to affect tumor progression.

Front Immunol

2022 Nov 2

Wang S, Sun J, Dastgheyb RM

Front Immunol

2022 Nov 2

Amoafo EB, Entsie P, Albayati S

Sepsis, a complex clinical syndrome resulting from a serious infection, is a major healthcare problem associated with high mortality. Sex-related differences in the immune response to sepsis have been proposed but the mechanism is still unknown. Purinergic signaling is a sex-specific regulatory mechanism in immune cell physiology. Our studies have shown that blocking the ADP-receptor P2Y12 but not P2Y1 receptor was protective in male mice during sepsis, but not female. We now hypothesize that there are sex-related differences in modulating P2Y12 or P2Y1 signaling pathways during sepsis. Male and female wild-type (WT), P2Y12 knock-out (KO), and P2Y1 KO mice underwent sham surgery or cecal ligation and puncture (CLP) to induce sepsis. The P2Y12 antagonist ticagrelor or the P2Y1 antagonist MRS2279 were administered intra-peritoneally after surgery to septic male and female mice. Blood, lungs and kidneys were collected 24 hours post-surgery. Sepsis-induced changes in platelet activation, secretion and platelet interaction with immune cells were measured by flow cytometry. Neutrophil infiltration in the lung and kidney was determined by a myeloperoxidase (MPO) colorimetric assay kit. Sepsis-induced platelet activation, secretion and aggregate formation were reduced in male CLP P2Y12 KO and in female CLP P2Y1 KO mice compared with their CLP WT counterpart. Sepsis-induced MPO activity was reduced in male CLP P2Y12 KO and CLP P2Y1 KO female mice. CLP males treated with ticagrelor or MRS2279 showed a decrease in sepsis-induced MPO levels in lung and kidneys, aggregate formation, and platelet activation as compared to untreated male CLP mice. There were no differences in platelet activation, aggregate formation, and neutrophil infiltration in lung and kidney between female CLP mice and female CLP mice treated with ticagrelor or MRS2279. In human T lymphocytes, blocking P2Y1 or P2Y12 alters cell growth and secretion in vitro in a sex-dependent manner, supporting the data obtained in mice. In conclusion, targeting purinergic signaling represents a promising therapy for sepsis but drug targeting purinergic signaling is sex-specific and needs to be investigated to determine sex-related targeted therapies in sepsis.

162. SARS-CoV-2 infected children form early immune memory responses dominated by nucleocapsid-specific CD8+ T cells and antibodies.

Front Immunol

2022 Nov 2

Lima K, Fontoura JC, de Souza PO

163. Vessel state and immune infiltration of the angiogenesis subgroup and construction of a prediction model in osteosarcoma.

Front Immunol

2022 Nov 2

Wu J, Jin Z, Lin J

164. HSP90AA1 interacts with CSFV NS5A protein and regulates CSFV replication via the JAK/STAT and NF-κB signaling pathway.

Front Immunol

2022 Nov 2

Liu C, Zhao W, Su J

165. Membranous nephropathy: Clearer pathology and mechanisms identify potential strategies for treatment.

Front Immunol

2022 Nov 2

Chung EYM, Wang YM, Keung K

166. Increased stromal PFKFB3-mediated glycolysis in inflammatory bowel disease contributes to intestinal inflammation.

Front Immunol

2022 Nov 2

Zhou Z, Plug LG, Patente TA

Inflammatory bowel disease (IBD) is a chronic relapsing inflammation of the intestinal tract with currently not well-understood pathogenesis. In addition to the involvement of immune cells, increasing studies show an important role for fibroblasts in the pathogenesis of IBD. Previous work showed that glycolysis is the preferred energy source for fibroblasts in fibrotic diseases. 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) is a key kinase supporting glycolysis. Increased expression of PFKFB3 in several cancers and inflammatory diseases has been previously reported, but the metabolic status of fibroblasts and the role of PFKFB3 in patients with IBD are currently unknown. Therefore, in this study, we evaluated the role of glycolysis and PFKFB3 expression in IBD. Single-sample gene set enrichment analysis (ssGSEA) revealed that glycolysis was significantly higher in IBD intestinal samples, compared to healthy controls, which was confirmed in the validation cohorts of IBD patients. Single-cell sequencing data indicated that PFKFB3 expression was higher in IBD-derived stromal cells. In vitro, PFKFB3 expression in IBD-derived fibroblasts was increased after the stimulation with pro-inflammatory cytokines. Using seahorse real-time cell metabolic analysis, inflamed fibroblasts were shown to have a higher extracellular acidification rate and a lower oxygen consumption rate, which could be reversed by inhibition of JAK/STAT pathway. Furthermore, increased expression of pro-inflammatory cytokines and chemokines in fibroblasts could be reverted by PFK15, a specific inhibitor of PFKFB3. In vivo experiments showed that PFK15 reduced the severity of dextran sulfate sodium (DSS)- and Tcell transfer induced colitis, which was accompanied by a reduction in immune cell infiltration in the intestines. These findings suggest that increased stromal PFKFB3 expression contributes to inflammation and the pathological function of fibroblasts in IBD. Inhibition of PFKFB3 suppressed their inflammatory characteristics.

167. Cutting edges and therapeutic opportunities on tumor-associated macrophages in lung cancer.

Front Immunol

2022 Nov 2

Hu Q, Wu G, Wang R

168. Dynamic changes in kynurenine pathway metabolites in multiple sclerosis: A systematic review.

Front Immunol

2022 Nov 2

Fathi M, Vakili K, Yaghoobpoor S

BACKGROUND: Multiple sclerosis (MS) is a debilitating neurodegenerative disorder characterized by axonal damage, demyelination, and perivascular inflammatory lesions in the white matter of the central nervous system (CNS). Kynurenine pathway (KP), which is the major route of tryptophan (TRP) metabolism, generates a variety of neurotoxic as well as neuroprotective compounds, affecting MS pathology and the severity of impairments. Alterations in KP have been described not only in MS, but also in various psychiatric and neurodegenerative diseases. The purpose of this systematic review is to investigate the previously reported dysregulation of KP and differences in its metabolites and enzymes in patients with MS compared to healthy control subjects. METHOD: Electronic databases of PubMed, Scopus, Cochrane Database of Systematic Reviews, and Web of Science were searched to identify studies measuring concentrations of KP metabolites and enzymes in MS patients and control subjects. The following metabolites and enzymes implicated in the KP were investigated: TRP, kynurenine (KYN), kynurenic acid (KYNA), quinolinic acid (QUIN), picolinic acid (PIC), hydroxyindoleacetic acid (HIAA), indoleamine 2,3-dioxygenase (IDO), kynurenine aminotransferase (KAT), and their related ratios. RESULT: Ten studies were included in our systematic review. Our review demonstrates that IDO expression is reduced in the peripheral blood mononuclear cells (PBMCs) of MS patients compared to healthy controls. Also, increased levels of QUIN and QUIN/KYNA in the serum and cerebrospinal fluid (CSF) of MS patients is observed. Differences in levels of other metabolites and enzymes of KP are also reported in some of the reviewed studies, however there are discrepancies among the included reports. CONCLUSION: The results of this investigation suggest a possible connection between alterations in the levels of KP metabolite or enzymes and MS. QUIN levels in CSF were higher in MS patients than in healthy controls, suggesting that QUIN may be involved in the pathogenesis of MS. The data indicate that differences in the serum/blood or CSF levels of certain KP metabolites and enzymes could potentially be used to differentiate between MS patients and control subjects.

169. The yin/yang balance of the MHC-self-immunopeptidome.

Front Immunol

2022 Nov 2

Santambrogio L, Franco A.

170. A nomogram model based on the number of examined lymph nodes-related signature to predict prognosis and guide clinical therapy in gastric cancer.

Front Immunol

2022 Nov 2

Li H, Lin D, Yu Z

BACKGROUND: Increasing evidence suggests that the number of examined lymph nodes (ELNs) is strongly linked to the survivorship of gastric cancer (GC). The goal of this study was to assess the prognostic implications of the ELNs number and to construct an ELNs-based risk signature and nomogram model to predict overall survival (OS) characteristics in GC patients. METHODS: This inception cohort study included 19,317 GC patients from the U.S. Surveillance, Epidemiology, and End Results (SEER) database, who were separated into a training group and an internal validation group. The nomogram was built with the training set, then internally verified with SEER data, and externally validated with two different data sets. Based on the RNA-seq data, ELNs-related DERNAs (DElncRNAs, DEmiRNAs, andDEmRNAs) and immune cells were identified. The LASSO-Cox regression analysis was utilized to construct ELNs-related DERNAs and immune cell prognostic signature in The Cancer Genome Atlas (TCGA) cohort. The OS of subgroups with high- and low-ELN signature was compared using the Kaplan-Meier (K-M) analysis. A nomogram was successfully constructed based on the ELNs signature and other clinical characteristics. The concordance index (C-index), calibration plot, receiver operating characteristic curve, and decision curve analysis (DCA) were all used to evaluate the nomogram model. The meta-analysis, the Gene Expression Profiling Interactive Analysis database, and reverse transcription-quantitative PCR (RT-qPCR) were utilized to validate the RNA expression or abundance of prognostic genes and immune cells between GC tissues and normal gastric tissues, respectively. Finally, we analyzed the correlations between immune checkpoints, chemotherapy drug sensitivity, and risk score. RESULTS: The multivariate analysis revealed that the high ELNs improved OS compared with low ELNs (hazard ratio [HR] = 0.659, 95% confidence interval [CI]: 0.626-0.694, p < 0.0001). Using the training set, a nomogram incorporating ELNs was built and proven to have good calibration and discrimination (C-index [95% CI], 0.714 [0.710-0.718]), which was validated in the internal validation set (C-index [95% CI], 0.720 [0.714-0.726]), the TCGA set (C-index [95% CI], 0.693 [0.662-0.724]), and the Chinese set (C-index [95% CI], 0.750 [0.720-0.782]). An ELNs-related signature model based on ELNs group, regulatory T cells (Tregs), neutrophils, CDKN2B-AS1, H19, HOTTIP, LINC00643, MIR663AHG, TMEM236, ZNF705A, and hsa-miR-135a-5p was constructed by the LASSO-Cox regression analysis. The result showed that OS was remarkably lower in patients with high-ELNs signature compared with those with low-ELN signature (HR = 2.418, 95% CI: 1.804-3.241, p < 0.001). This signature performed well in predicting 1-, 3-, and 5-year survival (AUC [95% CI] = 0.688 [0.612-0.763], 0.744 [0.659-0.830], and 0.778 [0.647-0.909], respectively). The multivariate Cox analysis illustrated that the risk score was an independent predictor of survival for patients with GC. Moreover, the expression of prognostic genes (LINC00643, TMEM236, and hsa-miR-135a-5p) displayed differences between GC tissues and adjacent non-tumor tissues. The C-index of the nomogram that can be used to predict the OS of GC patients was 0.710 (95% CI: 0.663-0.753). Both the calibration plots and DCA showed that the nomogram has good predictive performance. Moreover, the signature was significantly correlated with the N stage and T stage. According to our analysis, GC patients in the low-ELN signature group may have a better immunotherapy response and OS outcome. CONCLUSIONS: We explored the prognostic role of ELNs in GC and successfully constructed an ELNs signature linked to the GC prognosis in TCGA. The findings manifested that the signature is a powerful predictive indicator for patients with GC. The signature might contain potential biomarkers for treatment response prediction for GC patients. Additionally, we identified a novel and robust nomogram combining the characteristics of ELNs and clinical factors for predicting 1-, 3-, and 5-year OS in GC patients, which will facilitate personalized survival prediction and aid clinical decision-making in GC patients.

171. Anticardiolipin and/or anti-β2-glycoprotein-I antibodies are associated with adverse IVF outcomes.

Front Immunol

2022 Nov 2

Wu L, Fang X, Lu F

172. Identification of HLA class I-restricted immunogenic neoantigens in triple negative breast cancer.

Front Immunol

2022 Nov 2

Aparicio B, Repáraz D, Ruiz M

173. Identification of diagnostic genes for both Alzheimer's disease and Metabolic syndrome by the machine learning algorithm.

Front Immunol

2022 Nov 2

Li J, Zhang Y, Lu T

BACKGROUND: Alzheimer's disease is the most common neurodegenerative disease worldwide. Metabolic syndrome is the most common metabolic and endocrine disease in the elderly. Some studies have suggested a possible association between MetS and AD, but few studied genes that have a co-diagnostic role in both diseases. METHODS: The microarray data of AD (GSE63060 and GSE63061 were merged after the batch effect was removed) and MetS (GSE98895) in the GEO database were downloaded. The WGCNA was used to identify the co-expression modules related to AD and MetS. RF and LASSO were used to identify the candidate genes. Machine learning XGBoost improves the diagnostic effect of hub gene in AD and MetS. The CIBERSORT algorithm was performed to assess immune cell infiltration MetS and AD samples and to investigate the relationship between biomarkers and infiltrating immune cells. The peripheral blood mononuclear cells (PBMCs) single-cell RNA (scRNA) sequencing data from patients with AD and normal individuals were visualized with the Seurat standard flow dimension reduction clustering the metabolic pathway activity changes each cell with ssGSEA. RESULTS: The brown module was identified as the significant module with AD and MetS. GO analysis of shared genes showed that intracellular transport and establishment of localization in cell and organelle organization were enriched in the pathophysiology of AD and MetS. By using RF and Lasso learning methods, we finally obtained eight diagnostic genes, namely ARHGAP4, SNRPG, UQCRB, PSMA3, DPM1, MED6, RPL36AL and RPS27A. Their AUC were all greater than 0.7. Higher immune cell infiltrations expressions were found in the two diseases and were positively linked to the characteristic genes. The scRNA-seq datasets finally obtained seven cell clusters. Seven major cell types including CD8 T cell, monocytes, T cells, NK cell, B cells, dendritic cells and macrophages were clustered according to immune cell markers. The ssGSEA revealed that immune-related gene (SNRPG) was significantly regulated in the glycolysis-metabolic pathway. CONCLUSION: We identified genes with common diagnostic effects on both MetS and AD, and found genes involved in multiple metabolic pathways associated with various immune cells.

174. Editorial: The role of omics characteristics in the diagnosis, treatment, and prognosis of autoimmune diseases.

Front Immunol

2022 Nov 2

Wu Q, Ning K, Zhao X

175. αDβ2 as a novel target of experimental polymicrobial sepsis.

Front Immunol

2022 Nov 18

Koutsogiannaki S, Hou L, Okuno T

176. Rapid identification of CMV-specific TCRs via reverse TCR cloning system based on bulk TCR repertoire data.

Front Immunol

2022 Nov 18

Hong CH, Pyo HS, Baek IC

177. The oral microbiota and cardiometabolic health: A comprehensive review and emerging insights.

Front Immunol

2022 Nov 18

Li Y, Zhu M, Liu Y

178. Cellular stress modulates severity of the inflammatory response in lungs via cell surface BiP.

Front Immunol

2022 Nov 18

Rico-Llanos G, Porras-Perales Ó, Escalante S

179. Disruption of the HLA-E/NKG2X axis is associated with uncontrolled HIV infections.

Front Immunol

2022 Nov 18

Romero-Martín L, Duran-Castells C, Olivella M

180. Evolutionary analyses of polymeric immunoglobulin receptor (pIgR) in the mammals reveals an outstanding mutation rate in the lagomorphs.

Front Immunol

2022 Nov 18

Neves F, de Sousa-Pereira P, Melo-Ferreira J

181. Identification of fatty acid metabolism-related molecular subtype biomarkers and their correlation with immune checkpoints in cutaneous melanoma.

Front Immunol

2022 Nov 18

Xu Y, Chen Y, Jiang W

PURPOSE: Fatty acid metabolism (FAM) affects the immune phenotype in a metabolically dynamic tumor microenvironment (TME), but the use of FAM-related genes (FAMGs) to predict the prognosis and immunotherapy response of cutaneous melanoma (CM) patients has not been investigated. In this study, we aimed to construct FAM molecular subtypes and identify key prognostic biomarkers in CM. METHODS: We used a CM dataset in The Cancer Genome Atlas (TCGA) to construct FAM molecular subtypes. We performed Kaplan-Meier (K-M) analysis, gene set enrichment analysis (GSEA), and TME analysis to assess differences in the prognosis and immune phenotype between subtypes. We used weighted gene co-expression network analysis (WGCNA) to identify key biomarkers that regulate tumor metabolism and immunity between the subtypes. We compared overall survival (OS), progression-free survival (PFS), and disease-specific survival (DSS) between CM patients with high or low biomarker expression. We applied univariable and multivariable Cox analyses to verify the independent prognostic value of the FAM biomarkers. We used GSEA and TME analysis to investigate the immune-related regulation mechanism of the FAM subtype biomarker. We evaluated the immune checkpoint inhibition (ICI) response and chemotherapy sensitivity between CM patients with high or low biomarker expression. We performed real-time fluorescent quantitative PCR (qRT-PCR) and semi-quantitative analysis of the immunohistochemical (IHC) data from the Human Protein Atlas to evaluate the mRNA and protein expression levels of the FAM biomarkers in CM. RESULTS: We identified 2 FAM molecular subtypes (cluster 1 and cluster 2). K-M analysis showed that cluster 2 had better OS and PFS than cluster 1 did. GSEA showed that, compared with cluster 1, cluster 2 had significantly upregulated immune response pathways. The TME analysis indicated that immune cell subpopulations and immune functions were highly enriched in cluster 2 as compared with cluster 1. WGCNA identified 6 hub genes (ACSL5, ALOX5AP, CD1D, CD74, IL4I1, and TBXAS1) as FAM biomarkers. CM patients with high expression levels of the six biomarkers had better OS, PFS, and DSS than those with low expression levels of the biomarkers. The Cox regression analyses verified that the 6 FAM biomarkers can be independent prognostic factors for CM patients. The single-gene GSEA showed that the high expression levels of the 6 genes were mainly enriched in T-cell antigen presentation, the PD-1 signaling pathway, and tumor escape. The TME analysis confirmed that the FAM subtype biomarkers were not only related to immune infiltration but also highly correlated with immune checkpoints such as PD-1, PD-L1, and CTLA-4. TIDE scores confirmed that patients with high expression levels of the 6 biomarkers had worse immunotherapy responses. The 6 genes conveyed significant sensitivity to some chemotherapy drugs. qRT-PCR and IHC analyses verified the expression levels of the 6 biomarkers in CM cells. CONCLUSION: Our FAM subtypes verify that different FAM reprogramming affects the function and phenotype of infiltrating immune cells in the CM TME. The FAM molecular subtype biomarkers can be independent predictors of prognosis and immunotherapy response in CM patients.

182. Short-term oral pre-exposure prophylaxis against HIV-1 modulates the transcriptome of foreskin tissue in young men in Africa.

Front Immunol

2022 Nov 18

Petkov S, Herrera C, Else L

183. Differential diagnosis and identification of prognostic markers for peripheral T-cell lymphoma subtypes based on flow cytometry immunophenotype profiles.

Front Immunol

2022 Nov 18

Pu Q, Qiao J, Liu Y

We compared the differential expression of 15 markers in PTCL (Peripheral T-cell lymphoma) subtypes and T-CUS (T-cell clones of uncertain significance), and summarized the specific immunophenotype profiles of each subtype and its impact on prognosis. PD-1 and CD10 are diagnostic markers for AITL (angioimmunoblastic T-cell lymphoma). To avoid confusion with T-CUS of benign clones, it is recommended to define AITL as bounded by PD-1+%>38.01 and/or CD10+%>7.46. T cell-derived ENKTL-N (extranodal NKT cell lymphoma) specifically expresses CD56. ALCL (anaplastic large cell lymphoma) characteristically expresses CD30 and HLA-DR. PTCL-NOS (peripheral T-cell lymphoma unspecified) still lacks a relatively specific phenotype and is prone to loss of basic lineage markers CD3, CD5, and CD7. The determination of T-CUS can be verified by the overall assessment of the bone marrow and a certain period of follow-up. The clustering results showed that the expression of 8 specific markers was significantly different among the 5 groups, suggesting that a combination of related markers can be analyzed in the identification of PTCLs subtypes. The study explores the advantages of TRBC1 combined with CD45RA/CD45RO in detecting T cell clonality, which can efficiently and sensitively analyze multiple target T cell populations at the same time. The sensitivity of PB to replace BM to monitor the tumor burden or MRD (minimal residual disease) of PTCLs is as high as 85.71%, which can relieve the huge pressure of clinical sampling and improve patient compliance. CD7, CD38, and Ki-67 are prognostic indicators for AITL. CD3 and CD8 on PTCL-NOS, and CD56 and HLA-DR on ENKTL-N have prognostic role. This study supports and validates the current classification of PTCL subtypes and establishes an immunophenotypic profile that can be used for precise diagnosis. The important clinical value of PTCLs immunophenotype in routine classification diagnosis, clonality confirmation, prognosis prediction, and treatment target selection was emphasized.

184. Regulation of differentiation and generation of osteoclasts in rheumatoid arthritis.

Front Immunol

2022 Nov 18

Niu Q, Gao J, Wang L

185. The effect of the intratumoral microbiome on tumor occurrence, progression, prognosis and treatment.

Front Immunol

2022 Nov 18

Gao F, Yu B, Rao B

186. Influence of nutrients and metabolites on the differentiation of plasma cells and implications for autoimmunity.

Front Immunol

2022 Nov 18

Föh B, Buhre JS, Sina C

187. Dysregulated hepatic lipid metabolism and gut microbiota associated with early-stage NAFLD in ASPP2-deficiency mice.

Front Immunol

2022 Nov 18

Xie F, Xu HF, Zhang J

BACKGROUND: Growing evidence indicates that lipid metabolism disorders and gut microbiota dysbiosis were related to the progression of non-alcoholic fatty liver disease (NAFLD). Apoptosis-stimulating p53 protein 2 (ASPP2) has been reported to protect against hepatocyte injury by regulating the lipid metabolism, but the mechanisms remain largely unknown. In this study, we investigate the effect of ASPP2 deficiency on NAFLD, lipid metabolism and gut microbiota using ASPP2 globally heterozygous knockout (ASPP2+/-) mice. METHODS: ASPP2+/- Balb/c mice were fed with methionine and choline deficient diet for 3, 10 and 40 day to induce an early and later-stage of NAFLD, respectively. Fresh fecal samples were collected and followed by 16S rRNA sequencing. HPLC-MRM relative quantification analysis was used to identify changes in hepatic lipid profiles. The expression level of innate immunity-, lipid metabolism- and intestinal permeability-related genes were determined. A spearman's rank correlation analysis was performed to identify possible correlation between hepatic medium and long-chain fatty acid and gut microbiota in ASPP2-deficiency mice. RESULTS: Compared with the WT control, ASPP2-deficiency mice developed moderate steatosis at day 10 and severe steatosis at day 40. The levels of hepatic long chain omega-3 fatty acid, eicosapentaenoic (EPA, 20:5 n-3) and docosahexaenoic (DHA, 22:6 n-3), were decreased at day 10 and increased at day 40 in ASPP+/- mice. Fecal microbiota analysis showed significantly increased alpha and beta diversity, as well as the composition of gut microbiota at the phylum, class, order, family, genus, species levels in ASPP2+/- mice. Moreover, ASPP-deficiency mice exhibited impaired intestinal barrier function, reduced expression of genes associated with chemical barrier (REG3B, REG3G, Lysozyme and IAP), and increased expression of innate immune components (TLR4 and TLR2). Furthermore, correlation analysis between gut microbiota and fatty acids revealed that EPA was significantly negatively correlated with Bifidobacterium family. CONCLUSION: Our findings suggested that ASPP2-deficiency promotes the progression of NAFLD, alterations in fatty acid metabolism and gut microbiota dysbiosis. The long chain fatty acid EPA was significantly negatively correlated with Bifidobacterial abundance, which is a specific feature of NAFLD in ASPP2-deficiency mice. Totally, the results provide evidence for a mechanism of ASPP2 on dysregulation of fatty acid metabolism and gut microbiota dysbiosis.

188. Integrated multi-omics reveals novel microbe-host lipid metabolism and immune interactions in the donkey hindgut.

Front Immunol

2022 Nov 18

Li Y, Ma Q, Shi X

Evidence has shown that gut microbiota play a key role in host metabolism and health; however, little is known about the microbial community in the donkey hindgut as well as the interactions that occur between gut microbes and the host. This study aimed to explore the gut microbiome differences by analyzing the microbial community and differentially expressed genes (DEGs) related to lipid metabolism and the immune system along the donkey hindgut. The hindgut tissues (cecum, ventral colon, and dorsal colon) were separated, and the contents of each section were collected from six male donkeys for multi-omics analysis. There were significant differences in terms of dominant bacteria among the three sections, especially between the cecum and dorsal colon sites. For instance, species belonging to Prevotella and Treponema were most abundant in the cecum, while the Clostridiales_bacterium, Streptococcus_equinus, Ruminococcaceae_bacterium, etc., were more abundant in the dorsal colon. Apart from propionate, the concentrations of acetate, isobutyrate, valerate and isovalerate were all lower in the cecum than in the dorsal colon (p < 0.05). Furthermore, we identified some interesting DEGs related to lipid metabolism (e.g., ME1, MBOAT1, ACOX1, ACOX2 and LIPH) and the immune system (e.g., MUC3B, mucin-2-like, IL17RC, IL1R2, IL33, C1QA, and MMP9) between the cecum and dorsal colon and found that the PPAR pathway was mainly enriched in the cecum. Finally, we found a complex relationship between the gut microbiome and gene expression, especially with respect to the immune system, and combined with protein-protein interaction (PPI) data, suggesting that the PPAR pathway might be responsible, at least in part, for the role of the hindgut microbiota in the donkeys' gut homeostasis. Our data provide an in-depth understanding of the interaction between the microbiota and function in the healthy equine hindgut and may also provide guidance for improving animal performance metrics (such as product quality) and equine welfare.

189. Systemic immune-inflammation index is associated with hepatic steatosis: Evidence from NHANES 2015-2018.

Front Immunol

2022 Nov 18

Song Y, Guo W, Li Z

190. Transcriptomic study reveals lncRNA-mediated downregulation of innate immune and inflammatory response in the SARS-CoV-2 vaccination breakthrough infections.

Front Immunol

2022 Nov 18

Chattopadhyay P, Mishra P, Mehta P

INTRODUCTION: The emergence of multiple variants of concerns (VOCs) with higher number of Spike mutations have led to enhanced immune escape by the SARS-CoV-2. With the increasing number of vaccination breakthrough (VBT) infections, it is important to understand the possible reason/s of the breakthrough infections. METHODS: We performed transcriptome sequencing of 57 VBT and unvaccinated COVID-19 patients, followed by differential expression and co-expression analysis of the lncRNAs and the mRNAs. The regulatory mechanism was highlighted by analysis towards repeat element distribution within the co-expressed lncRNAs, followed by repeats driven homologous interaction between the lncRNAs and the promoter regions of genes from the same topologically associated domains (TAD). RESULTS: We identified 727 differentially expressed lncRNAs (153 upregulated and 574 downregulated) and 338 mRNAs (34 up- and 334 downregulated) in the VBT patients. This includes LUCAT1, MALAT1, ROR1-AS1, UGDH-AS1 and LINC00273 mediated modulation of immune response, whereas MALAT1, NEAT1 and GAS5 regulated inflammatory response in the VBT. LncRNA-mRNA co-expression analysis highlighted 34 lncRNAs interacting with 267 mRNAs. We also observed a higher abundance of Alu, LINE1 and LTRs within the interacting lncRNAs of the VBT patients. These interacting lncRNAs have higher interaction with the promoter region of the genes from the same TAD, compared to the non-interacting lncRNAs with the enrichment of Alu and LINE1 in the gene promoter. DISCUSSION: Significant downregulation and GSEA of the TAD gene suggest Alu and LINE1 driven homologous interaction between the lncRNAs and the TAD genes as a possible mechanism of lncRNA-mediated suppression of innate immune/inflammatory responses and activation of adaptive immune response. The lncRNA-mediated suppression of innate immune/inflammatory responses and activation of adaptive immune response might explain the SARS-CoV-2 breakthrough infections with milder symptoms in the VBT. Besides, the study also highlights repeat element mediated regulation of genes in 3D as another possible way of lncRNA-mediated immune-regulation modulating vaccination breakthroughs milder disease phenotype and shorter hospital stay.

191. Pathologic responses and surgical outcomes after neoadjuvant immunochemotherapy versus neoadjuvant chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma.

Front Immunol

2022 Nov 17

Xu L, Wei XF, Li CJ

BACKGROUND: Currently, the role of immunotherapy in neoadjuvant setting for patients with locally advanced esophageal squamous cell carcinoma (ESCC) is gradually attracting attention. Few studies compared the efficacy of neoadjuvant immunochemotherapy (NICT) and neoadjuvant chemoradiotherapy (NCRT). Our study aimed to compare treatment response and postoperative complications after NICT followed by surgery with that after conventional NCRT in patients with locally advanced ESCC. METHODS: Of 468 patients with locally advanced ESCC, 154 received conventional NCRT, whereas 314 received NICT. Treatment response, postoperative complications and mortality between two groups were compared. Pathological response of primary tumor was evaluated using the Mandard tumor regression grade (TRG) scoring system. Pathological complete response (pCR) of metastatic lymph nodes (LNs) was defined as no viable tumor cell within all resected metastatic LNs. According to regression directionality, tumor regression pattern was summarized into four categories: type I, regression toward the lumen; type II, regression toward the invasive front; type III, concentric regression; and type IV, scattered regression. Inverse probability propensity score weighting was performed to minimize the influence of confounding factors. RESULTS: After adjusting for baseline characteristics, the R0 resection rates (90.9% vs. 89.0%, P=0.302) and pCR (ypT0N0) rates (29.8% vs. 34.0%, P=0.167) were comparable between two groups. Patients receiving NCRT showed lower TRG score (P<0.001) and higher major pathological response (MPR) rate (64.7% vs. 53.6%, P=0.001) compared to those receiving NICT. However, NICT brought a higher pCR rate of metastatic LNs than conventional NCRT (53.9% vs. 37.1%, P<0.001). The rates of type I/II/III/IV regression patterns were 44.6%, 6.8%, 11.4% and 37.1% in the NICT group, 16.9%, 8.2%, 18.3% and 56.6% in the NCRT group, indicating a significant difference (P<0.001). Moreover, there were no significant differences in the incidence of total postoperative complications (35.8% vs. 39.9%, P=0.189) and 30-d mortality (0.0% vs. 1.1%, P=0.062). CONCLUSION: For patients with locally advanced ESCC, NICT showed a R0 resection rate and pCR (ypT0N0) rate comparable to conventional NCRT, without increased incidence of postoperative complications and mortality. Notablely, NICT followed by surgery might bring a promising treatment response of metastatic LNs.

192. Human lymphoid tissue sampling for vaccinology.

Front Immunol

2022 Nov 17

Kwiatkowska KM, Mkindi CG, Nielsen CM.

193. Low fish meal diet supplemented with probiotics ameliorates intestinal barrier and immunological function of Macrobrachium rosenbergii via the targeted modulation of gut microbes and derived secondary metabolites.

Front Immunol

2022 Nov 17

Zheng X, Liu B, Wang N

The unsuitable substitution ratio of fish meal by plant protein will reshape the intestinal microbial composition and intestine immunity. However, previous studies were mostly limited to investigating how different feed or probiotics characterized the microbial composition but ignored the biological interactions between bacteria and host physiology through secondary metabolites. Therefore, this study integrates the apparent indicators monitoring, 16S rDNA sequencing, and metabonomics to systematically investigate the effects of cottonseed protein concentrate (CPC) substitution of fish meal and Bacillus coagulans intervention on gut microbes, secondary metabolites, and intestinal immunity of Macrobrachium rosenbergii. Prawns were fed with three diets for 70 days: HF diets contained 25% fish meal, CPC in LF diets were replaced with 10% fish meal, and LF diets supplemented with 2 × 108 CFU/g diet B. coagulans were designated as BC diets. Results showed that CPC substitution induced a significant decrease in digestive enzyme activities (trypsin and lipase) and gut barrier protein PT-1 expression and a significant increase in γ-GT enzyme activity and inflammatory-related factors (Relish and Toll) expression. B. coagulans treatment mitigated the negative changes of the above indicators. Meanwhile, it significantly improved the expression levels of the barrier factor PT-1, the reparative cytokine IL-22, and Cu/Zn-SOD. CPC substitution resulted in a remarkable downregulated abundance of Firmicutes phyla, Flavobacterium spp., and Bacillus spp. B. coagulans treatment induced the callback of Firmicutes abundance and improved the relative abundance of Sphingomonas, Bacillus, and Ralstonia. Functional prediction indicated that CPC substitution resulted in elevated potential pathogenicity of microbial flora, and B. coagulans reduces the pathogenesis risk. Pearson's correlation analysis established a significant positive correlation between differential genera (Sphingomonas, Bacillus, and Ralstonia) and secondary metabolites (including sphingosine, dehydrophytosphingosine, amino acid metabolites, etc.). Meanwhile, the latter were significantly associated with intestinal immunoregulation-related genes (Cu/Zn-SOD, IL-22, PT-1, Toll, and Relish). This study indicated that B. coagulans could mediate specific gut microbes and the combined action of multiple functional secondary metabolites to affect intestinal barrier function, digestion, and inflammation. Our study revealed the decisive role of gut microbes and derived secondary metabolites in the model of dietary composition-induced intestinal injury and probiotic treatment from a new perspective.

194. Novel T-cell signature based on cell pair algorithm predicts survival and immunotherapy response for patients with bladder urothelial carcinoma.

Front Immunol

2022 Nov 17

Yan X, Zhang X, Wu HH

195. Prospective longitudinal analysis of antibody response after standard and booster doses of SARS-COV2 vaccination in patients with early breast cancer.

Front Immunol

2022 Nov 17

Kim J, Jeong J, Lee CM

196. Circular RNA hsa_circ_0007990 as a blood biomarker for unruptured intracranial aneurysm with aneurysm wall enhancement.

Front Immunol

2022 Nov 17

Wu XB, Wu YT, Guo XX

BACKGROUND: Circular RNAs (circRNAs) may involve the formation and rupture of intracranial aneurysms (IA). Inflammation plays a vital role in the development and progression of IA, which can be reflected by aneurysm wall enhancement (AWE) on high-resolution vessel wall magnetic resonance imaging (HR-VWI). This study aims to evaluate the role of circRNAs as the blood inflammatory biomarker for unruptured IA (UIA) patients with AWE on HR-VWI. METHODS: We analyzed the circRNA expression profiles in the peripheral blood samples among subjects from saccular UIA with AWE, UIA without AWE, and healthy controls by the circRNA microarray. The differential expression of hsa_circ_0007990 was assessed. We constructed the hsa_circ_0007990-microRNA-mRNA network and the regulatory axis of hub genes associated with the AWE in UIA. RESULTS: Eighteen patients harboring saccular UIAs with HR VWI and five healthy controls were included. We found 412 differentially expressed circRNAs between UIA patients and healthy controls by circRNA microarray. Two hundred thirty-one circRNAs were significantly differentially expressed in UIA patients with AWE compared with those without AWE. Twelve upregulated circRNAs were associated with AWE of UIA, including hsa_circ_0007990, hsa_circ_0114507, hsa_circ_0020460, hsa_circ_0053944, hsa_circ_0000758, hsa_circ_0000034, hsa_circ_0009127, hsa_circ_0052793, hsa_circ_0000301 and hsa_circ_0000729. The expression of hsa_circ_0007990 was increased gradually in the healthy control, UIA without AWE, and UIA with AWE confirmed by RT-PCR (P<0.001). We predicted 4 RNA binding proteins (Ago2, DGCR8, EIF4A3, PTB) and period circadian regulator 1 as an encoding protein with hsa_circ_0007990. The hsa_circ_0007990-microRNA-mRNA network containing five microRNAs (miR-4717-5p, miR-1275, miR-150-3p, miR-18a-5p, miR-18b-5p), and 97 mRNAs was constructed. The five hub genes (hypoxia-inducible factor 1 subunit alpha, estrogen receptor 1, forkhead box O1, insulin-like growth factor 1, CREB binding protein) were involved in the inflammatory response. CONCLUSION: Differentially expressed blood circRNAs associated with AWE on HR-VWI may be the novel inflammatory biomarkers for assessing UIA patients. The mechanism of hsa_circRNA_0007990 for UIA progression needs to investigate further.

197. Hepatitis B functional cure and immune response.

Front Immunol

2022 Nov 17

Zheng JR, Wang ZL, Feng B.

198. Cell-based therapy in prophylaxis and treatment of chronic graft-versus-host disease.

Front Immunol

2022 Nov 17

Doglio M, Crossland RE, Alho AC

199. Comprehensive (18)F-FDG PET-based radiomics in elevating the pathological response to neoadjuvant immunochemotherapy for resectable stage III non-small-cell lung cancer: A pilot study.

Front Immunol

2022 Nov 17

Cui Y, Lin Y, Zhao Z

PURPOSE: To develop a comprehensive PET radiomics model to predict the pathological response after neoadjuvant toripalimab with chemotherapy in resectable stage III non-small-cell lung cancer (NSCLC) patients. METHODS: Stage III NSCLC patients who received three cycles of neoadjuvant toripalimab with chemotherapy and underwent 18F-FDG PET/CT were enrolled. Baseline 18F-FDG PET/CT was performed before treatment, and preoperative 18F-FDG PET/CT was performed three weeks after the completion of neoadjuvant treatment. Surgical resection was performed 4-5 weeks after the completion of neoadjuvant treatment. Standardized uptake value (SUV) statistics features and radiomics features were derived from baseline and preoperative PET images. Delta features were derived. The radiologic response and metabolic response were assessed by iRECIST and iPERCIST, respectively. The correlations between PD-L1 expression, driver-gene status, peripheral blood biomarkers, and the pathological responses (complete pathological response [CPR]; major pathological response [MPR]) were assessed. Associations between PET features and pathological responses were evaluated by logistic regression. RESULTS: Thirty patients underwent surgery and 29 of them performed preoperative PET/CT. Twenty patients achieved MPR and 16 of them achieved CPR. In univariate analysis, five SUV statistics features and two radiomics features were significantly associated with pathological responses. In multi-variate analysis, SUVmax, SUVpeak, SULpeak, and End-PET-GLDM-LargeDependenceHighGrayLevelEmphasis (End-GLDM-LDHGLE) were independently associated with CPR. SUVpeak and SULpeak performed better than SUVmax and SULmax for MPR prediction. No significant correlation, neither between the radiologic response and the pathological response, nor among PD-L1, driver gene status, and baseline PET features was found. Inflammatory response biomarkers by peripheral blood showed no difference in different treatment responses. CONCLUSION: The logistic regression model using comprehensive PET features contributed to predicting the pathological response after neoadjuvant toripalimab with chemotherapy in resectable stage III NSCLC patients.

200. What role for cellular metabolism in the control of hepatitis viruses?

Front Immunol

2022 Nov 17

Diaz O, Vidalain PO, Ramière C

201. The effect of organ-specific tumor microenvironments on response patterns to immunotherapy.

Front Immunol

2022 Nov 17

Conway JW, Braden J, Wilmott JS

202. Effects of cysteine addition to low-fishmeal diets on the growth, anti-oxidative stress, intestine immunity, and Streptococcus agalactiae resistance in juvenile golden pompano (Trachinotus ovatus).

Front Immunol

2022 Nov 17

Liu JX, Zhu KC, Guo HY

As the precursor of taurine, cysteine serves physiological functions, such as anti-oxidative stress and immune improvement. Investigation of cysteine and its derivatives has made positive progress in avian and mammalian species, yet the study and application of cysteine in aquatic animals are relatively rare. Therefore, we evaluated the effects of supplementing a low-fishmeal diet with various levels of cysteine on the growth, antioxidant capacity, intestine immunity, and resistance against Streptococcus agalactiae of the juvenile golden pompano (Trachinotus ovatus). According to our study, exogenous supplementation with 0.6-1.2% cysteine greatly increased the final body weight (FBW) and specific growth rate (SGR) of golden pompano compared to the control group. Under the present conditions, the optimum dietary cysteine supplementation level for golden pompano was 0.91% based on the polynomial regression analysis of SGR. Meanwhile, we found that the Nrf2/Keap1/HO-1 signaling pathway was notably upregulated with the increase of exogenous cysteine, which increased antioxidant enzyme activity in serum and gene expression in the intestine and reduced the level of reactive oxygen species (ROS) in the serum of golden pompano. In addition, morphological analysis of the midgut demonstrated that exogenous cysteine improved muscle thickness and villi length, which suggested that the physical barrier of the intestine was greatly strengthened by cysteine. Moreover, cysteine increased the diversity and relative abundance of the intestinal flora of golden pompano. Cysteine suppressed intestinal NF-κB/IKK/IκB signaling and pro-inflammatory cytokine mRNA levels. Conversely, intestinal anti-inflammatory cytokine gene expression and serum immune parameters were upregulated with the supplementary volume of cysteine and improved intestine immunity. Further, exogenous cysteine supplementation greatly reduced the mortality rate of golden pompano challenged with S. agalactiae. In general, our findings provide more valuable information and new insights into the rational use of cysteine in the culture of healthy aquatic animals.

203. Response of immunoglobulin M in gut mucosal immunity of common carp (Cyprinus carpio) infected with Aeromonas hydrophila.

Front Immunol

2022 Nov 17

Mu Q, Dong Z, Kong W

204. Multiple CAR-T cell therapy for acute B-cell lymphoblastic leukemia after hematopoietic stem cell transplantation: A case report.

Front Immunol

2022 Nov 17

Deng L, Xiaolin Y, Wu Q

205. Neutrophil extracellular traps and complications of liver transplantation.

Front Immunol

2022 Nov 17

Liu Y, Yan P, Bin Y

206. Case Report: Mutations in JAK3 causing severe combined immunodeficiency complicated by disseminated Bacille Calmette-Guérin disease and Pneumocystis pneumonia.

Front Immunol

2022 Nov 17

Pan Y, Pan H, Lian C

207. The associations of maternal and children's gut microbiota with the development of atopic dermatitis for children aged 2 years.

Front Immunol

2022 Nov 17

Fan X, Zang T, Dai J

208. Memory-like innate lymphoid cells in the pathogenesis of asthma.

Front Immunol

2022 Nov 17

Ham J, Lim M, Kim D

209. Radiotherapy plus CAR-T cell therapy to date: A note for cautions optimism?

Front Immunol

2022 Nov 17

Huan T, Li H, Tang B.

210. The immunosuppressive microenvironment and immunotherapy in human glioblastoma.

Front Immunol

2022 Nov 17

Zhang X, Zhao L, Zhang H

211. In vitro systems to study inborn errors of immunity using human induced pluripotent stem cells.

Front Immunol

2022 Nov 17

Nikolouli E, Reichstein J, Hansen G

212. Construction and validation of an angiogenesis-related scoring model to predict prognosis, tumor immune microenvironment and therapeutic response in hepatocellular carcinoma.

Front Immunol

2022 Nov 17

Tang B, Zhang X, Yang X

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world with high morbidity and mortality. Identifying an effective marker for predicting the prognosis and therapeutic response is extremely meaningful. Angiogenesis-related genes (ARGs) play important roles in the tumor progression and immune-suppressive microenvironment formation. METHODS: The differential expressed ARGs associated with the prognosis of HCC were identified in the TCGA dataset. Univariate Cox and least absolute shrinkage selection operator (LASSO) regression were applied to construct a ARGs Scoring model. The prognostic value of the ARGs Scoring model was assessed by Cox regression, Kaplan-Meier (KM) and ROC curve analyses. Then the model was further validated in an external dataset, ICGC dataset. The patients were split into two groups based on the ARGs Score and the clinical features were compared. TIMER, CIBERSORT and xCell algorithms were utilized to analyze the correlation between the ARGs Score and tumor immune microenvironment (TIME). Furthermore, we analyzed the efficacy of the model in predicting the therapeutic response for immunotherapy, targeted therapy and TACE treatment in different cohorts. RESULTS: A total of 97 differential expressed ARGs were identified relating to the prognosis of HCC patients from the TCGA dataset. Then the ARGs Scoring model based on a 9-gene signature was constructed using the Cox and LASSO regression analyses. Higher ARGs Score had a poor clinical outcome and was considered to be an independent prognostic predictor for HCC in the multivariate Cox analysis. The ARGs Score was related to the enrichment of various immune cells, such as CD4+ T cells, Treg, macrophage, neutrophil and dendritic cells, exhibiting a more immunosuppressive phenotype. Higher ARGs Score was correlated with higher expression of immune checkpoint genes and poor response to immunotherapy. Furthermore, higher ARGs Score indicated poor therapeutic response in the sorafenib and TACE treatment cohorts, individually. CONCLUSIONS: The ARGs Scoring model exhibited robust predictive value for the prognosis and TIME for HCC patients. Higher ARGs Score indicated poor therapeutic response of the immunotherapy, sorafenib and TACE treatment. The ARGs Scoring model could be used as a biomarker to help physicians to develop more individualized treatment for HCC patients.

213. Liquid biopsy" - extracellular vesicles as potential novel players towards precision medicine in asthma.

Front Immunol

2022 Nov 17

Ambrożej D, Stelmaszczyk-Emmel A, Czystowska-Kuźmicz M

214. Differentially induced immunity in buccal and nasal mucosae after vaccination for SARS-CoV-2: Prospects for mass scale immunity-screening in large populations.

Front Immunol

2022 Nov 17

Tsamadou C, Ludwig C, Scholz J

Front Immunol

2022 Nov 17

Cossu D, Yokoyama K, Sato S

216. T cell-intrinsic protein kinase D3 is dispensable for the cells' activation.

Front Immunol

2022 Nov 17

Koutník J, Leitges M, Siegmund K.

217. Perturbations of the T-cell immune repertoire in kidney transplant rejection.

Front Immunol

2022 Nov 16

Sigdel TK, Fields PA, Liberto J

218. Brain-gut axis and psychiatric disorders: A perspective from bibliometric and visual analysis.

Front Immunol

2022 Nov 16

Chen P, Zhang L, Feng Y

219. Emerging insights and challenges for understanding T cell function through the proteome.

Front Immunol

2022 Nov 16

Solt LA.

220. Orofacial clefts lead to increased pro-inflammatory cytokine levels on neonatal oral mucosa.

Front Immunol

2022 Nov 16

Seidel CL, Percivalle E, Tschaftari M

221. CNS and CNS diseases in relation to their immune system.

Front Immunol

2022 Nov 16

Xu J, Ma C, Hua M

222. Multiplex flow cytometry-based assay for quantifying tumor- and virus-associated antibodies induced by immunotherapies.

Front Immunol

2022 Nov 16

Minott JA, van Vloten JP, Yates JGE

223. Microglia autophagy in ischemic stroke: A double-edged sword.

Front Immunol

2022 Nov 16

Peng L, Hu G, Yao Q

224. Indirubin combined with umbilical cord mesenchymal stem cells to relieve psoriasis-like skin lesions in BALB/c mice.

Front Immunol

2022 Nov 16

Lu X, Wang H, Wang H

OBJECTIVE: To investigate the efficacy of indirubin combined with human umbilical cord mesenchymal stem cells (hUC-MSCs) in the treatment of psoriatic lesions in BALB/c mice and to explore the related mechanism of indirubin in the treatment of psoriasis. METHODS: A BALB/c mouse psoriasis model induced by imiquimod was established and randomly divided into the control group, model group, indirubin group, hUC-MSCs group, and indirubin combined with hUC-MSCs group. Psoriasis area and severity index (PASI) score was used to observe skin lesion changes in the psoriasis-like mouse model. The epidermal scale, the degree of keratinization, and the infiltration of inflammatory cells were observed by hematoxylin eosin (HE) staining. The concentrations of TNF-α, IFN-γ, IL-17A, and IL-23 in serum of mice were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: The PASI integral trend chart indicates that hUC-MSCs and indirubin and the combination of drugs could relieve the appearance of skin lesions and accelerate the recovery of skin lesions. The indirubin group had the best effect in improving the scale of skin lesions. HE staining showed that the number of parakeratosis cells in the three treatment groups was significantly reduced, the degree of erythrocyte extravasation dermis hyperplasia and inflammatory cell infiltration was significantly lower than that in the model group, and the skin thickness and spleen index of the combined treatment group exhibited the most noticeable improvement. ELISA showed that the concentrations of TNF-α, IFN-γ, IL-17A, and IL-23 in serum of mice in the hUC-MSCs treatment group, indirubin group, and combined administration group were all decreased compared with those in the model group, and the concentrations of IFN-γ, IL-17A, and IL-23 could be decreased significantly in the indirubin group. CONCLUSIONS: Both hUC-MSCs and indirubin can effectively reduce psoriasis-like lesions in BALB/c mice, and the combined administration of these drugs has the best effect.

225. Gata3 (ZsG) and Gata3 (ZsG-fl): Novel murine Gata3 reporter alleles for identifying and studying Th2 cells and ILC2s in vivo.

Front Immunol

2022 Nov 16

Gurram RK, Wei D, Yu Q

T helper-2 (Th2) cells and type 2 innate lymphoid cells (ILC2s) play crucial roles during type 2 immune responses; the transcription factor GATA3 is essential for the differentiation and functions of these cell types. It has been demonstrated that GATA3 is critical for maintaining Th2 and ILC2 phenotype in vitro; GATA3 not only positively regulates type 2 lymphocyte-associated genes, it also negatively regulates many genes associated with other lineages. However, such functions cannot be easily verified in vivo because the expression of the markers for identifying Th2 and ILC2s depends on GATA3. Thus, whether Th2 cells and ILC2s disappear after Gata3 deletion or these Gata3-deleted "Th2 cells" or "ILC2s" acquire an alternative lineage fate is unknown. In this study, we generated novel GATA3 reporter mouse strains carrying the Gata3 ZsG or Gata3 ZsG-fl allele. This was achieved by inserting a ZsGreen-T2A cassette at the translation initiation site of either the wild type Gata3 allele or the modified Gata3 allele which carries two loxP sites flanking the exon 4. ZsGreen faithfully reflected the endogenous GATA3 protein expression in Th2 cells and ILC2s both in vitro and in vivo. These reporter mice also allowed us to visualize Th2 cells and ILC2s in vivo. An inducible Gata3 deletion system was created by crossing Gata3 ZsG-fl/fl mice with a tamoxifen-inducible Cre. Continuous expression of ZsGreen even after the Gata3 exon 4 deletion was noted, which allows us to isolate and monitor GATA3-deficient "Th2" cells and "ILC2s" during in vivo immune responses. Our results not only indicated that functional GATA3 is dispensable for regulating its own expression in mature type 2 lymphocytes, but also revealed that GATA3-deficient "ILC2s" might be much more stable in vivo than in vitro. Overall, the generation of these novel GATA3 reporters will provide valuable research tools to the scientific community in investigating type 2 immune responses in vivo.

226. An intranasal vaccine targeting the receptor binding domain of SARS-CoV-2 elicits a protective immune response.

Front Immunol

2022 Nov 16

Chen L, Zhang H, Li M

227. Tissue-resident memory T cells in the era of (Neo) adjuvant melanoma management.

Front Immunol

2022 Nov 16

Plunkett KR, Armitage JD, Inderjeeth AJ

228. A novel costimulatory molecule gene-modified leukemia cell-derived exosome-targeted CD4(+) T cell vaccine efficiently enhances anti-leukemia immunity.

Front Immunol

2022 Nov 16

Li J, Huang F, Jiang Y

Previous studies demonstrated that CD4+ T cells can uptake tumor antigen-pulsed dendritic cell-derived exosomes (DEXO), which harbor tumor antigen peptide/pMHC I complex and costimulatory molecules and show potent effects on inducing antitumor immunity. However, in preliminary study, CD4+ T cells targeted by leukemia cell-derived exosomes (LEXs) did not show the expected effects in inducing effective anti-leukemia immunity, indicating that LEX is poorly immunogenetic largely due to an inadequate costimulatory capacity. Therefore, LEX-based anti-leukemia vaccines need to be optimized. In this study, we constructed a novel LEX-based vaccine by combining CD4+ T cells with costimulatory molecules gene-modified LEXs, which harbor upregulated CD80 and CD86, and the anti-leukemia immunity of CD80 and CD86 gene-modified LEX-targeted CD4+ T cells was investigated. We used lentiviral vectors encoding CD80 and CD86 to successfully transduced the L1210 leukemia cells, and the expression of CD80 and CD86 was remarkably upregulated in leukemia cells. The LEXs highly expressing CD80 and CD86 were obtained from the supernatants of gene-transduced leukemia cells. Our data have shown that LEX-CD8086 could promote CD4+ T cell proliferation and Th1 cytokine secretion more efficiently than control LEXs. Moreover, CD4+ TLEX-CD8086 expressed the acquired exosomal costimulatory molecules. With acquired costimulatory molecules, CD4+ TLEX-CD8086 can act as APCs and are capable of directly stimulating the leukemia cell antigen-specific CD8+ CTL response. This response was higher in potency compared to that noted by the other formulations. Furthermore, the animal study revealed that the CD4+ TLEX-CD8086 significantly inhibited tumor growth and prolonged survival of tumor-bearing mice than other formulations did in both protective and therapeutic models. In conclusion, this study revealed that CD4+ TLEX-CD8086 could effectively induce more potential anti-leukemia immunity than LEX-CD8086 alone, suggesting that the utilization of a costimulatory molecule gene-modified leukemia cell-derived exosome-targeted CD4+ T cell vaccine may have promising potential for leukemia immunotherapy.

229. Editorial: The complement system in autoimmunity.

Front Immunol

2022 Nov 16

Wu EY, Alexander JJ, Fukui S.

230. The dichotomous outcomes of TNFα signaling in CD4(+) T cells.

Front Immunol

2022 Nov 16

Skartsis N, Ferreira LMR, Tang Q.

231. Diagnostic and therapeutic potential of RNASET2 in Crohn's disease: Disease-risk polymorphism modulates allelic-imbalance in expression and circulating protein levels and recombinant-RNASET2 attenuates pro-inflammatory cytokine secretion.

Front Immunol

2022 Nov 16

Biener-Ramanujan E, Rosier F, Coetzee SG

232. Recent progress and perspectives on the relationship between hyperuricemia and periodontitis.

Front Immunol

2022 Nov 16

Hou W, Xia X, Li Y

233. Circulating mitochondrial cell-free DNA dynamics in patients with mycobacterial pulmonary infections: Potential for a novel biomarker of disease.

Front Immunol

2022 Nov 15

Pan SW, Syed RR, Catanzaro DG

234. A cellular senescence-related classifier based on a tumorigenesis- and immune infiltration-guided strategy can predict prognosis, immunotherapy response, and candidate drugs in hepatocellular carcinoma.

Front Immunol

2022 Nov 15

Luo Y, Liu H, Fu H

BACKGROUND: Cellular senescence plays an irreplaceable role in tumorigenesis, progression, and tumor microenvironment (TME) remodeling. However, to date, there is limited research delineating the landscape of cellular senescence in hepatocellular carcinoma (HCC), and an improved understanding on the interaction of tumor-associated cellular senescence with HCC prognosis, TME, and response to immunotherapy is warrant. METHODS: Tumorigenic and immune infiltration-associated senescence genes were determined by weighted gene co-expression network analysis (WGCNA) and the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm, and subsequently, a prognostic scoring model (named TIS) was constructed using multiple survival analysis algorithms to classify the senescence-related subtypes of HCC. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were conducted to identify the distinct hallmark pathways between high- and low-risk subtypes. Additionally, we carried out correlation analyses for TIS and clinical traits, senescence-associated secretory phenotype (SASP), immune infiltration and evasion, immune checkpoint factors, drug response, and immunotherapeutic efficacy. External experimental validation was conducted to delineate the association of CPEP3 (a TIS gene) with HCC phenotypes through assays of proliferation, colony formation, and invasion. RESULTS: A five-gene TIS, composed of NET1, ATP6V0B, MMP1, GTDC1, and CPEB3, was constructed and validated using TCGA and ICGC datasets, respectively, and showed a highly robust and plausible signature for overall survival (OS) prediction of HCC in both training and validation cohorts. Patients in the TIS-high group were accompanied by worse OS, activation of carcinogenetic pathways, infiltration of immunosuppressive cells, exclusion of effector killing cells, overexpression of immunomodulatory genes and SASP, and unsatisfied response to immunotherapy. In response to anticancer drugs, patients in the TIS-high group exhibited enhanced susceptibility to several conventional chemotherapeutic agents (5-fluorouracil, docetaxel, doxorubicin, gemcitabine, and etoposide), as well as several inhibitors of pathways involved in cellular senescence (cell-cycle inhibitors, bromodomain and extraterminal domain family (BET) inhibitors, PI3K-AKT pathway inhibitors, and multikinase inhibitors). Additionally, four putative drugs (palbociclib, JAK3 inhibitor VI, floxuridine, and lestaurtinib) were identified as potential compounds for patients in the TIS-high group. Notably, in vitro functional validation showed that CPEB3 knockdown boosted the phenotypes of proliferation, clonogenicity, and invasion in HCC cells, whereas CPEB3 overexpression attenuated these phenotypes. CONCLUSIONS: Our study provides comprehensive clues demonstrating the role of novel TIS in predicting HCC prognosis, immunotherapeutic response, and candidate drugs. This work highlights the significance of tumorigenesis- and immune infiltration-related cellular senescence in cancer therapy.

235. CAR T-cells for colorectal cancer immunotherapy: Ready to go?

Front Immunol

2022 Nov 15

Ghazi B, El Ghanmi A, Kandoussi S

236. Constrast-enhanced computed tomography radiomics predicts CD27 expression and clinical prognosis in head and neck squamous cell carcinoma.

Front Immunol

2022 Nov 15

Wang F, Zhang W, Chai Y

237. Case report: The remarkable response of pembrolizumab combined with RC48 in the third-line treatment of metastatic urothelial carcinoma.

Front Immunol

2022 Nov 15

Xu Z, Ma J, Chen T

238. Analysis of T cell repertoires of CD45RO CD4 T cells in cohorts of patients with bullous pemphigoid: A pilot study.

Front Immunol

2022 Nov 15

Niebuhr M, Bahreini F, Fähnrich A

239. Lower dose of ATG combined with basiliximab for haploidentical hematopoietic stem cell transplantation is associated with effective control of GVHD and less CMV viremia.

Front Immunol

2022 Nov 15

Huang Z, Yan H, Teng Y

Currently, the graft-versus-host disease (GVHD) prophylaxis consists of an immunosuppressive therapy mainly based on antithymocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy). GVHD remains a major complication and limitation to successful allogeneic haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We modified the ATG-based GVHD prophylaxis with the addition of basiliximab in the setting of haplo-HSCT and attempted to explore the appropriate dosages. We conducted a retrospective analysis of 239 patients with intermediate- or high-risk hematologic malignancies who received haplo-HSCT with unmanipulated peripheral blood stem cells combined or not with bone marrow. All patients received the same GVHD prophylaxis consisting of the combination of methotrexate, cyclosporine or tacrolimus, mycofenolate-mofetil, and basiliximab with different doses of ATG (5-9mg/kg). With a median time of 11 days (range, 7-40 days), the rate of neutrophil engraftment was 96.65%. The 100-day cumulative incidences (CIs) of grade II-IV and III-IV aGVHD were 15.8 ± 2.5% and 5.0 ± 1.5%, while the 2-year CIs of total cGVHD and extensive cGVHD were 9.8 ± 2.2% and 4.1 ± 1.5%, respectively. The 3-year CIs of treatment-related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DFS) were 14.6 ± 2.6%, 28.1 ± 3.4%, 60.9 ± 3.4%, 57.3 ± 3.4%, respectively. Furthermore, the impact of the reduction of the ATG dose to 6 mg/kg or less in combination with basiliximab on GVHD prevention and transplant outcomes among patients was analyzed. Compared to higher dose of ATG(>6mg/kg), lower dose of ATG (≤6mg/kg) was associated with a significant reduced risk of CMV viremia (52.38% vs 79.35%, P<0.001), while the incidences of aGVHD and cGVHD were similar between the two dose levels. No significant effect was found with regard to the risk of relapse, TRM, and OS. ATG combined with basiliximab could prevent GVHD efficiently and safely. The optimal scheme of using this combined regimen of ATG and basiliximab is that administration of lower dose ATG (≤6mg/kg), which seems to be more appropriate for balancing infection control and GVHD prophylaxis.

240. Multiple sclerosis and obesity: The role of adipokines.

Front Immunol

2022 Nov 15

Correale J, Marrodan M.

Multiple Sclerosis (MS), a chronic inflammatory disease of the central nervous system that leads to demyelination and neurodegeneration has been associated with various environmental and lifestyle factors. Population-based studies have provided evidence showing the prevalence of MS is increasing worldwide. Because a similar trend has been observed for obesity and metabolic syndrome, interest has grown in possible underlying biological mechanisms shared by both conditions. Adipokines, a family of soluble factors produced by adipose tissue that participate in a wide range of biological functions, contribute to a low state of chronic inflammation observed in obesity, and influence immune function, metabolism, and nutritional state. In this review, we aim to describe epidemiological and biological factors common to MS and obesity, as well as provide an update on current knowledge of how different pro- and anti-inflammatory adipokines participate as immune response mediators in MS, as well as in the animal model for MS, namely, experimental autoimmune encephalomyelitis (EAE). Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination, and neurodegeneration. Although its pathogenesis is not yet fully understood, there is considerable evidence to suggest MS arises from complex interactions between individual genetic susceptibility and external environmental factors. In recent decades, population-based studies have provided evidence indicating the prevalence of MS is increasing worldwide, in parallel with the rise in obesity and metabolic syndrome. This synchronous increment in the incidence of both MS and obesity has led to a search for potential biological mechanisms linking both conditions. Notably, a large number of studies have established significant correlation between obesity and higher prevalence, or worse prognosis, of several immune-mediated conditions. Fat tissue has been found to produce a variety of soluble factors named adipokines. These mediators, secreted by both adipocytes as well as diverse immune cells, participate in a wide range of biological functions, further strengthening the concept of a link between immune function, metabolism, and nutritional state. Because obesity causes overproduction of pro-inflammatory adipokines (namely leptin, resistin and visfatin) and reduction of anti-inflammatory adipokines (adiponectin and apelin), adipose tissue dysregulation would appear to contribute to a state of chronic, low-grade inflammation favoring the development of disease. In this review, we present a summary of current knowledge related to the pathological effects of different adipokines, prevalent in obese MS patients.

241. Development and external validation of a novel nomogram model for predicting postoperative recurrence-free survival in non-muscle-invasive bladder cancer.

Front Immunol

2022 Nov 15

Ding L, Deng X, Xia W

BACKGROUND: Transurethral resection of the bladder tumor with or without adjuvant intravesical instillation (IVI) has been the standard treatment for non-muscle-invasive bladder cancer (NMIBC), whereas a high percentage of patients still experience local tumor recurrence and disease progression after receiving the standard treatment modalities. Unfortunately, current relevant prediction models for determining the recurrent and progression risk of NMIBC patients are far from impeccable. METHODS: Clinicopathological characteristics and follow-up information were retrospectively collected from two tertiary medical centers between October 2018 and June 2021. The least absolute shrinkage and selection operator (LASSO) and Cox regression analysis were used to screen potential risk factors affecting recurrence-free survival (RFS) of patients. A nomogram model was established, and the patients were risk-stratified based on the model scores. Both internal and external validation were performed by sampling the model with 1,000 bootstrap resamples. RESULTS: The study included 299 patient data obtained from the Affiliated Hospital of Xuzhou Medical University and 117 patient data obtained from the First Affiliated Hospital of Guangxi Medical University. Univariate regression analysis suggested that urine red blood cell count and different tumor invasion locations might be potential predictors of RFS. LASSO-Cox regression confirmed that prior recurrence status, times of IVI, and systemic immune-inflammation index (SII) were independent factors for predicting RFS. The area under the curve for predicting 1-, 2-, and 3-year RFS was 0.835, 0.833, and 0.871, respectively. Based on the risk stratification, patients at high risk of recurrence and progression could be accurately identified. A user-friendly risk calculator based on the model is deposited at https://dl0710.shinyapps.io/nmibc_rfs/. CONCLUSION: Internal and external validation analyses showed that our model had excellent predictive discriminatory ability and stability. The risk calculator can be used for individualized assessment of survival risk in NMIBC patients and can assist in guiding clinical decision-making.

242. Protective interaction of human phagocytic APC subsets with Cryptococcus neoformans induces genes associated with metabolism and antigen presentation.

Front Immunol

2022 Nov 15

Nelson BN, Daugherty CS, Sharp RR

Cryptococcal meningitis is the most common cause of meningitis among HIV/AIDS patients in sub-Saharan Africa, and worldwide causes over 223,000 cases leading to more than 181,000 annual deaths. Usually, the fungus gets inhaled into the lungs where the initial interactions occur with pulmonary phagocytes such as dendritic cells and macrophages. Following phagocytosis, the pathogen can be killed or can replicate intracellularly. Previous studies in mice showed that different subsets of these innate immune cells can either be antifungal or permissive for intracellular fungal growth. Our studies tested phagocytic antigen-presenting cell (APC) subsets from the human lung against C. neoformans. Human bronchoalveolar lavage was processed for phagocytic APCs and incubated with C. neoformans for two hours to analyze the initial interactions and fate of the fungus, living or killed. Results showed all subsets (3 macrophage and 3 dendritic cell subsets) interacted with the fungus, and both living and killed morphologies were discernable within the subsets using imaging flow cytometry. Single cell RNA-seq identified several different clusters of cells which more closely related to interactions with C. neoformans and its protective capacity against the pathogen rather than discrete cellular subsets. Differential gene expression analyses identified several changes in the innate immune cell's transcriptome as it kills the fungus including increases of TNF-α (TNF) and the switch to using fatty acid metabolism by upregulation of the gene FABP4. Also, increases of TNF-α correlated to cryptococcal interactions and uptake. Together, these analyses implicated signaling networks that regulate expression of many different genes - both metabolic and immune - as certain clusters of cells mount a protective response and kill the pathogen. Future studies will examine these genes and networks to understand the exact mechanism(s) these phagocytic APC subsets use to kill C. neoformans in order to develop immunotherapeutic strategies to combat this deadly disease.

243. Neutrophils inhibit γδ T cell functions in the imiquimod-induced mouse model of psoriasis.

Front Immunol

2022 Nov 15

Costa S, Bevilacqua D, Caveggion E

244. SRSF1 acts as an IFN-I-regulated cellular dependency factor decisively affecting HIV-1 post-integration steps.

Front Immunol

2022 Nov 15

Sertznig H, Roesmann F, Wilhelm A

Efficient HIV-1 replication depends on balanced levels of host cell components including cellular splicing factors as the family of serine/arginine-rich splicing factors (SRSF, 1-10). Type I interferons (IFN-I) play a crucial role in the innate immunity against HIV-1 by inducing the expression of IFN-stimulated genes (ISGs) including potent host restriction factors. The less well known IFN-repressed genes (IRepGs) might additionally affect viral replication by downregulating host dependency factors that are essential for the viral life cycle; however, so far, the knowledge about IRepGs involved in HIV-1 infection is very limited. In this work, we could demonstrate that HIV-1 infection and the associated ISG induction correlated with low SRSF1 levels in intestinal lamina propria mononuclear cells (LPMCs) and peripheral blood mononuclear cells (PBMCs) during acute and chronic HIV-1 infection. In HIV-1-susceptible cell lines as well as primary monocyte-derived macrophages (MDMs), expression levels of SRSF1 were transiently repressed upon treatment with specific IFNα subtypes in vitro. Mechanically, 4sU labeling of newly transcribed mRNAs revealed that IFN-mediated SRSF1 repression is regulated on early RNA level. SRSF1 knockdown led to an increase in total viral RNA levels, but the relative proportion of the HIV-1 viral infectivity factor (Vif) coding transcripts, which is essential to counteract APOBEC3G-mediated host restriction, was significantly reduced. In the presence of high APOBEC3G levels, however, increased LTR activity upon SRSF1 knockdown facilitated the overall replication, despite decreased vif mRNA levels. In contrast, SRSF1 overexpression significantly impaired HIV-1 post-integration steps including LTR transcription, alternative splice site usage, and virus particle production. Since balanced SRSF1 levels are crucial for efficient viral replication, our data highlight the so far undescribed role of SRSF1 acting as an IFN-modulated cellular dependency factor decisively regulating HIV-1 post-integration steps.

245. MSCs interaction with the host lung microenvironment: An overlooked aspect?

Front Immunol

2022 Nov 15

Weiss DJ, Rolandsson Enes S.

246. The β-carboline Harmine improves the therapeutic benefit of anti-PD1 in melanoma by increasing the MHC-I-dependent antigen presentation.

Front Immunol

2022 Nov 15

Noman MZ, Bocci IA, Karam M

247. Harnessing the small intestinal axis to resolve systemic inflammation.

Front Immunol

2022 Nov 15

Bodmer M, Itano A, McInnes I.

248. Understanding AL amyloidosis with a little help from in vivo models.

Front Immunol

2022 Nov 15

Martinez-Rivas G, Bender S, Sirac C.

249. Nectin4 is a potential therapeutic target for asthma.

Front Immunol

2022 Nov 15

Lee PH, Choi SM, An MH

250. Mouse models of lung-specific SARS-CoV-2 infection with moderate pathological traits.

Front Immunol

2022 Nov 15

Kim SH, Kim J, Jang JY

251. Case report: Novel FHR2 variants in atypical Hemolytic Uremic Syndrome: A case study of a translational medicine approach in renal transplantation.

Front Immunol

2022 Nov 14

Stea ED, Skerka C, Accetturo M

Atypical hemolytic-uremic syndrome (aHUS) is a severe thrombotic microangiopathy in which kidney involvement is common. aHUS can be due to either genetic or acquired abnormalities, with most abnormalities affecting the alternative complement pathway. Several genetic factors/alterations can drive the clinical presentation, therapeutic response, and risk of recurrence, especially recurrence following kidney transplantation. We report here the case of a 22-year-old man who developed a severe form of aHUS. Renal biopsy revealed thrombotic microangiopathy and features of chronic renal damage. Despite two eculizumab infusions, the patient remained dialysis dependent. Two novel rare variants, c.109G>A (p.E37K) and c.159 C>A (p.Y53*), were identified in the factor H-related 2 (FHR2) gene, and western blot analysis revealed a significant reduction in the level of FHR2 protein in the patient's serum. Although FHR2 involvement in complement 3 glomerulopathy has been reported previously, a role for FRH2 as a complement modulator has not yet been definitively shown. In addition, no cases of aHUS in individuals with FHR2 variants have been reported. Given the role of FHRs in the complement system and the fact that this patient was a candidate for a kidney transplant, we studied the relevance of low FHR2 plasma levels through a set of functional in vitro assays. The aim of our work was to determine if low FHR2 plasma levels could influence complement control at the endothelial surface with a view to identifying a therapeutic approach tailored to this specific patient. Interestingly, we observed that low FHR2 levels in the patient's serum could induce complement activation, as well as C5b-9 deposition on human endothelial cells, and affected cell morphology. As C5b-9 deposition is a prerequisite for endothelial cell damage, these results suggest that extremely low FHR2 plasma levels increase the risk of aHUS. Given their ability to reduce C5b-9 deposition, recombinant FHR2 and eculizumab were tested in vitro and found to inhibit hemolysis and endothelial cell surface damage. Both molecules showed effective and comparable profiles. Based on these results, the patient underwent a kidney transplant, and received eculizumab as induction and maintenance therapy. Five years after transplantation, the patient remains in good general health, with stable graft function and no evidence of disease recurrence. To our knowledge, this is first reported case of an aHUS patient carrying FHR2 mutations and provides an example of a translational therapeutic approach in kidney transplantation.

252. Waning of specific antibodies against Delta and Omicron variants five months after a third dose of BNT162b2 SARS-CoV-2 vaccine in elderly individuals.

Front Immunol

2022 Nov 14

Goh YS, Rouers A, Fong SW

Author information: (1)ASTAR Infectious Diseases Labs (ASTAR ID Labs), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore. (2)Singapore Immunology Network, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore. (3)Bioinformatics Institute, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore. (4)Global Data Science Initiative (GISAID), Munich, Germany. (5)Infectious Diseases, Ng Teng Fong General Hospital, Singapore, Singapore. (6)Infectious Diseases, Alexandra Hospital, Singapore, Singapore. (7)National University Polyclinic, Singapore, Singapore. (8)Division of Infectious Diseases, Department of Medicine, National University Hospital, National University Health System, Singapore, Singapore. (9)Clinical Research Unit, National Healthcare Group Polyclincs, Singapore, Singapore. (10)Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. (11)National Public Health Laboratory, National Centre for Infectious Diseases (NCID), Singapore, Singapore. (12)Department of Biological Sciences, National University of Singapore, Singapore, Singapore. (13)National Centre for Infectious Diseases (NCID), Singapore, Singapore. (14)Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore, Singapore. (15)Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore. (16)Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (17)Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (18)National Institute of Health Research, Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, United Kingdom. (19)Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom. (20)School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.

253. Increased peripheral inflammatory responses in myelin oligodendrocyte glycoprotein associated disease and aquaporin-4 antibody positive neuromyelitis optica spectrum disorder.

Front Immunol

2022 Nov 14

Bauer A, Rudzki D, Berek K

Autoantibody-associated demyelinating diseases of the central nervous system such as myelin oligodendrocyte glycoprotein-antibody associated disease (MOGAD) and aquaporin 4-antibody positive neuromyelitis optica spectrum disorders (AQP4+ NMOSD) are rare diseases but can cause severe disability. In both diseases, associated neuroinflammation is accompanied by blood and cerebrospinal fluid cytokine and chemokine signatures, which were shown to be distinct from those observed in patients with multiple sclerosis (MS). In this study, we aimed to confirm and extend these findings by analyzing a larger number of serum cytokines, chemokines and related molecules in patients with MOGAD or AQP4+ NMOSD in comparison to MS, to better understand the pathophysiology and to identify biomarkers potentially useful in clinical practice for diagnostic and treatment purposes. A total of 65 serum cytokines, chemokines and related molecules like growth factors and soluble receptors were measured by Procartaplex multiplex immunoassays in 40 MOGAD, 40 AQP4+ NMOSD and 54 MS patients at baseline. Furthermore, follow-up samples of 25 AQP4+ NMOSD and 40 MOGAD patients were measured after 6-12 months. Selected analytes were validated in a subgroup of samples using other bead-based assays and ELISA. At baseline, 36 analytes in MOGAD and 30 in AQP4+ NMOSD were significantly increased compared to MS. K-means cluster analysis of all significantly altered molecules revealed three distinct groups: Cluster I, including 12 MOGAD, 2 AQP4+ NMOSD and 3 MS patients, had a specific association with 11 IL-6/IL-17A associated cytokines. In this cluster, 9/17 (53%) patients were children. Cluster II with 13 MOGAD, 24 AQP4+ NMOSD and 1 MS patient was associated with 31 upregulated analytes. Cluster III contained 15 MOGAD, 14 AQP4+ NMOSD and 50 MS patients. In cluster II and III the majority were adults (82% and 92%). Most measured analytes remained stable over time. Validation of selected cytokines and chemokines using other analytical methods revealed moderate to high correlation coefficients, but absolute values differed between assays. In conclusion, these results obtained by bead-based multiplex assays highlight a significant association of biomarkers of peripheral inflammation in patients with antibody-associated demyelinating diseases in comparison with MS.

254. C-Reactive Protein (CRP): A poor prognostic biomarker in COVID-19.

Front Immunol

2022 Nov 14

Bouayed MZ, Laaribi I, Chatar CEM

INTRODUCTION: The COVID-19 pandemic continues to be rampant with considerable morbidity and mortality worldwide since its emergence in December 2019. Several studies have focused on identifying different predictive factors of poor prognosis, including biological markers, such as C Reactive Protein among others. The objective of our work was to determine whether the CRP levels on admission to the intensive care unit are predictive of an unfavorable evolution of patients with COVID-19 through the experience of the Anesthesia and Intensive Care Unit of the University Hospital of Oujda and to compare our results with those reported in the literature. METHODS: We conducted a retrospective, monocentric, descriptive and analytical study in the Department of Anesthesia and Intensive Care of the Mohammed VI University Hospital of Oujda, Morocco, between March 2020 and October 2021, including all critically ill patients admitted to the department during this period and meeting the inclusion criteria. The baseline admission CRP value was arbitrarily set at 100mg/d, thus conditioning the division of our patients into two groups (group 1: CRP < 100mg/L, group 2: CRP ≥ 100mg/L). RESULTS: Among our 1035 included patients, 291 patients with had a CRP<100mlg/L (group 1) and 744 presented a CRP level equal or superior to 100mg/L (group 2). Lung parenchymal involvement was more severe or even critical (CT involvement > 75%) in group 2 (60.8%) compared to group 1 (39.2%). In group 2, 79.8% of patients were mechanically ventilated, compared to 20.2% of patients in group 1. Finally, the mortality rate in patients with a CRP ≥ 100mg/l was 77.4%, compared with 22.6% for patients with a CRP < 100mg/l. These findings are all statistically highly significant (p<0.001). CONCLUSION: Given the high contagiousness of the virus and the emergence of several variants, the management of the COVID-19 pandemic has focused more on prevention through vaccination against the virus, but also on an early identification of patients likely to evolve unfavorably for a personalized management.

255. Oncolytic vaccinia virus expressing a bispecific T-cell engager enhances immune responses in EpCAM positive solid tumors.

Front Immunol

2022 Nov 14

Wei M, Zuo S, Chen Z

256. A novel cuproptosis-related lncRNA signature predicts the prognosis and immune landscape in bladder cancer.

Front Immunol

2022 Nov 14

Bai Y, Zhang Q, Liu F

BACKGROUND: Bladder cancer (BLCA) is one of the deadliest diseases, with over 550,000 new cases and 170,000 deaths globally every year. Cuproptosis is a copper-triggered programmed cell death and is associated with the prognosis and immune response of various cancers. Long non-coding RNA (lncRNA) could serve as a prognostic biomarker and is involved in the progression of BLCA. METHODS: The gene expression profile of cuproptosis-related lncRNAs was analyzed by using data from The Cancer Genome Atlas. Cox regression analysis and least absolute shrinkage and selection operator analysis were performed to construct a cuproptosis-related lncRNA prognostic signature. The predictive performance of this signature was verified by ROC curves and a nomogram. We also explored the difference in immune-related activity, tumor mutation burden (TMB), tumor immune dysfunction and exclusion (TIDE), and drug sensitivity between the high- and low-risk groups. RESULTS: We successfully constructed a cuproptosis-related lncRNA prognostic signature for BLCA including eight lncRNAs (RNF139-AS1, LINC00996, NR2F2-AS1, AL590428.1, SEC24B-AS1, AC006566.1, UBE2Q1-AS1, and AL021978.1). Multivariate Cox analysis suggested that age, clinical stage, and risk score were the independent risk factors for predicting prognosis of BLCA. Further analysis revealed that this signature not only had higher diagnostic efficiency compared to other clinical features but also had a good performance in predicting the 1-year, 3-year, and 5-year overall survival rate in BLCA. Notably, BLCA patients with a low risk score seemed to be associated with an inflamed tumor immune microenvironment and had a higher TMB level than those with a high risk score. In addition, patients with a high risk score had a higher TIDE score and a higher half maximal inhibitory concentration value of many therapeutic drugs than those with a low risk score. CONCLUSION: We identified a novel cuproptosis-related lncRNA signature that could predict the prognosis and immune landscape of BLCA.

257. Prognostic peripheral blood biomarkers at ICU admission predict COVID-19 clinical outcomes.

Front Immunol

2022 Nov 14

Messing M, Sekhon MS, Hughes MR

258. Platelet in thrombo-inflammation: Unraveling new therapeutic targets.

Front Immunol

2022 Nov 14

Sharma S, Tyagi T, Antoniak S.

In the broad range of human diseases, thrombo-inflammation appears as a clinical manifestation. Clinically, it is well characterized in context of superficial thrombophlebitis that is recognized as thrombosis and inflammation of superficial veins. However, it is more hazardous when developed in the microvasculature of injured/inflamed/infected tissues and organs. Several diseases like sepsis and ischemia-reperfusion can cause formation of microvascular thrombosis subsequently leading to thrombo-inflammation. Thrombo-inflammation can also occur in cases of antiphospholipid syndrome, preeclampsia, sickle cell disease, bacterial and viral infection. One of the major contributors to thrombo-inflammation is the loss of normal anti-thrombotic and anti-inflammatory potential of the endothelial cells of vasculature. This manifest itself in the form of dysregulation of the coagulation pathway and complement system, pathologic platelet activation, and increased recruitment of leukocyte within the microvasculature. The role of platelets in hemostasis and formation of thrombi under pathologic and non-pathologic conditions is well established. Platelets are anucleate cells known for their essential role in primary hemostasis and the coagulation pathway. In recent years, studies provide strong evidence for the critical involvement of platelets in inflammatory processes like acute ischemic stroke, and viral infections like Coronavirus disease 2019 (COVID-19). This has encouraged the researchers to investigate the contribution of platelets in the pathology of various thrombo-inflammatory diseases. The inhibition of platelet surface receptors or their intracellular signaling which mediate initial platelet activation and adhesion might prove to be suitable targets in thrombo-inflammatory disorders. Thus, the present review summarizes the concept and mechanism of platelet signaling and briefly discuss their role in sterile and non-sterile thrombo-inflammation, with the emphasis on role of platelets in COVID-19 induced thrombo-inflammation. The aim of this review is to summarize the recent developments in deciphering the role of the platelets in thrombo-inflammation and discuss their potential as pharmaceutical targets.

259. Immunomodulatory effects of two recombinant arginine kinases in Sarcoptes Scabiei on host peripheral blood mononuclear cells.

Front Immunol

2022 Nov 14

Xu Y, Xu Z, Gu X

260. Autoantibodies as biomarkers for breast cancer diagnosis and prognosis.

Front Immunol

2022 Nov 14

Yang R, Han Y, Yi W

261. Characterization of immune checkpoint inhibitor-associated fulminant type 1 diabetes associated with autoantibody status and ethnic origin.

Front Immunol

2022 Nov 14

Qiu J, Luo S, Yin W

262. Dynamics of humoral immune response in SARS-CoV-2 infected individuals with different clinical stages.

Front Immunol

2022 Nov 14

Mendez-Cortina Y, Rodriguez-Perea AL, Chvatal-Medina M

BACKGROUND: The COVID-19 pandemic remains a global health problem. As in other viral infections, the humoral immune response against SARS-CoV-2 is thought to be crucial for controlling the infection. However, the dynamic of B cells in the clinical spectrum of this disease is still controversial. This study aimed to characterize B cell subsets and neutralizing responses in COVID-19 patients according to disease severity through a one-month follow-up. METHODS: A cohort of 71 individuals with SARS-CoV-2 infection confirmed by RT-PCR were recruited and classified into four groups: i) asymptomatic; ii) symptomatic outpatients; iii) hospitalized in ward, and iv) intensive care unit patients (ICU). Samples were taken at days 0 (inclusion to the study), 7 and 30. B cell subsets and neutralizing antibodies were assessed using multiparametric flow cytometry and plaque reduction neutralization, respectively. RESULTS: Older age, male gender and body mass index over 25 were common factors among hospitalized and ICU patients, compared to those with milder clinical presentations. In addition, those requiring hospitalization had more comorbidities. A significant increase in the frequencies of CD19+ cells at day 0 was observed in hospitalized and ICU patients compared to asymptomatic and symptomatic groups. Likewise, the frequency of plasmablasts was significantly increased at the first sample in the ICU group compared to the asymptomatic group, but then waned over time. The frequency of naïve B cells decreased at days 7 and 30 compared to day 0 in hospitalized and ICU patients. The neutralizing antibody titers were higher as the severity of COVID-19 increased; in asymptomatic individuals, it was strongly correlated with the percentage of IgM+ switched memory B cells, and a moderate correlation was found with plasmablasts. CONCLUSION: The humoral immune response is variable among SARS-CoV-2 infected people depending on the severity and time of clinical evolution. In severe COVID-19 patients, a higher plasmablast frequency and neutralizing antibody response were observed, suggesting that, despite having a robust humoral immunity, this response could be late, having a low impact on disease outcome.

263. Potential biomarkers: Identifying powerful tumor specific T cells in adoptive cellular therapy.

Front Immunol

2022 Nov 14

Ge W, Dong Y, Deng Y

264. Pilot genome-wide association study of antibody response to inactivated SARS-CoV-2 vaccines.

Front Immunol

2022 Nov 14

Li P, Shi D, Shen W

265. Challenges in diagnostic testing of nephritic factors.

Front Immunol

2022 Nov 14

Michels MAHM, Volokhina EB, van de Kar NCAJ

266. Burn-injured skin is marked by a prolonged local acute inflammatory response of innate immune cells and pro-inflammatory cytokines.

Front Immunol

2022 Nov 14

Mulder PPG, Vlig M, Fasse E

267. Comparative study of subcutaneous, intramuscular, and oral administration of bovine pathogenic Escherichia coli bacterial ghost vaccine in mice.

Front Immunol

2022 Nov 14

Mu J, Lei L, Zheng Y

Escherichia coli is one of the most common bacterial pathogens in cattle. Prophylactic vaccines are considered promising strategies with the potential to reduce the incidence of colibacillosis. Some studies suggested that bacterial ghosts may serve as a novel approach for preventing bacterial infections. However, the roles of administration route on vaccine immunogenicity and efficacy have not been investigated. In this study, the efficacy of vaccination via different immune routes in generating humoral and cellular immune response was compared through subcutaneous (SC), intramuscular (IM), and oral (O) administration in female BALB/c mice with bacterial ghosts prepared using wild type Escherichia coli isolates CE9, while phosphate buffer saline (PBS) and inactivated vaccines containing aluminum adjuvants (Killed) were used as control. Our results showed that the plasmid pBV220-E-aa-SNA containing E. coli was efficiently cleaved at 42°C with 94.8% positive ratio as assessed by colony counts. Transmission electron microscopy (TEM) confirmed bacteria retained intact surface structure while devoid of cytoplasmic component. We found that total IgG titers in killed, IM and SC groups showed significant increase on 7, 14, 21 and 28 days post-immunization. The IgA level of the IM group was higher than that of all other groups on the 28th day. Meanwhile, four experimental groups showed a significant difference in IgA levels compared with PBS control. In the IM group, an increase in the relative percentages of CD3+CD4+ T cells was accompanied by an increase in the relative percentages of splenic CD3+CD8+ T cells. In comparison with the inactivated vaccine, intramuscular CE9 ghosts immunization elicited higher levels of IL-1β, IL-2, IL-6 and IL-12. Subcutaneous and intramuscular immunizations were significantly associated with improved survival in comparison with oral route, traditional vaccine and the control. Pathologic assessment revealed that less severe tissue damage and inflammation were found in lung, kidney, and intestine of IM group compared with other groups. The results above demonstrate that immunization of Escherichia coli CE9 ghosts via intramuscular injection elicits a more robust antigen-specific immune response in mice to prevent the Escherichia coli infection.

268. Extracellular vesicle-derived miRNAs improve stem cell-based therapeutic approaches in muscle wasting conditions.

Front Immunol

2022 Nov 14

Yedigaryan L, Martínez-Sarrà E, Giacomazzi G

269. PD-L1 is upregulated in CD163+ tonsillar macrophages from children undergoing EBV primary infection.

Front Immunol

2022 Nov 14

Moyano A, Ferressini N, De Matteo E

270. A minimally-edited mouse model for infection with multiple SARS-CoV-2 strains.

Front Immunol

2022 Nov 14

Nakandakari-Higa S, Parsa R, Reis BS

271. Tailoring biomaterials and applications targeting tumor-associated macrophages in cancers.

Front Immunol

2022 Nov 11

Jing F, Liu X, Chen X

272. Integrating RNA-seq and scRNA-seq to explore the biological significance of NAD + metabolism-related genes in the initial diagnosis and relapse of childhood B-cell acute lymphoblastic leukemia.

Front Immunol

2022 Nov 11

Lin C, Xu JQ, Zhong GC

BACKGROUND: Nicotinamide Adenine Dinucleotide (NAD) depletion is reported to be a potential treatment for B-cell Acute Lymphoblastic Leukemia (B-ALL), but the mechanism of NAD metabolism-related genes (NMRGs) in B-ALL relapse remains unclear. METHODS: Transcriptome data (GSE3912), and single-cell sequencing data (GSE130116) of B-ALL patients were downloaded from Gene Expression Omnibus (GEO) database. NMRGs were sourced from Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases. Further, the differentially expressed NMRGs (DE-NMRGs) were selected from the analysis between initial diagnosis and relapse B-ALL samples, which further performed functional enrichment analyses. The biomarkers were obtained through random forest (RF) algorithm and repeated cross validation. Additionally, cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm was used to evaluate the immune cell differences between the initial diagnosis and relapse samples, and the correlations between biomarkers and gene markers of differential immune cells were analyzed. Furthermore, single cell RNA sequencing was conducted in the GSE130116 dataset to find key cell clusters. In addition, according to biomarkers expressions, cell clusters were categorized into high and low biomarker expression groups, and Gene Set Enrichment Analysis (GSEA) analysis was performed on them. Finally, the cell clusters with the highest expression of biomarkers were selected to explore the roles of biomarkers in different cell clusters and identify transcription factors (TFs) influencing biological markers. RESULTS: 23 DE-NMRGs were screened out, which were mainly enriched in nucleoside phosphate metabolic process, nucleotide metabolic process, and Nicotinate and nicotinamide metabolism. Moreover, 3 biomarkers (NADSYN1, SIRT3, and PARP6) were identified from the machine learning. CIBERSORT results demonstrated that four types of immune cells (B Cells naive, Monocyte, Neutrophils, and T cells CD4 memory Activated) were significantly different between the initial diagnosis and the relapse B-ALL samples, and there were strong correlations between biomarkers and differential immune cells such as positive correlation between NADSYN1 and B Cells naive. The single cell analyses showed that the biomarkers were highly expressed in common myeloid progenitors (CMP), granulocyte-macrophage progenitor (GMP), and megakaryocyte-erythroid progenitor (MEP) cell clusters. Gene set enrichment analysis (GSEA) results indicated that 55 GO terms and 3 KEGG pathways were enriched by the genes in high and low biomarker expression groups. It was found that TF CREB3L2(+) was significantly reduced in the high expression group, which may be the TF affecting biomarkers in the high expression group. CONCLUSION: This study identified NADSYN1, SIRT3, and PARP6 as the biomarkers of B-ALL, explored biological significance of NMRGs in the initial diagnosis and relapse of B-ALL, and revealed mechanism of biomarkers at the level of the single cell.

273. Real-world landscape transition of death causes in the immunotherapy era for metastatic non-small cell lung cancer.

Front Immunol

2022 Nov 11

Wu Y, Yao Z, Zhang J

274. Implication of platelets and complement C3 as link between innate immunity and tubulointerstitial injury in renal vasculitis with MPO-ANCA seropositivity.

Front Immunol

2022 Nov 11

Baier E, Tampe D, Kluge IA

INTRODUCTION: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a potentially life-threatening systemic small-vessel vasculitis that is characterized by pauci-immune glomerulonephritis, depicting in turn a major denominator of AAV mortality. It is well established that AAV patients feature an increased risk of developing thrombotic events, and platelets are activated in AAV patients being triggered by the alternative complement pathway. Platelets guard vessels integrity and initiate thrombus formation in response to endothelial damage, further constituting a triangular interconnection with the activation of neutrophils and the complement system. We here aimed to systematically assess the relevance of platelet counts and systemic complement system activation regarding distinct histopathological lesions in ANCA-associated renal vasculitis. METHODS: A cohort of 53 biopsy-proven cases of ANCA-associated renal vasculitis were retrospectively enrolled in a single-center observational study. Univariate and multivariate regression analysis was performed to identify parameters associated with platelet counts in ANCA-associated renal vasculitis compared to disease controls. Finally, the relevance of platelets for disease course and recovery was assessed by survival analysis. RESULTS: Lower platelet counts correlated with markers of kidney injury including eGFR loss (p=0.0004) and lower complement C3 levels (p=0.0037). Multivariate and subgroup analysis revealed that this association was only present in the subgroup with MPO-ANCA seropositivity (eGFR loss: p=0.0009, lower C3: p=0.0032). While lower platelet counts correlated with kidney injury in the PR3-ANCA subgroup (eGFR loss: p=0.0272), we did not observe an independent association with complement C3 levels (p=0.4497). Independent of any glomerular lesion, lower platelet counts correlated with interstitial fibrosis (p=0.0313), tubular atrophy (p=0.0073), and tubulitis in areas of interstitial fibrosis and tubular atrophy (p=0.0033). Finally, we observed significant differences with increased requirement of kidney replacement therapy (KRT) or death in the subgroup below median platelet counts (HR: 4.1, 95% CI: 1.6-10, p=0.0047), associated with a lower probability of discharge and prolonged hospitalization in this subgroup (HR: 0.5, 95% CI: 0.3-0.9, p=0.0113). CONCLUSION: Based on our observation that an association between platelets and complement system activation is only observed in the MPO-ANCA subgroup, this could implicate that platelets and complement C3 link innate immunity to tubulointerstitial injury in the presence of MPO-ANCA autoantibodies.

275. Vedolizumab for acute gastrointestinal graft-versus-host disease: A systematic review and meta-analysis.

Front Immunol

2022 Nov 11

Li AC, Dong C, Tay ST

OBJECTIVE: To determine the safety and efficacy of vedolizumab for the prophylaxis and treatment of gastrointestinal involvement of acute graft-versus-host disease (GVHD) (GI-aGVHD). METHODS: Literature search within PubMed, EMBASE, Web of Science, and Cochrane Library for observational studies and clinical trials that evaluated the effect of vedolizumab on GI-aGVHD was done through 17 May 2022. A bivariate and random-effect meta-analysis derived the pooled observational percentages and pooled risk ratios (RRs) from baseline of primary endpoints including overall response, complete response, mortality, and adverse events. RESULTS: There was a total of 122 participants in eight eligible studies, including one study on the prophylactic use of vedolizumab and seven studies on vedolizumab for the treatment of GI-aGVHD. Of seven studies that reported details on baseline grades of GI-aGVHD, a total of 47 patients (47.95%) were of stage 4, 31 patients (31.63%) were of stage 3, 10 patients (10.2%) were of stage 2, and 10 patients (10.2%) were of stage 1. The use of vedolizumab for the treatment of GI-aGVHD yielded a significantly improved objective response rate (ORR) at 14 days (pooled ORR = 60.53%, pooled RR = 14.14, 95% CI: 2.95-67.71), 28 days (pooled ORR = 50%, RR = 7.36, 95% CI = 2.14-25.37), and 12 months (pooled ORR = 76.92%, RR = 13.66, 95% CI = 3.5-53.35) from baseline. Likewise, the use of vedolizumab was followed by a significantly improved complete response (CR) at 12 months (pooled CR = 27.27%, RR = 5.50, 95% CI = 1.01-29.95), yet the CR at 14 days and 28 days did not reach statistical significance. Fifty-seven out of 87 (pooled overall survival, OS = 34.5%) and 46 out of 65 (pooled OS = 29.2%) patients expired at 6 and 12 months after the use of vedolizumab, respectively. Prophylactic use of vedolizumab was not associated with any specific type of reported adverse events, while patients with GI-aGVHD on vedolizumab presented with significantly increased risks of adverse events including infections (RR = 7.55) and impaired metabolism or nutritional complications (RR = 9.00). All analyses were of a low heterogeneity (all I-squares = 0%). CONCLUSION: Vedolizumab was safe and effective for the prophylaxis and management of early grade GI-aGVHD. More clinical evidence is warranted to validate these findings. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=345584, identifier CRD42022345584.

276. Comparison of the frequency and phenotypic profile of Mycobacterium tuberculosis-specific CD4 T cells between the site of disease and blood in pericardial tuberculosis.

Front Immunol

2022 Nov 11

Du Bruyn E, Ruzive S, Howlett P

277. Inhibition of the CD47-SIRPα axis for cancer therapy: A systematic review and meta-analysis of emerging clinical data.

Front Immunol

2022 Nov 11

Son J, Hsieh RC, Lin HY

CD47-SIRPα interaction acts as a "don't eat me" signal and is exploited by cancer to downregulate innate and adaptive immune surveillance. There has been intense interest to develop a mechanism of blockade, and we aimed to analyze the emerging data from early clinical trials. We performed a systematic review and meta-analysis of relevant databases and conference abstracts including clinical trials using CD47 and/or SIRPα inhibitors in cancer treatment. Nonlinear mixed models were applied for comparison of response and toxicity. We retrieved 317 articles, 24 of which were eligible. These included 771 response-evaluable patients with hematologic (47.1%) and solid tumors (52.9%). Of these, 6.4% experienced complete response, 10.4% partial response, and 26.1% stable disease for a 16.7% objective response rate (ORR), 42.8% disease control rate, and 4.8-month median duration of response. ORR was significantly higher for hematologic cancers (25.3%) than solid cancers (9.1%, p=0.042). Comparing by mechanism, seven CD47 monoclonal antibodies (mAbs) and six selective SIRPα blockers were given alone or combined with checkpoint inhibitors, targeted therapy, and/or chemotherapy. In solid cancers, selective SIRPα blockade showed a higher ORR (16.2%) than anti-CD47 mAbs (2.8%, p=0.079), which was significant for combination therapies (ORR 28.3% vs 3.0%, respectively, p=0.010). Responses were seen in head and neck, colorectal, endometrial, ovarian, hepatocellular, non-small cell lung, and HER2+gastroesophageal cancers. Dose-limiting toxicity (DLT) was seen in 3.3% of patients (5.4% anti-CD47 mAbs, 1.4% selective SIRPα blockers; p=0.01). The frequency of treatment-related adverse events (TRAEs) ≥grade 3 was 18.0%, similar between the two groups (p=0.082), and mostly laboratory abnormalities. For anti-CD47 mAbs, the most common toxicities included grade 1-2 fatigue (27.2%), headache (21.0%), and anemia (20.5%). For selective SIRPα blockers, these included grade 1-2 infusion reaction (23.1%) and fatigue (15.8%). Anti-CD47 mAbs were significantly more likely than selective SIRPα blockers to cause grade 1-2 fever, chills, nausea/vomiting, headache, and anemia. In conclusion, combination therapies using selective SIRPα blockade had higher response rates in solid tumors than anti-CD47 mAb combinations. Hematologic changes were the main TRAEs, and selective SIRPα blockers seemed to have a better grade 1-2 toxicity profile. Treatment was well-tolerated with minimal DLTs.

278. Efficacy and safety of copanlisib in relapsed/refractory B-cell non-Hodgkin lymphoma: A meta-analysis of prospective clinical trials.

Front Immunol

2022 Nov 11

Wang J, Zhou H, Mu M

BACKGROUND: Copanlisib is an intravenously administered pan-class I PI3K inhibitor that has been demonstrated to have appreciable effects in the treatment of patients with lymphoma. The purpose of this meta-analysis was to evaluate the efficacy and safety of copanlisib for treating patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). METHODS: PubMed, Web of Science, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for relevant studies published prior to July 2022. The efficacy evaluation included complete response rate (CR), partial response rate (PR), rate of stable disease (SDR), overall response rate (ORR), disease control rate (DCR), rate of progressive disease (PDR), median progression-free survival (PFS), and median overall survival (OS). Any grade adverse events (AEs) and grade ≥3 AEs were synthesized to assess its safety. RESULTS: Eight studies with a total of 652 patients with R/R B-NHL were identified. The pooled CR, PR, ORR, SDR, DCR, and PDR from all 8 articles were 13%, 40%, 57%, 19%, 86%, and 9%, respectively. The CR and ORR of combination therapy with rituximab were higher than those with copanlisib monotherapy for R/R B-NHL (34% vs. 6%, p<0.01; 89% vs. 42%, p<0.01). For patients with R/R indolent B-NHL, CR and ORR were lower with copanlisib monotherapy than with combination therapy with rituximab (7% vs. 34%, p<0.01; 58% vs. 92%, p<0.01). In R/R B-NHL patients receiving copanlisib monotherapy and combination therapy with rituximab, the risk of any grade AEs was 99% and 96%, respectively, and the risk of grade ≥3 AEs was 84% and 91%, respectively. The common any grade AEs included hyperglycemia (66.75%), hypertension (48.57%), diarrhea (35.06%), nausea (34.98%) and fatigue (30.33%). The common grade ≥3 AEs included hyperglycemia (45.14%), hypertension (35.07%), and neutropenia (14.75%). The comparison of AEs between the copanlisib monotherapy and the combination therapy with rituximab showed that hyperglycemia of any grade (p<0.0001), hypertension of any grade (p=0.0368), fatigue of any grade (p<0.0001), grade ≥3 hypertension (p<0.0001) and grade ≥3 hyperglycemia (p=0.0074) were significantly different between the two groups. CONCLUSION: Our meta-analysis demonstrated that the efficacy of both copanlisib monotherapy and combination therapy with rituximab in patients with R/R B-NHL was satisfactory, while treatment-related AEs were tolerable. Compared with copanlisib monotherapy, combination therapy with rituximab showed superior efficacy for treating R/R B-NHL, and its safety was manageable. SYSTEMATIC REVIEW REGISTRATION: https://inplasy.com/inplasy-2022-10-0008/, identifier INPLASY2022100008.

279. Impact of selenium on the intestinal microbiome-eCBome axis in the context of diet-related metabolic health in mice.

Front Immunol

2022 Nov 11

Guevara Agudelo FA, Leblanc N, Bourdeau-Julien I

Dietary micronutrients act at the intestinal level, thereby influencing microbial communities, the host endocannabinoidome, and immune and anti-oxidative response. Selenium (Se) is a trace element with several health benefits. Indeed, Se plays an important role in the regulation of enzymes with antioxidative and anti-inflammatory activity as well as indicators of the level of oxidative stress, which, together with chronic low-grade inflammation, is associated to obesity. To understand how Se variations affect diet-related metabolic health, we fed female and male mice for 28 days with Se-depleted or Se-enriched diets combined with low- and high-fat/sucrose diets. We quantified the plasma and intestinal endocannabinoidome, profiled the gut microbiota, and measured intestinal gene expression related to the immune and the antioxidant responses in the intestinal microenvironment. Overall, we show that intestinal segment-specific microbiota alterations occur following high-fat or low-fat diets enriched or depleted in Se, concomitantly with modifications of circulating endocannabinoidome mediators and changes in cytokine and antioxidant enzyme expression. Specifically, Se enrichment was associated with increased circulating plasma levels of 2-docosahexaenoyl-glycerol (2-DHG), a mediator with putative beneficial actions on metabolism and inflammation. Others eCBome mediators also responded to the diets. Concomitantly, changes in gut microbiota were observed in Se-enriched diets following a high-fat diet, including an increase in the relative abundance of Peptostreptococcaceae and Lactobacillaceae. With respect to the intestinal immune response and anti-oxidative gene expression, we observed a decrease in the expression of proinflammatory genes Il1β and Tnfα in high-fat Se-enriched diets in caecum, while in ileum an increase in the expression levels of the antioxidant gene Gpx4 was observed following Se depletion. The sex of the animal influenced the response to the diet of both the gut microbiota and endocannabinoid mediators. These results identify Se as a regulator of the gut microbiome and endocannabinoidome in conjunction with high-fat diet, and might be relevant to the development of new nutritional strategies to improve metabolic health and chronic low-grade inflammation associated to metabolic disorders.

280. Indoleamine 2,3-dioxygenase 1 signaling orchestrates immune tolerance in Echinococcus multilocularis-infected mice.

Front Immunol

2022 Nov 11

Meng R, Fu Y, Zhang Y

281. Narrowband ultraviolet B response in cutaneous T-cell lymphoma is characterized by increased bacterial diversity and reduced Staphylococcus aureus and Staphylococcus lugdunensis.

Front Immunol

2022 Nov 11

Hooper MJ, Enriquez GL, Veon FL

Skin microbiota have been linked to disease activity in cutaneous T-cell lymphoma (CTCL). As the skin microbiome has been shown to change after exposure to narrowband ultraviolet B (nbUVB) phototherapy, a common treatment modality used for CTCL, we performed a longitudinal analysis of the skin microbiome in CTCL patients treated with nbUVB. 16S V4 rRNA gene amplicon sequencing for genus-level taxonomic resolution, tuf2 amplicon next generation sequencing for staphylococcal speciation, and bioinformatics were performed on DNA extracted from skin swabs taken from lesional and non-lesional skin of 25 CTCL patients receiving nbUVB and 15 CTCL patients not receiving nbUVB from the same geographical region. Disease responsiveness to nbUVB was determined using the modified Severity Weighted Assessment Tool: 14 (56%) patients responded to nbUVB while 11 (44%) patients had progressive disease. Microbial α-diversity increased in nbUVB-responders after phototherapy. The relative abundance of Staphylococcus, Corynebacterium, Acinetobacter, Streptococcus, and Anaerococcus differentiated nbUVB responders and non-responders after treatment (q<0.05). Microbial signatures of nbUVB-treated patients demonstrated significant post-exposure depletion of S. aureus (q=0.024) and S. lugdunensis (q=0.004) relative abundances. Before nbUVB, responder lesional skin harboured higher levels of S. capitis (q=0.028) and S. warneri (q=0.026) than non-responder lesional skin. S. capitis relative abundance increased in the lesional skin of responders (q=0.05) after phototherapy; a similar upward trend was observed in non-responders (q=0.09). Post-treatment skin of responders exhibited significantly reduced S. aureus (q=0.008) and significantly increased S. hominis (q=0.006), S. pettenkoferi (q=0.021), and S. warneri (q=0.029) relative abundances compared to that of no-nbUVB patients. Staphylococcus species abundance was more similar between non-responders and no-nbUVB patients than between responders and no-nbUVB patients. In sum, the skin microbiome of CTCL patients who respond to nbUVB is different from that of non-responders and untreated patients, and is characterized by shifts in S. aureus and S. lugdunensis. Non-responsiveness to phototherapy may reflect more aggressive disease at baseline.

282. Identification and validation of a signature based on macrophage cell marker genes to predict recurrent miscarriage by integrated analysis of single-cell and bulk RNA-sequencing.

Front Immunol

2022 Nov 11

Wei P, Dong M, Bi Y

283. Artificial intelligence for precision medicine in autoimmune liver disease.

Front Immunol

2022 Nov 11

Gerussi A, Scaravaglio M, Cristoferi L

284. Integrativesubtractive proteomics, immunoinformatics, docking, and simulation approaches reveal candidate vaccine against Sin Nombre orthohantavirus.

Front Immunol

2022 Nov 11

Alabbas AB.

The emergence of Sin Nombre orthohantavirus, an etiological agent of hantavirus cardiopulmonary syndrome, exacerbates the situation and imposes a heavy financial burden on healthcare organizations. Multidrug-resistant forms of the disease are prevalent, and there is currently no licensed commercial vaccine. Due to the numerous limitations of experimental vaccines, vaccines against various bacterial and viral diseases have developed via computational vaccine design. Several subtractive proteomics, immunoinformatics, docking, and simulation approaches were used in this study to develop a multi-epitope-based vaccine against Sin Nombre orthohantavirus. One possible antigenic protein-the glycoprotein precursor of surface glycoproteins (accession number >AAC42202.1)-was selected as a candidate for B cell-derived T cell epitopes mapping the detailed analysis of the core genome. Among the predicted epitopes, four epitopes (QVDWTKKSST, GLAASPPHL, SSYSYRRKLV, and MESGWSDTA), which were probably antigenic, nonallergenic, nontoxic, and water soluble, were used in the multi-epitope vaccine's construction. The shortlisted epitopes have the potency to cover 99.78% of the world's population, 97.93% of the Chinese population, and 97.36% of the Indian population. The epitopes were connected through AAY linkers and joined with >50S ribosomal adjuvant to enhance their efficacy. The vaccine comprises 182 amino acids with a molecular weight of 19.03770 kDa and an instability index of 26.52, indicating that the protein is stable. A molecular docking study revealed that the vaccine has a good binding affinity with TLR-4 and TLR-8, which is vital for inducing the immune system. Top-1 docked complexes of vaccine- TLR-4 and TLR-8 with the lowest binding energy of -12.52 kc/mol and -5.42 kc/mol, respectively, were considered for molecular dynamic simulation analysis. Furthermore, we predicted that the docked complexes are properly stable throughout simulation time in both normal mode and AMBER-based simulation analysis. The MMGBSA analysis calculated -122.17 and -125.4 net binding energies for the TLR-8- and TLR4-vaccine complexes, respectively, while the MMPBSA analysis estimated -115.63 and -118.19 for the TLR-8- and TLR4-vaccine complex, respectively, confirming that the binding stability with receptors is stable, which is important for inducing a strong response. However, the current work is computation-based, so experimental validation is highly recommended.

285. Crosslinking of membrane CD13 in human neutrophils mediates phagocytosis and production of reactive oxygen species, neutrophil extracellular traps and proinflammatory cytokines.

Front Immunol

2022 Nov 10

Pérez-Figueroa E, Álvarez-Carrasco P, Ortega E.

286. The impact of tumor associated macrophages on tumor biology under the lens of mathematical modelling: A review.

Front Immunol

2022 Nov 10

Shojaee P, Mornata F, Deutsch A

287. Assessing organ-level immunoreactivity in a rat model of sepsis using TSPO PET imaging.

Front Immunol

2022 Nov 10

Martinez-Orengo N, Tahmazian S, Lai J

288. Antiviral prophylaxis or preemptive therapy for cytomegalovirus after liver transplantation?: A systematic review and meta-analysis.

Front Immunol

2022 Nov 10

Yadav DK, Adhikari VP, Yadav RK

289. Manipulation of the crosstalk between tumor angiogenesis and immunosuppression in the tumor microenvironment: Insight into the combination therapy of anti-angiogenesis and immune checkpoint blockade.

Front Immunol

2022 Nov 10

Zheng W, Qian C, Tang Y

290. Ischemic stroke and concomitant gastrointestinal complications- a fatal combination for patient recovery.

Front Immunol

2022 Nov 10

Tuz AA, Hasenberg A, Hermann DM

291. Single-cell transcriptomic characterization reveals the landscape of airway remodeling and inflammation in a cynomolgus monkey model of asthma.

Front Immunol

2022 Nov 10

Wang Y, Dong X, Pan C

Monkey disease models, which are comparable to humans in terms of genetic, anatomical, and physiological characteristics, are important for understanding disease mechanisms and evaluating the efficiency of biological treatments. Here, we established an A.suum-induced model of asthma in cynomolgus monkeys to profile airway inflammation and remodeling in the lungs by single-cell RNA sequencing (scRNA-seq). The asthma model results in airway hyperresponsiveness and remodeling, demonstrated by pulmonary function test and histological characterization. scRNA-seq reveals that the model elevates the numbers of stromal, epithelial and mesenchymal cells (MCs). Particularly, the model increases the numbers of endothelial cells (ECs), fibroblasts (Fibs) and smooth muscle cells (SMCs) in the lungs, with upregulated gene expression associated with cell functions enriched in cell migration and angiogenesis in ECs and Fibs, and VEGF-driven cell proliferation, apoptotic process and complement activation in SMCs. Interestingly, we discover a novel Fib subtype that mediates type I inflammation in the asthmatic lungs. Moreover, MCs in the asthmatic lungs are found to regulate airway remodeling and immunological responses, with elevated gene expression enriched in cell migration, proliferation, angiogenesis and innate immunological responses. Not only the numbers of epithelial cells in the asthmatic lungs change at the time of lung tissue collection, but also their gene expressions are significantly altered, with an enrichment in the biological processes of IL-17 signaling pathway and apoptosis in the majority of subtypes of epithelial cells. Moreover, the ubiquitin process and DNA repair are more prevalent in ciliated epithelial cells. Last, cell-to-cell interaction analysis reveals a complex network among stromal cells, MCs and macrophages that contribute to the development of asthma and airway remodeling. Our findings provide a critical resource for understanding the principle underlying airway remodeling and inflammation in a monkey model of asthma, as well as valuable hints for the future treatment of asthma, especially the airway remodeling-characterized refractory asthma.

292. Remodeling tumor microenvironment with natural products to overcome drug resistance.

Front Immunol

2022 Nov 10

Zhang W, Li S, Li C

293. Dorsal switch protein 1 as a damage signal in insect gut immunity to activate dual oxidase via an eicosanoid, PGE(2).

Front Immunol

2022 Nov 10

Roy MC, Ahmed S, Kim Y.

294. Barcode clonal tracking of tissue-resident immune cells in rhesus macaque highlights distinct clonal distribution pattern of tissue NK cells.

Front Immunol

2022 Nov 10

Wu C, Liang JA, Brenchley JM

Tissue resident (TR) immune cells play important roles in facilitating tissue homeostasis, coordinating immune responses against infections and tumors, and maintaining immunological memory. While studies have shown these cells are distinct phenotypically and functionally from cells found in the peripheral blood (PB), the clonal relationship between these populations across tissues has not been comprehensively studied in primates or humans. We utilized autologous transplantation of rhesus macaque hematopoietic stem and progenitor cells containing high diversity barcodes to track the clonal distribution of T, B, myeloid and natural killer (NK) cell populations across tissues, including liver, spleen, lung, and gastrointestinal (GI) tract, in comparison with PB longitudinally post-transplantation, in particular we focused on NK cells which do not contain endogenous clonal markers and have not been previously studied in this context. T cells demonstrated tissue-specific clonal expansions as expected, both overlapping and distinct from blood T cells. In contrast, B and myeloid cells showed a much more homogeneous clonal pattern across various tissues and the blood. The clonal distribution of TR NK was more heterogenous between individual animals. In some animals, as we have previously reported, we observed large PB clonal expansions in mature CD56-CD16+ NK cells. Notably, we found a separate set of highly expanded PB clones in CD16-CD56- (DN) NK subset that were also contributing to TR NK cells in all tissues examined, both in TR CD56-CD16+ and DN populations but absent in CD56+16- TR NK across all tissues analyzed. Additionally, we observed sets of TR NK clones specific to individual tissues such as lung or GI tract and sets of TR NK clones shared across liver and spleen, distinct from other tissues. Combined with prior functional data that suggests NK memory is restricted to liver or other TR NK cells, these clonally expanded TR NK cells may be of interest for future investigation into NK cell tissue immunological memory, with implications for development of NK based immunotherapies and an understanding of NK memory.

295. IgA in human health and diseases: Potential regulator of commensal microbiota.

Front Immunol

2022 Nov 10

Takeuchi T, Ohno H.

296. Hypersensitivity reactions to small molecule drugs.

Front Immunol

2022 Nov 10

Han J, Pan C, Tang X

297. Research progress on anti-ovarian cancer mechanism of miRNA regulating tumor microenvironment.

Front Immunol

2022 Nov 10

Cui M, Liu Y, Cheng L

298. Peripheral ulcerative keratitis, nodular episcleritis, and pulmonary nodules as the initial signs of rheumatic arthritis: A Case Report.

Front Immunol

2022 Nov 10

Wang J, Zhang Q, Shi W

299. Characterizing and correcting immune dysfunction in non-tuberculous mycobacterial disease.

Front Immunol

2022 Nov 10

Ratnatunga CN, Tungatt K, Proietti C

300. Neglected mycobiome in HIV infection: Alterations, common fungal diseases and antifungal immunity.

Front Immunol

2022 Nov 10

Li S, Yang X, Moog C

301. Ascaris suum excretory/secretory products differentially modulate porcine dendritic cell subsets.

Front Immunol

2022 Nov 10

Hamid B, Ebner F, Bechtold L

302. Phase separation drives the formation of biomolecular condensates in the immune system.

Front Immunol

2022 Nov 10

Wen Y, Ma J.

303. miR-142 favors naïve B cell residence in peripheral lymph nodes.

Front Immunol

2022 Nov 10

Hagen M, Chakraborty T, Olson WJ

B lymphocyte development proceeds through a well-ordered sequence of steps, leading to the formation of a sizeable mature B population recognizing a diversity of antigens. These latter cells are ultimately responsible for the production of antibodies upon immune challenges. The detection of threats to the organism is facilitated by the ability of naïve follicular B cells, the main subset of mature B cells in mice, to circulate between lymphoid tissues in search of their cognate antigens. miRNA-mediated fine-tuning of mRNA stability and translation participates in the optimal expression of genetic programs. This regulatory mechanism has been shown to contribute to B cell biology, although the role of individual miRNAs remains understudied. Here, we selectively inactivated the miR-142 locus in B cells. As a consequence, the mature B compartment was visibly perturbed, in agreement with work in miR-142 knockout mice. However, our strategy allowed us to identify roles for the miR-142 locus in B cell physiology obscured by the complexity of the immune phenotype in the null mutant mice. Thus, these miRNAs are necessary for the proper formation of the pre-B cell compartment during development. More remarkably, naïve follicular B cells demonstrated altered migratory properties upon conditional inactivation of the miR-142 locus. The latter mutant cells expressed reduced levels of the homing molecule CD62L. They also migrated more efficiently towards sphingosine-1-phosphate in vitro and displayed an increased abundance of the sphingosine-1-phosphate receptor 1, compatible with improved lymphocyte egress in vivo. In line with these observations, the ablation of the miR-142 locus in B cells caused a paucity of B cells in the lymph nodes. Mutant B cell accumulation in the latter tissues was also compromised upon transfer into a wild-type environment. These changes coincided with suboptimal levels of FOXO1, a positive regulator of CD62L transcription, in mutant B cells. Overall, our findings indicate contributions for the miR-142 locus in various aspects of the B cell life cycle. Notably, this locus appears to favor the establishment of the migratory behavior required for naïve follicular B cell patrolling activity.

304. TRIM21 aggravates cardiac injury after myocardial infarction by promoting M1 macrophage polarization.

Front Immunol

2022 Nov 10

Li Z, Liu X, Zhang X

305. CD11c regulates late-stage T cell development in the thymus.

Front Immunol

2022 Nov 10

Hou L, Yuki K.

306. A randomized controlled trial to verify the irrigation of salivary glands in relieving xerostomia in patients with Sjögren's syndrome.

Front Immunol

2022 Nov 10

Du H, Fu Z, Zhong Y

OBJECTIVE: To verify the effect of triamcinolone acetonide (TA) and major salivary glands saline irrigation on relieving xerostomia in Sjögren's syndrome (SS) patients. METHODS: The enrolled 49 SS patients were randomly assigned to the control group (no irrigation, n=16), saline group (irrigation with saline, n=17) and TA group (irrigation with TA, n=16). Fourteen cases of each group were treated differently but received the same examinations. The examinations include unstimulated whole saliva flow (UWS), chewing-stimulated whole saliva flow (SWS), citric acid-stimulated parotid flow (SPF), Clinical Oral Dryness Score (CODS), Xerostomia Inventory (XI) and EULAR SS Patient Reported Index (ESSPRI) of 1 week before irrigation (T0) and 1 week(T1), 8 weeks (T8), 16 weeks (T16) and 24 weeks (T24) after major salivary irrigation. RESULTS: Each group had 14 cases with completed follow-ups. Both TA and saline irrigation of major salivary glands resulted in higher SWS and SPF of T8, T16 and than those at T0. ESSPRI (oral dryness domain) of T8, T16 and T24 were significantly lower than that at T0, respectively (P < 0.05). SWS and SPF of T8, T16 and T24 in the saline group were significantly higher than in the control group (P< 0.05). XI and ESSPRI (oral dress domain) of T8, T16 and T24 in the saline group were significantly lower than those in the control group, respectively (P< 0.05). SWS and SPF of T16 and T24 in the TA group were significantly higher than in the control group (P< 0.05). All cases with completed follow-up in TA and saline groups were divided into responders and non-responders. Compared with responders, the UWS, SWS, SPF and CODS of T0 in non-responders were significantly increased (P<0.05). Compared with responders, the XI and ESSPRI of T0 in non-responders were significantly decreased (P<0.05). CONCLUSION: The irrigation of major salivary glands by TA and saline relieve xerostomia in SS patients. Patients with non-severe xerostomia (responders) have better relief after irrigation than patients with severe xerostomia (non-responders). CLINICAL TRIAL REGISTRATION: www.chictr.org.cn, identifier (ChiCTR210052314).

307. Interplay between programmed death-ligand 1 and non-coding RNAs.

Front Immunol

2022 Nov 1

Ghafouri-Fard S, Shoorei H, Hussen BM

308. Establishment and analysis of a disease risk prediction model for the systemic lupus erythematosus with random forest.

Front Immunol

2022 Nov 1

Chen H, Huang L, Jiang X

Systemic lupus erythematosus (SLE) is a latent, insidious autoimmune disease, and with the development of gene sequencing in recent years, our study aims to develop a gene-based predictive model to explore the identification of SLE at the genetic level. First, gene expression datasets of SLE whole blood samples were collected from the Gene Expression Omnibus (GEO) database. After the datasets were merged, they were divided into training and validation datasets in the ratio of 7:3, where the SLE samples and healthy samples of the training dataset were 334 and 71, respectively, and the SLE samples and healthy samples of the validation dataset were 143 and 30, respectively. The training dataset was used to build the disease risk prediction model, and the validation dataset was used to verify the model identification ability. We first analyzed differentially expressed genes (DEGs) and then used Lasso and random forest (RF) to screen out six key genes (OAS3, USP18, RTP4, SPATS2L, IFI27 and OAS1), which are essential to distinguish SLE from healthy samples. With six key genes incorporated and five iterations of 10-fold cross-validation performed into the RF model, we finally determined the RF model with optimal mtry. The mean values of area under the curve (AUC) and accuracy of the models were over 0.95. The validation dataset was then used to evaluate the AUC performance and our model had an AUC of 0.948. An external validation dataset (GSE99967) with an AUC of 0.810, an accuracy of 0.836, and a sensitivity of 0.921 was used to assess the model's performance. The external validation dataset (GSE185047) of all SLE patients yielded an SLE sensitivity of up to 0.954. The final high-throughput RF model had a mean value of AUC over 0.9, again showing good results. In conclusion, we identified key genetic biomarkers and successfully developed a novel disease risk prediction model for SLE that can be used as a new SLE disease risk prediction aid and contribute to the identification of SLE.

309. MicroRNAs modulate neuroinflammation after intracerebral hemorrhage: Prospects for new therapy.

Front Immunol

2022 Nov 1

Xia S, Zheng Y, Yan F

310. Immune infiltration in aggressive papillary craniopharyngioma: High infiltration but low action.

Front Immunol

2022 Nov 1

Jia Y, Ma L, Cai K

311. Triggering receptor expressed on myeloid cells 2 deficiency exacerbates injury-induced inflammation in a mouse model of tauopathy.

Front Immunol

2022 Nov 1

Katsumoto A, Kokiko-Cochran ON, Bemiller SM

312. Combining all-trans retinoid acid treatment targeting myeloid-derived suppressive cells with cryo-thermal therapy enhances antitumor immunity in breast cancer.

Front Immunol

2022 Nov 1

Lou Y, Peng P, Wang S

313. Editorial: The role of leukocyte extracellular traps in Inflammation and autoimmunity.

Front Immunol

2022 Nov 1

Appelgren D, O'Sullivan KM.

314. The neonatal Fc receptor expression during macrophage differentiation is related to autophagy.

Front Immunol

2022 Nov 1

Lamamy J, Larue A, Mariot J

315. A 9-mRNA signature measured from whole blood by a prototype PCR panel predicts 28-day mortality upon admission of critically ill COVID-19 patients.

Front Immunol

2022 Nov 1

Tardiveau C, Monneret G, Lukaszewicz AC

316. Environmentally-triggered contraction of the norovirus virion determines diarrheagenic potential.

Front Immunol

2022 Nov 1

Helm EW, Peiper AM, Phillips M

317. IL-1β promotes IL-9-producing Th cell differentiation in IL-2-limiting conditions through the inhibition of BCL6.

Front Immunol

2022 Nov 1

Canaria DA, Clare MG, Yan B

318. Effect of the m6ARNA gene on the prognosis of thyroid cancer, immune infiltration, and promising immunotherapy.

Front Immunol

2022 Nov 1

Xia M, Wang S, Ye Y

BACKGROUND: Accumulating evidence suggests that N6-methyladenosine (m6A) RNA methylation plays an important role in tumor proliferation and growth. However, its effect on the clinical prognosis, immune infiltration, and immunotherapy response of thyroid cancer patients has not been investigated in detail. METHODS: Clinical data and RNA expression profiles of thyroid cancer were extracted from the Cancer Genome Atlas-thyroid carcinoma (TCGA-THCA) and preprocessed for consensus clustering. The risk model was constructed based on differentially expressed genes (DEGs) using Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression analyses. The associations between risk score and clinical traits, immune infiltration, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), immune infiltration, and immunotherapy were assessed. Immunohistochemistry was used to substantiate the clinical traits of our samples. RESULTS: Gene expression analysis showed that 17 genes, except YHTDF2, had significant differences (vs healthy control, P<0.001). Consensus clustering yielded 2 clusters according to their clinical features and estimated a poorer prognosis for Cluster 1 (P=0.03). The heatmap between the 2 clusters showed differences in T (P<0.01), N (P<0.001) and stage (P<0.01). Based on univariate Cox and LASSO regression, a risk model consisting of three high-risk genes (KIAA1429, RBM15, FTO) was established, and the expression difference between normal and tumor tissues of three genes was confirmed by immunohistochemical results of our clinical tissues. KEGG and GSEA analyses showed that the risk DEGs were related mainly to proteolysis, immune response, and cancer pathways. The levels of immune infiltration in the high- and low-risk groups were different mainly in iDCs (P<0.05), NK cells (P<0.05), and type-INF-II (P<0.001). Immunotherapy analysis yielded 30 drugs associated with the expression of each gene and 20 drugs associated with the risk score. CONCLUSIONS: Our risk model can act as an independent marker for thyroid cancer and provides promising immunotherapy targets for its treatment.

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