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Front Immunol

2021 Nov 9

Song J, Tang Y, Luo X

2. The Function of cGAS-STING Pathway in Treatment of Pancreatic Cancer.

Front Immunol

2021 Nov 9

Mohseni G, Li J, Ariston Gabriel AN

3. The Protective Effects of Lactobacillus plantarum KLDS 1.0344 on LPS-Induced Mastitis In Vitro and In Vivo.

Front Immunol

2021 Nov 9

Chen Q, Wang S, Guo J

4. Targeting TBK1 Attenuates LPS-Induced NLRP3 Inflammasome Activation by Regulating of mTORC1 Pathways in Trophoblasts.

Front Immunol

2021 Nov 9

Lee S, Shin J, Kim JS

5. Systemic Sclerosis in Zimbabwe: Autoantibody Biomarkers, Clinical, and Laboratory Correlates.

Front Immunol

2021 Nov 9

Sibanda EN, Dube Y, Chakawa M

INTRODUCTION: Systemic sclerosis (SScl) is an autoimmune disease whose prevalence is rarely reported in Africa. Autoantibodies are the biomarkers of the condition, precede overt disease and determine disease phenotypes. SSc specific autoantibodies also vary between racial groupings. Objective: To investigate the clinical and laboratory characteristics of Zimbabwean patients who were reactive SSc specific autoantibodies. MATERIALS AND METHOD: 240 patients, 173 of them female with SSc specific autoantibodies were included. Autoantibodies were detected by indirect immunofluorescence microscopy and immunoblotting using a panel of 13 SScl (Euroimmun Ag., Germany). Demographic, clinical and laboratory parameters relevant to the monitoring of SScl were captured. These included pulmonary function tests, hematology, clinical chemistry, serology and thyroid function tests. Allergy skin prick tests (SPT) to inhalant and food allergen sources were conducted when indicated. RESULTS: All the 240 patients (median age was 36 years) expressed SSc specific autoantibodies. 86% were Black, 11% White and 3% Asian and a fifth (20%) were younger than 16 years. Eleven (4.6%) fulfilled the ACR/EULAR classification of SSc. Clinically they had limited cutaneous (n=6), diffuse cutaneous (n=3) and SScl/inflammatory myopathy overlap (n=2). The most frequently detected antibodies anti-RNA polymerase III (RNAP) 55%, anti-Th/To (28%) anti-RNAP 11 (22%), anti-CENPB (18%) and anti-Scl-70/ATA (13%). Racial variations in the expression of these antibodies were apparent between Black, White and Asian patients. The majority (95%), who did not fulfil the ARA/EULAR criteria were symptomatic. Raynaud's Phenomenon was documented in 24%. Respiratory symptoms included coughing, dyspnea and wheezing. There was a restrictive ventilatory defect with increased FEV1/FVC ratio. Pruritus, urticaria and skin depigmentation were the main cutaneous features while constipation, bloating, Gastroesophageal reflux disease (GERD) and abdominal pain dominated GI symptoms. Mean blood pressure readings while normal varied with biomarkers. Haematology and biochemistry parameters were within normal reference ranges. CONCLUSION: The expression of SSc specific autoantibodies is common and associated with known SSc symptoms. The types and frequency of autoantibodies varied with racial groupings. A fifth of the patients were children below the age of 16 years.

6. Differential Signature of the Microbiome and Neutrophils in the Oral Cavity of HIV-Infected Individuals.

Front Immunol

2021 Nov 9

Perez Rosero E, Heron S, Jovel J

7. Pathogenesis of IgA Vasculitis: An Up-To-Date Review.

Front Immunol

2021 Nov 9

Song Y, Huang X, Yu G

8. An Oxidative Stress-Related Gene Pair (CCNB1/PKD1), Competitive Endogenous RNAs, and Immune-Infiltration Patterns Potentially Regulate Intervertebral Disc Degeneration Development.

Front Immunol

2021 Nov 9

Cao S, Liu H, Fan J

Oxidative stress (OS) irreversibly affects the pathogenesis of intervertebral disc degeneration (IDD). Certain non-coding RNAs act as competitive endogenous RNAs (ceRNAs) that regulate IDD progression. Analyzing the signatures of oxidative stress-related gene (OSRG) pairs and regulatory ceRNA mechanisms and immune-infiltration patterns associated with IDD may enable researchers to distinguish IDD and reveal the underlying mechanisms. In this study, OSRGs were downloaded and identified using the Gene Expression Omnibus database. Functional-enrichment analysis revealed the involvement of oxidative stress-related pathways and processes, and a ceRNA network was generated. Differentially expressed oxidative stress-related genes (De-OSRGs) were used to construct De-OSRG pairs, which were screened, and candidate De-OSRG pairs were identified. Immune cell-related gene pairs were selected via immune-infiltration analysis. A potential long non-coding RNA-microRNA-mRNA axis was determined, and clinical values were assessed. Eighteen De-OSRGs were identified that were primarily related to intricate signal-transduction pathways, apoptosis-related biological processes, and multiple kinase-related molecular functions. A ceRNA network consisting of 653 long non-coding RNA-microRNA links and 42 mRNA-miRNA links was constructed. Three candidate De-OSRG pairs were screened out from 13 De-OSRG pairs. The abundances of resting memory CD4+ T cells, resting dendritic cells, and CD8+ T cells differed between the control and IDD groups. CD8+ T cell infiltration correlated negatively with cyclin B1 (CCNB1) expression and positively with protein kinase D1 (PKD1) expression. CCNB1-PKD1 was the only pair that was differentially expressed in IDD, was correlated with CD8+ T cells, and displayed better predictive accuracy compared to individual genes. The PKD1-miR-20b-5p-AP000797 and CCNB1-miR-212-3p-AC079834 axes may regulate IDD. Our findings indicate that the OSRG pair CCNB1-PKD1, which regulates oxidative stress during IDD development, is a robust signature for identifying IDD. This OSRG pair and increased infiltration of CD8+ T cells, which play important roles in IDD, were functionally associated. Thus, the OSRG pair CCNB1-PKD1 is promising target for treating IDD.

9. Citrullinated Epitopes Identified on Tumour MHC Class II by Peptide Elution Stimulate Both Regulatory and Th1 Responses and Require Careful Selection for Optimal Anti-Tumour Responses.

Front Immunol

2021 Nov 9

Symonds P, Marcu A, Cook KW

BACKGROUND: Somatic mutations or post-translational modifications of proteins result in changes that enable immune recognition. One such post-translational modification is citrullination, the conversion of arginine residues to citrulline. Citrullinated peptides are presented on MHC class II (MHCII) via autophagy which is upregulated by cellular stresses such as tumourigenesis. METHODS: Peptides were eluted from B16 melanoma expressing HLA-DP4 and analysed by mass spectrometry to profile the presented citrullinated repertoire. Initially, seven of the identified citrullinated peptides were used in combination to vaccinate HLA-DP4 transgenic mice. Immune responses were characterised from the combination and individual vaccines by ex vivo cytokine ELISpot assay and assessed for tumour therapy. RESULTS: The combination vaccine induced only weak anti-tumour therapy in the B16cDP4 melanoma model. Immune phenotyping revealed a dominant IFNγ response to citrullinated matrix metalloproteinase-21 peptide (citMMP21) and an IL-10 response to cytochrome p450 peptide (citCp450). Exclusion of the IL-10 inducing citCp450 peptide from the combined vaccine failed to recover a strong anti-tumour response. Single peptide immunisation confirmed the IFNγ response from citMMP21 and the IL-10 response from citCp450 but also showed that citrullinated Glutamate receptor ionotropic (citGRI) peptide stimulated a low avidity IFNγ response. Interestingly, both citMMP21 and citGRI peptides individually, stimulated strong anti-tumour responses that were significantly better than the combined vaccine. In line with the citGRI T cell avidity, it required high dose immunisation to induce an anti-tumour response. This suggests that as the peptides within the combined vaccine had similar binding affinities to MHC-II the combination vaccine may have resulted in lower presentation of each epitope and weak anti-tumour immunity. CONCLUSION: We demonstrate that tumours present citrullinated peptides that can stimulate Th1 and regulatory responses and that competition likely exists between similar affinity peptides. Characterisation of responses from epitopes identified by peptide elution are necessary to optimise selection for tumour therapy.

10. Recognition of Variants of Concern by Antibodies and T Cells Induced by a SARS-CoV-2 Inactivated Vaccine.

Front Immunol

2021 Nov 9

Melo-González F, Soto JA, González LA

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible of the current pandemic ongoing all around the world. Since its discovery in 2019, several circulating variants have emerged and some of them are associated with increased infections and death rate. Despite the genetic differences among these variants, vaccines approved for human use have shown a good immunogenic and protective response against them. In Chile, over 70% of the vaccinated population is immunized with CoronaVac, an inactivated SARS-CoV-2 vaccine. The immune response elicited by this vaccine has been described against the first SARS-CoV-2 strain isolated from Wuhan, China and the D614G strain (lineage B). To date, four SARS-CoV-2 variants of concern described have circulated worldwide. Here, we describe the neutralizing capacities of antibodies secreted by volunteers in the Chilean population immunized with CoronaVac against variants of concern Alpha (B.1.1.7), Beta (B.1.351) Gamma (P.1) and Delta (B.617.2). METHODS: Volunteers enrolled in a phase 3 clinical trial were vaccinated with two doses of CoronaVac in 0-14 or 0-28 immunization schedules. Sera samples were used to evaluate the capacity of antibodies induced by the vaccine to block the binding between Receptor Binding Domain (RBD) from variants of concern and the human ACE2 receptor by an in-house ELISA. Further, conventional microneutralization assays were used to test neutralization of SARS-CoV-2 infection. Moreover, interferon-γ-secreting T cells against Spike from variants of concern were evaluated in PBMCs from vaccinated subjects using ELISPOT. RESULTS: CoronaVac promotes the secretion of antibodies able to block the RBD of all the SARS-CoV-2 variants studied. Seropositivity rates of neutralizing antibodies in the population evaluated were over 97% for the lineage B strain, over 80% for Alpha and Gamma variants, over 75% for Delta variant and over 60% for the Beta variant. Geometric means titers of blocking antibodies were reduced when tested against SARS-CoV-2 variants as compared to ancestral strain. We also observed that antibodies from vaccinated subjects were able to neutralize the infection of variants D614G, Alpha, Gamma and Delta in a conventional microneutralization assay. Importantly, after SARS-CoV-2 infection, we observed that the blocking capacity of antibodies from vaccinated volunteers increased up to ten times for all the variants tested. We compared the number of interferon-γ-secreting T cells specific for SARS-CoV-2 Spike WT and variants of concern from vaccinated subjects and we did not detect significant differences. CONCLUSION: Immunization with CoronaVac in either immunization schedule promotes the secretion of antibodies able to block SARS-CoV-2 variants of concern and partially neutralizes SARS-CoV-2 infection. In addition, it stimulates cellular responses against all variants of concern.

11. Associations of Serum Resistin With the Severity and Prognosis in Patients With Community-Acquired Pneumonia.

Front Immunol

2021 Nov 9

Feng CM, Cheng JY, Xu Z

Front Immunol

2021 Nov 9

Li S, Zhou C, Xu Y

BACKGROUND: This bioinformatics study aimed to reveal potential cross-talk genes, related pathways, and transcription factors between periimplantitis and rheumatoid arthritis (RA). METHODS: The datasets GSE33774 (seven periimplantitis and eight control samples) and GSE106090 (six periimplantitis and six control samples) were included from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO). A differential expression analysis (p < 0.05 and |logFC (fold change)| ≥ 1) and a functional enrichment analysis (p < 0.05) were performed. Based on this, a protein-protein interaction (PPI) network was constructed by Cytoscape. RA-related genes were extracted from DisGeNET database, and an overlap between periimplantitis-related genes and these RA-related genes was examined to identify potential cross-talk genes. Gene expression was merged between two datasets, and feature selection was performed by Recursive Feature Elimination (RFE) algorithm. For the feature selection cross-talk genes, support vector machine (SVM) models were constructed. The expression of these feature genes was determined from GSE93272 for RA. Finally, a network including cross-talk genes, related pathways, and transcription factors was constructed. RESULTS: Periimplantitis datasets included 138 common differentially expressed genes (DEGs) including 101 up- and 37 downregulated DEGs. The PPI interwork of periimplantitis comprised 1,818 nodes and 2,517 edges. The RFE method selected six features, i.e., MERTK, CD14, MAPT, CCR1, C3AR1, and FCGR2B, which had the highest prediction. Out of these feature genes, CD14 and FCGR2B were most highly expressed in periimplantitis and RA. The final activated pathway-gene network contained 181 nodes and 360 edges. Nuclear factor (NF) kappa B signaling pathway and osteoclast differentiation were identified as potentially relevant pathways. CONCLUSIONS: This current study revealed FCGR2B and CD14 as the most relevant potential cross-talk genes between RA and periimplantitis, which suggests a similarity between RA and periimplantitis and can serve as a theoretical basis for future research.

13. The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β.

Front Immunol

2021 Nov 9

Timmons GA, Carroll RG, O'Siorain JR

14. Multi-Antigen Outer Membrane Vesicle Engineering to Develop Polyvalent Vaccines: The Staphylococcus aureus Case.

Front Immunol

2021 Nov 8

König E, Gagliardi A, Riedmiller I

15. B Cell Recognition of Candida albicans Hyphae via TLR 2 Promotes IgG1 and IL-6 Secretion for T(H)17 Differentiation.

Front Immunol

2021 Nov 8

Ferreira-Gomes M, Wich M, Böde S

16. Indoleamine 2,3-Dioxygenase Cannot Inhibit Chlamydia trachomatis Growth in HL-60 Human Neutrophil Granulocytes.

Front Immunol

2021 Nov 8

Virok DP, Tömösi F, Keller-Pintér A

AIMS: Neutrophil granulocytes are the major cells involved in Chlamydia trachomatis (C. trachomatis)-mediated inflammation and histopathology. A key protein in human intracellular antichlamydial defense is the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) which limits the growth of the tryptophan auxotroph Chlamydia. Despite its importance, the role of IDO in the intracellular defense against Chlamydia in neutrophils is not well characterized. METHODS: Global gene expression screen was used to evaluate the effect of C. trachomatis serovar D infection on the transcriptome of human neutrophil granulocytes. Tryptophan metabolite concentrations in the Chlamydia-infected and/or interferon-gamma (IFNG)-treated neutrophils were measured by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). RESULTS: Our results indicate that the C. trachomatis infection had a major impact on neutrophil gene expression, inducing 1,295 genes and repressing 1,510 genes. A bioinformatics analysis revealed that important factors involved in the induction of neutrophil gene expression were the interferon-related transcription factors such as IRF1-5, IRF7-9, STAT2, ICSB, and ISGF3. One of the upregulated genes was ido1, a known infection- and interferon-induced host gene. The tryptophan-degrading activity of IDO1 was not induced significantly by Chlamydia infection alone, but the addition of IFNG greatly increased its activity. Despite the significant IDO activity in IFNG-treated cells, C. trachomatis growth was not affected by IFNG. This result was in contrast to what we observed in HeLa human cervical epithelial cells, where the IFNG-mediated inhibition of C. trachomatis growth was significant and the IFNG-induced IDO activity correlated with growth inhibition. CONCLUSIONS: IDO activity was not able to inhibit chlamydial growth in human neutrophils. Whether the IDO activity was not high enough for inhibition or other chlamydial growth-promoting host mechanisms were induced in the infected and interferon-treated neutrophils needs to be further investigated.

17. Meta-Inflammation and Metabolic Reprogramming of Macrophages in Diabetes and Obesity: The Importance of Metabolites.

Front Immunol

2021 Nov 5

Russo S, Kwiatkowski M, Govorukhina N

Diabetes mellitus type II and obesity are two important causes of death in modern society. They are characterized by low-grade chronic inflammation and metabolic dysfunction (meta-inflammation), which is observed in all tissues involved in energy homeostasis. A substantial body of evidence has established an important role for macrophages in these tissues during the development of diabetes mellitus type II and obesity. Macrophages can activate into specialized subsets by cues from their microenvironment to handle a variety of tasks. Many different subsets have been described and in diabetes/obesity literature two main classifications are widely used that are also defined by differential metabolic reprogramming taking place to fuel their main functions. Classically activated, pro-inflammatory macrophages (often referred to as M1) favor glycolysis, produce lactate instead of metabolizing pyruvate to acetyl-CoA, and have a tricarboxylic acid cycle that is interrupted at two points. Alternatively activated macrophages (often referred to as M2) mainly use beta-oxidation of fatty acids and oxidative phosphorylation to create energy-rich molecules such as ATP and are involved in tissue repair and downregulation of inflammation. Since diabetes type II and obesity are characterized by metabolic alterations at the organism level, these alterations may also induce changes in macrophage metabolism resulting in unique macrophage activation patterns in diabetes and obesity. This review describes the interactions between metabolic reprogramming of macrophages and conditions of metabolic dysfunction like diabetes and obesity. We also focus on different possibilities of measuring a range of metabolites intra-and extracellularly in a precise and comprehensive manner to better identify the subsets of polarized macrophages that are unique to diabetes and obesity. Advantages and disadvantages of the currently most widely used metabolite analysis approaches are highlighted. We further describe how their combined use may serve to provide a comprehensive overview of the metabolic changes that take place intracellularly during macrophage activation in conditions like diabetes and obesity.

18. The bZIP Transcription Factor ZIP-11 Is Required for the Innate Immune Regulation in Caenorhabditis elegans.

Front Immunol

2021 Nov 5

Zheng Z, Aihemaiti Y, Liu J

19. Continuous Modeling of T CD4 Lymphocyte Activation and Function.

Front Immunol

2021 Nov 5

Martínez-Méndez D, Mendoza L, Villarreal C

20. Interferons in Pain and Infections: Emerging Roles in Neuro-Immune and Neuro-Glial Interactions.

Front Immunol

2021 Nov 5

Tan PH, Ji J, Yeh CC

21. Hsa-miR-31 Governs T-Cell Homeostasis in HIV Protection via IFN-γ-Stat1-T-Bet Axis.

Front Immunol

2021 Nov 5

Zhu L, Qiu C, Dai L

22. Expression of Immune Related Genes and Possible Regulatory Mechanisms in Alzheimer's Disease.

Front Immunol

2021 Nov 5

Lu Y, Li K, Hu Y

23. FlowKit: A Python Toolkit for Integrated Manual and Automated Cytometry Analysis Workflows.

Front Immunol

2021 Nov 5

White S, Quinn J, Enzor J

24. Platelet-to-Lymphocyte Ratio as an Independent Factor Was Associated With the Severity of Ankylosing Spondylitis.

Front Immunol

2021 Nov 5

Liang T, Chen J, Xu G

25. Salmonella Infantis Delays the Death of Infected Epithelial Cells to Aggravate Bacterial Load by Intermittent Phosphorylation of Akt With SopB.

Front Immunol

2021 Nov 5

Chu BX, Li YN, Liu N

26. Changes in MDA5 and TLR3 Sensing of the Same Diabetogenic Virus Result in Different Autoimmune Disease Outcomes.

Front Immunol

2021 Nov 5

Lincez PJ, Shanina I, Horwitz MS.

27. The Pathogenesis of COVID-19 Myocardial Injury: An Immunohistochemical Study of Postmortem Biopsies.

Front Immunol

2021 Nov 5

Hartmann C, Miggiolaro AFRDS, Motta JDS

RATIONALE: Myocardial injury associates significantly and independently with mortality in COVID-19 patients. However, the pathogenesis of myocardial injury in COVID-19 remains unclear, and cardiac involvement by SARS-CoV-2 presents a major challenge worldwide. OBJECTIVE: This histological and immunohistochemical study sought to clarify the pathogenesis and propose a mechanism with pathways involved in COVID-19 myocardial injury. METHODS AND RESULTS: Postmortem minimally invasive autopsies were performed in six patients who died from COVID-19, and the myocardium samples were compared to a control group (n=11). Histological analysis was performed using hematoxylin-eosin and toluidine blue staining. Immunohistochemical (IHC) staining was performed using monoclonal antibodies against targets: caspase-1, caspase-9, gasdermin-d, ICAM-1, IL-1β, IL-4, IL-6, CD163, TNF-α, TGF-β, MMP-9, type 1 and type 3 collagen. The samples were also assessed for apoptotic cells by TUNEL. Histological analysis showed severe pericardiocyte interstitial edema and higher mast cells counts per high-power field in all COVID-19 myocardium samples. The IHC analysis showed increased expression of caspase-1, ICAM-1, IL-1β, IL-6, MMP-9, TNF-α, and other markers in the hearts of COVID-19 patients. Expression of caspase-9 did not differ from the controls, while gasdermin-d expression was less. The TUNEL assay was positive in all the COVID-19 samples supporting endothelial apoptosis. CONCLUSIONS: The pathogenesis of COVID-19 myocardial injury does not seem to relate to primary myocardiocyte involvement but to local inflammation with associated interstitial edema. We found heightened TGF-β and interstitial collagen expression in COVID-affected hearts, a potential harbinger of chronic myocardial fibrosis. These results suggest a need for continued clinical surveillance of patients for myocardial dysfunction and arrythmias after recovery from the acute phase of COVID-19.

28. Immunotherapy With Recombinant Alt a 1 Suppresses Allergic Asthma and Influences T Follicular Cells and Regulatory B Cells in Mice.

Front Immunol

2021 Nov 5

Liu J, Yin J.

BACKGROUND: Alternaria is a major source of asthma-inducing allergens. Allergen-specific immunotherapy improves the progression of allergic asthma. The current treatment is based on crude Alternaria extracts. Alt a 1 is the predominant allergen in Alternaria. However, the treatment efficacy of recombinant Alt a 1 (rAlt a 1) in an asthmatic animal model and its influence on Tfh and Breg cells are unknown. OBJECTIVE: To explore the therapeutic treatment effects of rAlt a 1 on the progress of an asthmatic mouse model and its effect on Tfh and Breg cells. METHODS: We synthesized and purified rAlt a 1. Alternaria-sensitized and challenged mice received subcutaneous immunotherapy (SCIT) with four different rAlt a 1 dosages (5, 50, 100, and 150 µg) or PBS only. Finally, lung and airway inflammation, mouse mast cell protease 1 (MMCP-1), serum immunoglobulin responses, Tfh and Breg cell levels, and the correlation between asthmatic features (inflammation grades and IL-4 and IL-10 levels) and these two cell types were measured after Alternaria rechallenge. RESULTS: High purity and allergenic potency of rAlt a 1 protein were obtained. Following treatment with four different rAlt a 1 dosages, both lung and airway inflammation ameliorated, including lung pathology, serum MMCP-1 levels, inflammatory cell numbers, and cytokine levels in bronchoalveolar lavage fluid (BALF). Additionally, rAlt a 1-SCIT increased the expression of Alternaria-sIgG1, rAlt a 1-sIgG1, rAlt a 1-sIgG2a, and rAlt a 1-sIgG2b in serum. Moreover, the number and percentage of CXCR5+PD-1+Tfh cells were increased in the PC control, while they decreased in the rAlt a 1-SCIT groups. Meanwhile, the absolute numbers and proportions of Breg cells were evaluated after administration of rAlt a 1. A positive correlation was observed between CXCR5+PD-1+Tfh cells and inflammation grades (r = 0.50, p = 0.01), as well as a slightly strong positive relationship with IL-4 (r = 0.55, p = 0.005) and IL-10 (r = 0.58, p = 0.003) levels; Breg cells showed an opposite correlation with the grades of inflammation (r = -0.68, p = 0.0003), along with a negative correlation to IL-4 (r = -0.61, p = 0.001) and IL-10 (r = -0.53, p = 0.008) levels. CONCLUSIONS: We verified that treatment with rAlt a 1 can alleviate asthma progression and further have a regulatory effect on Tfh and Breg cells in an Alternaria-induced asthmatic mouse model.

29. Protective Efficacy of an Orf Virus-Vector Encoding the Hemagglutinin and the Nucleoprotein of Influenza A Virus in Swine.

Front Immunol

2021 Nov 5

Joshi LR, Knudsen D, Piñeyro P

Swine influenza is a highly contagious respiratory disease of pigs caused by influenza A viruses (IAV-S). IAV-S causes significant economic losses to the swine industry and poses challenges to public health given its zoonotic potential. Thus effective IAV-S vaccines are needed and highly desirable and would benefit both animal and human health. Here, we developed two recombinant orf viruses, expressing the hemagglutinin (HA) gene (OV-HA) or the HA and the nucleoprotein (NP) genes of IAV-S (OV-HA-NP). The immunogenicity and protective efficacy of these two recombinant viruses were evaluated in pigs. Both OV-HA and OV-HA-NP recombinants elicited robust virus neutralizing antibody response in pigs, with higher levels of neutralizing antibodies (NA) being detected in OV-HA-NP-immunized animals pre-challenge infection. Although both recombinant viruses elicited IAV-S-specific T-cell responses, the frequency of IAV-S-specific proliferating CD8+ T cells upon re-stimulation was higher in OV-HA-NP-immunized animals than in the OV-HA group. Importantly, IgG1/IgG2 isotype ELISAs revealed that immunization with OV-HA induced Th2-biased immune responses, whereas immunization with OV-HA-NP virus resulted in a Th1-biased immune response. While pigs immunized with either OV-HA or OV-HA-NP were protected when compared to non-immunized controls, immunization with OV-HA-NP resulted in incremental protection against challenge infection as evidenced by a reduced secondary antibody response (NA and HI antibodies) following IAV-S challenge and reduced virus shedding in nasal secretions (lower viral RNA loads and frequency of animals shedding viral RNA and infectious virus), when compared to animals in the OV-HA group. Interestingly, broader cross neutralization activity was also observed in serum of OV-HA-NP-immunized animals against a panel of contemporary IAV-S isolates representing the major genetic clades circulating in swine. This study demonstrates the potential of ORFV-based vector for control of swine influenza virus in swine.

30. Interrelation Between Fibroblasts and T Cells in Fibrosing Interstitial Lung Diseases.

Front Immunol

2021 Nov 5

Lai Y, Wei X, Ye T

31. HIVEP1 Is a Negative Regulator of NF-κB That Inhibits Systemic Inflammation in Sepsis.

Front Immunol

2021 Nov 5

Matsumoto H, Scicluna BP, Jim KK

32. Splenic Transcriptional Responses in Severe Visceral Leishmaniasis: Impaired Leukocyte Chemotaxis and Cell Cycle Arrest.

Front Immunol

2021 Nov 5

de Melo CVB, Guimarães Torres F, Hermida MD

33. Anti-PD-1 Therapy-A Potential Treatment for Myocardial Metastasis From Nasopharyngeal Carcinoma: A Case Report.

Front Immunol

2021 Nov 5

Tang X, Zhou W, Huang D

34. Enhancing Natural Killer Cell Targeting of Pediatric Sarcoma.

Front Immunol

2021 Nov 4

Omer N, Nicholls W, Ruegg B

35. Implementing Logic Gates for Safer Immunotherapy of Cancer.

Front Immunol

2021 Nov 4

Savanur MA, Weinstein-Marom H, Gross G.

36. Inhibitor of Differentiation-2 Protein Ameliorates DSS-Induced Ulcerative Colitis by Inhibiting NF-κB Activation in Neutrophils.

Front Immunol

2021 Nov 4

Ren J, Yan D, Wang Y

37. A Dual Marker for Monitoring MDR-TB Treatment: Host-Derived miRNAs and M. tuberculosis-Derived RNA Sequences in Serum.

Front Immunol

2021 Nov 4

Carranza C, Herrera MT, Guzmán-Beltrán S

38. Case Report: Response to Immunotherapy, Can Radiotherapy Be a Troublemaker?

Front Immunol

2021 Nov 4

Martin-Romano P, Adam J, Scoazec JY

39. Revealing Chronic Granulomatous Disease in a Patient With Williams-Beuren Syndrome Using Whole Exome Sequencing.

Front Immunol

2021 Nov 4

Ripen AM, Chiow MY, Rama Rao PR

40. Identification of Methylation Immune Subtypes and Establishment of a Prognostic Signature for Gliomas Using Immune-Related Genes.

Front Immunol

2021 Nov 4

Hu Z, Zhang H, Fan F

41. Sequential Transplantation of Haploidentical Stem Cell and Unrelated Cord Blood With Using ATG/PTCY Increases Survival of Relapsed/Refractory Hematologic Malignancies.

Front Immunol

2021 Nov 4

Li H, Li X, Chen Y

42. Genetic Analyses of Common Infections in the Avon Longitudinal Study of Parents and Children Cohort.

Front Immunol

2021 Nov 4

Chong AHW, Mitchell RE, Hemani G

43. Oxidative Stress Leads to β-Cell Dysfunction Through Loss of β-Cell Identity.

Front Immunol

2021 Nov 4

Leenders F, Groen N, de Graaf N

44. Editorial: Neutrophil Functions in Host Immunity, Inflammation and Tissue Repair.

Front Immunol

2021 Nov 30

Vermeren S, Elks PM, Ellett F.

45. Tcf1 Sustains the Expression of Multiple Regulators in Promoting Early Natural Killer Cell Development.

Front Immunol

2021 Nov 30

Liu J, Wang Z, Hao S

46. Attenuated Negative Feedback in Monocyte-Derived Macrophages From Persons Living With HIV: A Role for IKAROS.

Front Immunol

2021 Nov 30

Faia C, Plaisance-Bonstaff K, Vittori C

47. Multicenter Study of Controlling Nutritional Status (CONUT) Score as a Prognostic Factor in Patients With HIV-Related Renal Cell Carcinoma.

Front Immunol

2021 Nov 30

Xue W, Zhang Y, Wang H

OBJECTIVE: In recent years, the controlled nutritional status (CONUT) score has been widely recognized as a new indicator for assessing survival in patients with urological neoplasms, including renal, ureteral, and bladder cancer. However, the CONUT score has not been analyzed in patients with HIV-related urological neoplasms. Therefore, we aimed to evaluate the prognostic significance of the CONUT score in patients with HIV-related renal cell carcinoma (RCC). METHODS: A total of 106 patients with HIV-related RCC were recruited from four hospitals between 2012 and 2021, and all included patients received radical nephrectomy or partial nephrectomy. The CONUT score was calculated by serum albumin, total lymphocyte counts, and total cholesterol concentrations. Patients with RCC were divided into two groups according to the optimal cutoff value of the CONUT score. Survival analysis of different CONUT groups was performed by the Kaplan-Meier method and a log rank test. A Cox proportional risk model was used to test for correlations between clinical variables and cancer-specific survival (CSS), overall survival (OS), and disease-free survival (DFS). Clinical variables included age, sex, hypertension, diabetes, tumor grade, Fuhrman grade, histology, surgery, and CD4+ T lymphocyte count. RESULT: The median age was 51 years, with 93 males and 13 females. At a median follow-up of 41 months, 25 patients (23.6%) had died or had tumor recurrence and metastasis. The optimal cutoff value for the CONUT score was 3, and a lower CONUT score was associated with the Fuhrman grade (P=0.024). Patients with lower CONUT scores had better CSS (HR 0.197, 95% CI 0.077-0.502, P=0.001), OS (HR 0.177, 95% CI 0.070-0.446, P<0.001) and DFS (HR 0.176, 95% CI 0.070-0.444, P<0.001). Multivariate Cox regression analysis indicated that a low CONUT score was an independent predictor of CSS, OS and DFS (CSS: HR=0.225, 95% CI 0.067-0.749, P=0.015; OS: HR=0.201, 95% CI 0.061-0.661, P=0.008; DFS: HR=0.227, 95% CI 0.078-0.664, P=0.007). In addition, a low Fuhrman grade was an independent predictor of CSS (HR 0.192, 95% CI 0.045-0.810, P=0.025), OS (HR 0.203, 95% CI 0.049-0.842, P=0.028), and DFS (HR 0.180, 95% CI 0.048-0.669, P=0.010), while other factors, such as age, sex, hypertension, diabetes, tumor grade, histology, surgery, and CD4+ T lymphocyte count, were not associated with survival outcome. CONCLUSION: The CONUT score, an easily measurable immune-nutritional biomarker, may provide useful prognostic information in HIV-related RCC.

48. ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function.

Front Immunol

2021 Nov 30

D'Amico S, D'Alicandro V, Compagnone M

49. Differential Regulation of Human Surfactant Protein A Genes, SFTPA1 and SFTPA2, and Their Corresponding Variants.

Front Immunol

2021 Nov 30

Floros J, Tsotakos N.

50. A Potential Probiotic for Diarrhea: Clostridium tyrobutyricum Protects Against LPS-Induced Epithelial Dysfunction via IL-22 Produced By Th17 Cells in the Ileum.

Front Immunol

2021 Nov 30

Xiao Z, Liu L, Pei X

51. Early Myeloid Derived Suppressor Cells (eMDSCs) Are Associated With High Donor Myeloid Chimerism Following Haploidentical HSCT for Sickle Cell Disease.

Front Immunol

2021 Nov 30

Bhat DK, Olkhanud PB, Gangaplara A

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a widely available curative option for patients with sickle cell disease (SCD). Our original non-myeloablative haplo-HSCT trial employing post-transplant (PT) cyclophosphamide had a low incidence of GVHD but had high rejection rates. Here, we aimed to evaluate immune reconstitution following haplo-HSCT and identify cytokines and cells associated with graft rejection/engraftment. 50 cytokines and 10 immune cell subsets were screened using multiplex-ELISA and flow cytometry, respectively, at baseline and PT-Days 30, 60, 100, and 180. We observed the most significant differences in cytokine levels between the engrafted and rejected groups at PT-Day 60, corresponding with clinical findings of secondary graft rejection. Of the 44 cytokines evaluated, plasma concentrations of 19 cytokines were different between the two groups at PT-Day 60. Factor analysis suggested two independent factors. The first factor (IL-17A, IL-10, IL-7, G-CSF, IL-2, MIP-1a, VEGF, and TGFb1 contributed significantly) was strongly associated with engraftment with OR = 2.7 (95%CI of 1.4 to 5.4), whereas the second factor (GROa and IL-18 contributed significantly) was not significantly associated with engraftment. Sufficient donor myeloid chimerism (DMC) is critical for the success of HSCT; here, we evaluated immune cells among high (H) DMC (DMC≥20%) and low (L) DMC (DMC<20%) groups along with engrafted and rejected groups. We found that early myeloid-derived suppressor cell (eMDSC) frequencies were elevated in engrafted patients and patients with HDMC at PT-Day 30 (P< 0.04 & P< 0.003, respectively). 9 of 20 patients were evaluated for the source of eMDSCs. The HDMC group had high mixed chimeric eMDSCs as compared to the LDMC group (P< 0.00001). We found a positive correlation between the frequencies of eMDSCs and Tregs at PT-Day 100 (r=0.72, P <0.0007); eMDSCs at BSL and Tregs at PT-Day 100 (r=0.63, P <0.004). Of 10 immune regulatory cells and 50 cytokines, we observed mixed chimeric eMDSCs and IL-17A, IL-10, IL-7, G-CSF, IL-2, MIP-1a, VEGF, TGFb1 as potential hits which could serve as prognostic markers in predicting allograft outcome towards engraftment following haploidentical HSCT employing post-transplant cyclophosphamide. The current findings need to be replicated and further explored in a larger cohort.

52. Potential Immune Biomarker Candidates and Immune Subtypes of Lung Adenocarcinoma for Developing mRNA Vaccines.

Front Immunol

2021 Nov 30

Wang Y, Tan H, Yu T

mRNA vaccines against cancer have advantages in safety, improved therapeutic efficacy, and large-scale production. Therefore, our purpose is to identify immune biomarkers and to analyze immune status for developing mRNA vaccines and selecting appropriate patients for vaccination. We downloaded clinical information and RNA-seq data of 494 LUAD patients from TCGA. LUAD mutational information was hierarchically clustered by NMF package (Version 0.23.0). DeconstructSigs package (Version 1.8.0) and NMF consistency clustering were used to identify mutation signatures. Maftools package (Version 2.6.05) was used to select LUAD-related immune biomarkers. TIMER was used to discuss the correlation between genetic mutations and cellular components. Unsupervised clustering Pam method was used to identify LUAD immune subtypes. Log-rank test and univariate/multivariate cox regression were used to predict the prognosis of immune subtypes. Dimensionality reduction analysis was dedicated to the description of LUAD immune landscape. LUAD patients are classified into four signatures: T >C, APOBEC mutation, age, and tobacco. Then, GPRIN1, MYRF, PLXNB2, SLC9A4, TRIM29, UBA6, and XDH are potential LUAD-related immune biomarker candidates to activate the immune response. Next, we clustered five LUAD-related immune subtypes (IS1-IS5) by prognostic prediction. IS3 showed prolonged survival. The reliability of our five immune subtypes was validated by Thorsson's results. IS2 and IS4 patients had high tumor mutation burden and large number of somatic mutations. Besides, we identified that immune subtypes of cold immunity (patients with IS2 and IS4) are ideal mRNA vaccination recipients. Finally, LUAD immune landscape revealed immune cells and prognostic conditions, which provides important information to select patients for vaccination. GPRIN1, MYRF, PLXNB2, SLC9A4, TRIM29, UBA6, and XDH are potential LUAD-related immune biomarker candidates to activate the immune response. Patients with IS2 and IS4 might potentially be immunization-sensitive patients for vaccination.

53. SNAIL1: Linking Tumor Metastasis to Immune Evasion.

Front Immunol

2021 Nov 30

Tang X, Sui X, Weng L

54. A Genome-Wide CRISPR/Cas9-Based Screen Identifies Heparan Sulfate Proteoglycans as Ligands of Killer-Cell Immunoglobulin-Like Receptors.

Front Immunol

2021 Nov 30

Klein K, Hölzemer A, Wang T

55. Crosstalk Between Circulating Follicular T Helper Cells and Regulatory B Cells in Children With Extrinsic Atopic Dermatitis.

Front Immunol

2021 Nov 30

Jiang J, Yan S, Zhou X

56. Increased B Cell Selection Stringency In Germinal Centers Can Explain Improved COVID-19 Vaccine Efficacies With Low Dose Prime or Delayed Boost.

Front Immunol

2021 Nov 30

Garg AK, Mittal S, Padmanabhan P

57. m(6)A Regulator-Mediated Methylation Modification Patterns and Characteristics of Immunity in Blood Leukocytes of COVID-19 Patients.

Front Immunol

2021 Nov 30

Qiu X, Hua X, Li Q

58. Safety of African Swine Fever Vaccine Candidate Lv17/WB/Rie1 in Wild Boar: Overdose and Repeated Doses.

Front Immunol

2021 Nov 30

Barasona JA, Cadenas-Fernández E, Kosowska A

59. The Global Epidemic of the SARS-CoV-2 Delta Variant, Key Spike Mutations and Immune Escape.

Front Immunol

2021 Nov 30

Tian D, Sun Y, Zhou J

60. Implication of SARS-CoV-2 Immune Escape Spike Variants on Secondary and Vaccine Breakthrough Infections.

Front Immunol

2021 Nov 3

Ahmad L.

61. Prenatal Maternal Stress Exacerbates Experimental Colitis of Offspring in Adulthood.

Front Immunol

2021 Nov 3

Sun Y, Xie R, Li L

The prevalence of inflammatory bowel disease (IBD) is increasing worldwide and correlates with dysregulated immune response because of gut microbiota dysbiosis. Some adverse early life events influence the establishment of the gut microbiota and act as risk factors for IBD. Prenatal maternal stress (PNMS) induces gut dysbiosis and perturbs the neuroimmune network of offspring. In this study, we aimed to investigate whether PNMS increases the susceptibility of offspring to colitis in adulthood. The related index was assessed during the weaning period and adulthood. We found that PNMS impaired the intestinal epithelial cell proliferation, goblet cell and Paneth cell differentiation, and mucosal barrier function in 3-week-old offspring. PNMS induced low-grade intestinal inflammation, but no signs of microscopic inflammatory changes were observed. Although there was no pronounced difference between the PNMS and control offspring in terms of their overall measures of alpha diversity for the gut microbiota, distinct microbial community changes characterized by increases in Desulfovibrio, Streptococcus, and Enterococcus and decreases in Bifidobacterium and Blautia were induced in the 3-week-old PNMS offspring. Notably, the overgrowth of Desulfovibrio persisted from the weaning period to adulthood, consistent with the results observed using fluorescence in situ hybridization in the colon mucosa. Mechanistically, the fecal microbiota transplantation experiment showed that the gut microbiota from the PNMS group impaired the intestinal barrier function and induced low-grade inflammation. The fecal bacterial solution from the PNMS group was more potent than that from the control group in inducing inflammation and gut barrier disruption in CaCo-2 cells. After treatment with a TNF-α inhibitor (adalimumab), no statistical difference in the indicators of inflammation and intestinal barrier function was observed between the two groups. Finally, exposure to PNMS remarkably increased the values of the histopathological parameters and the inflammatory cytokine production in a mouse model of experimental colitis in adulthood. These findings suggest that PNMS can inhibit intestinal development, impair the barrier function, and cause gut dysbiosis characterized by the persistent overgrowth of Desulfovibrio in the offspring, resulting in exacerbated experimental colitis in adulthood.

62. COVID-19 mRNA Vaccination in Lactation: Assessment of Adverse Events and Vaccine Related Antibodies in Mother-Infant Dyads.

Front Immunol

2021 Nov 3

Golan Y, Prahl M, Cassidy AG

63. Inflammatory Cytokines Shape an Altered Immune Response During Myeloid Malignancies.

Front Immunol

2021 Nov 3

Camacho V, Kuznetsova V, Welner RS.

64. Profiling Antibody Response Patterns in COVID-19: Spike S1-Reactive IgA Signature in the Evolution of SARS-CoV-2 Infection.

Front Immunol

2021 Nov 3

Siracusano G, Brombin C, Pastori C

65. HLA-DR Expression Level in CD8(+) T Cells Correlates With the Severity of Children With Acute Infectious Mononucleosis.

Front Immunol

2021 Nov 3

Wang Y, Luo Y, Tang G

66. Heritability Enrichment of Immunoglobulin G N-Glycosylation in Specific Tissues.

Front Immunol

2021 Nov 3

Li X, Wang H, Zhu Y

67. The Roles of Transient Receptor Potential Vanilloid 1 and 4 in Pneumococcal Nasal Colonization and Subsequent Development of Invasive Disease.

Front Immunol

2021 Nov 3

Kono M, Nanushaj D, Sakatani H

68. Editorial: The Versatile Role of Nicotinamide Adenine Dinucleotide in Immunity.

Front Immunol

2021 Nov 29

Rissiek B, Guse AH, Adriouch S

69. Monocyte Trajectories Endotypes Are Associated With Worsening in Septic Patients.

Front Immunol

2021 Nov 29

Bodinier M, Peronnet E, Brengel-Pesce K

70. COVID-19 Vaccine Hesitancy Among Chinese Population: A Large-Scale National Study.

Front Immunol

2021 Nov 29

Wu J, Li Q, Silver Tarimo C

Globally, vaccine hesitancy is a growing public health problem. It is detrimental to the consolidation of immunization program achievements and elimination of vaccine-targeted diseases. The objective of this study was to estimate the prevalence of COVID-19 vaccine hesitancy in China and explore its contributing factors. A national cross-sectional online survey among Chinese adults (≥18 years old) was conducted between August 6, 2021 and August 9 via a market research company. We collected sociodemographic information; lifestyle behavior; quality of life; the knowledge, awareness, and behavior of COVID-19; the knowledge, awareness, and behavior of COVID-19 vaccine; willingness of COVID-19 vaccination; accessibility of COVID-19 vaccination services; skepticism about COVID-19 and COVID-19 vaccine; doctor and vaccine developer scale; and so on. Odds ratios (OR) with 95% confidence intervals (CI) were used to estimate the associations by using logistic regression models. A total of 29,925 residents (48.64% men) were enrolled in our study with mean age of 30.99 years. We found an overall prevalence of COVID-19 vaccine hesitancy at 8.40% (95% CI, 8.09-8.72) in primary vaccination and 8.39% (95% CI, 8.07-8.70) in booster vaccination. In addition, after adjusting for potential confounders, we found that women, higher educational level, married residents, higher score of health condition, never smoked, increased washing hands, increased wearing mask, increased social distance, lower level of vaccine conspiracy beliefs, disease risks outweigh vaccine risk, higher level of convenient vaccination, and higher level of trust in doctor and developer were more willing to vaccinate than all others (all p < 0.05). Age, sex, educational level, marital status, chronic disease condition, smoking, healthy behaviors, the curability of COVID-19, the channel of accessing information of COVID-19 vaccine, endorsement of vaccine conspiracy beliefs, weigh risks of vaccination against risks of the disease, making a positive influence on the health of others around you, and lower trust in healthcare system may affect the variation of willingness to take a COVID-19 vaccine (all p < 0.05). The prevalence of COVID-19 vaccine hesitancy was modest in China, even with the slight resulting cascade of changing vaccination rates between the primary and booster vaccination. Urgent action to address vaccine hesitancy is needed in building trust in medical personnel and vaccine producers, promoting the convenience of vaccination services, and spreading reliable information of COVID-19 vaccination via the Internet and other media.

71. Viral Induced Effects on a Vulnerable Epithelium; Lessons Learned From Paediatric Asthma and Eosinophilic Oesophagitis.

Front Immunol

2021 Nov 29

Watkinson RL, Looi K, Laing IA

The epithelium is integral to the protection of many different biological systems and for the maintenance of biochemical homeostasis. Emerging evidence suggests that particular children have epithelial vulnerabilities leading to dysregulated barrier function and integrity, that resultantly contributes to disease pathogenesis. These epithelial vulnerabilities likely develop in utero or in early life due to various genetic, epigenetic and environmental factors. Although various epithelia are uniquely structured with specific function, prevalent allergic-type epithelial diseases in children potentially have common or parallel disease processes. These include inflammation and immune response dysregulation stemming from atypical epithelial barrier function and integrity. Two diseases where aetiology and pathogenesis are potentially linked to epithelial vulnerabilities include Paediatric Asthma and Eosinophilic Oesophagitis (EoE). For example, rhinovirus C (RV-C) is a known risk factor for paediatric asthma development and is known to disrupt respiratory epithelial barrier function causing acute inflammation. In addition, EoE, a prevalent atopic condition of the oesophageal epithelium, is characterised by similar innate immune and epithelial responses to viral injury. This review examines the current literature and identifies the gaps in the field defining viral-induced effects on a vulnerable respiratory epithelium and resulting chronic inflammation, drawing from knowledge generated in acute wheezing illness, paediatric asthma and EoE. Besides highlighting the importance of epithelial structure and barrier function in allergic disease pathogenesis regardless of specific epithelial sub-types, this review focuses on the importance of examining other parallel allergic-type disease processes that may uncover commonalities driving disease pathogenesis. This in turn may be beneficial in the development of common therapeutics for current clinical management and disease prevention in the future.

72. The Emerging Role of Non-Coding RNAs in Osteoarthritis.

Front Immunol

2021 Nov 29

Ghafouri-Fard S, Poulet C, Malaise M

73. Single-Cell and Bulk RNA-Sequencing Reveal Differences in Monocyte Susceptibility to Influenza A Virus Infection Between Africans and Europeans.

Front Immunol

2021 Nov 29

O'Neill MB, Quach H, Pothlichet J

74. Bruton's Tyrosine Kinase Inhibitors Impair FcγRIIA-Driven Platelet Responses to Bacteria in Chronic Lymphocytic Leukemia.

Front Immunol

2021 Nov 29

Naylor-Adamson L, Chacko AR, Booth Z

Bacterial infections are a major cause of morbidity and mortality in chronic lymphocytic leukemia (CLL), and infection risk increases in patients treated with the Bruton's tyrosine kinase (Btk) inhibitor, ibrutinib. Btk and related kinases (like Tec) are expressed in non-leukemic hematopoietic cells and can be targeted by ibrutinib. In platelets, ibrutinib therapy is associated with bleeding complications mostly due to off-target effects. But the ability of platelets to respond to bacteria in CLL, and the potential impact of ibrutinib on platelet innate immune functions remain unknown. FcγRIIA is a tyrosine kinase-dependent receptor critical for platelet activation in response to IgG-coated pathogens. Crosslinking of this receptor with monoclonal antibodies causes downstream activation of Btk and Tec in platelets, however, this has not been investigated in response to bacteria. We asked whether ibrutinib impacts on FcγRIIA-mediated activation of platelets derived from CLL patients and healthy donors after exposure to Staphylococcus aureus Newman and Escherichia coli RS218. Platelet aggregation, α-granule secretion and integrin αIIbβ3-dependent scavenging of bacteria were detected in CLL platelets but impaired in platelets from ibrutinib-treated patients and in healthy donor-derived platelets exposed to ibrutinib in vitro. While levels of surface FcγRIIA remained unaffected, CLL platelets had reduced expression of integrin αIIbβ3 and GPVI compared to controls regardless of therapy. In respect of intracellular signaling, bacteria induced Btk and Tec phosphorylation in both CLL and control platelets that was inhibited by ibrutinib. To address if Btk is essential for platelet activation in response to bacteria, platelets derived from X-linked agammaglobulinemia patients (lacking functional Btk) were exposed to S. aureus Newman and E. coli RS218, and FcγRIIA-dependent aggregation was observed. Our data suggest that ibrutinib impairment of FcγRIIA-mediated platelet activation by bacteria results from a combination of Btk and Tec inhibition, although off-target effects on additional kinases cannot be discarded. This is potentially relevant to control infection-risk in CLL patients and, thus, future studies should carefully evaluate the effects of CLL therapies, including Btk inhibitors with higher specificity for Btk, on platelet-mediated immune functions.

75. Impact of Cryopreservation on Viability, Phenotype, and Functionality of Porcine PBMC.

Front Immunol

2021 Nov 29

Li Y, Mateu E, Díaz I.

The use of frozen peripheral blood mononuclear cells (PBMC) is common in immunological studies. The impact of freezing PBMC has been assessed using human and mice cells, but little information is available regarding domestic animals. In the present study, the phenotype and functionality of frozen porcine PBMC were examined. In a preliminary experiment, three freezing media: fetal bovine serum plus 10% dimethyl sulfoxide, PSC cryopreservation kit, and Cryostor CS10, were compared regarding the preservation of cell viability and the response of PBMC to mitogens after thawing. After being stored one month in liquid nitrogen, cell viability was above 89% for all freezing media. The ELISPOT IFN-gamma (IFN-γ) results in response to PHA and of IgG ELISPOT in response to R848+IL-2 were similar to those obtained using fresh PBMC. In the second set of experiments, PBMC were obtained from five pigs vaccinated against Porcine reproductive and respiratory syndrome virus (PRRSV) and then frozen using Cryostor CS10. Recovered cells were phenotyped by flow cytometry using anti-CD3, CD4, CD8, and CD21 antibodies and were used to assess the PRRSV-specific responses in a proliferation experiment, an IFN-γ ELISPOT, and an IgG ELISPOT, and compared to the results obtained with fresh cells. The antigen-specific responses of frozen cells were significantly (p<0.05) impaired in the proliferation assay, particularly for CD4/CD8 double-positive T-cells and for CD21+ cells. Freezing resulted in decreased proliferation when Con A, but not PHA, was used. In ELISPOT, cryopreservation resulted in a decreased frequency of IFN-γ-secreting cells in response to PRRSV (p<0.05) but the response to PHA was not affected. No differences were observed in the IgG ELISPOT after polyclonal activation. Taken together, cryopreservation of porcine PBMC had a significant impact on the magnitude of recall antigen responses and therefore, it may affect the response of effector/memory cells but seems not to have a major impact on naïve T-cells. These results may help to the better use of frozen porcine PBMC, and to the interpretation of the results obtained from them.

76. Double Strike Approach for Tumor Attack: Engineering T Cells Using a CD40L:CD28 Chimeric Co-Stimulatory Switch Protein for Enhanced Tumor Targeting in Adoptive Cell Therapy.

Front Immunol

2021 Nov 29

Olguín-Contreras LF, Mendler AN, Popowicz G

Activation of co-stimulatory pathways in cytotoxic T lymphocytes expressing chimeric antigen receptors (CARs) have proven to boost effector activity, tumor rejection and long-term T cell persistence. When using antigen-specific T cell receptors (TCR) instead of CARs, the lack of co-stimulatory signals hampers robust antitumoral response, hence limiting clinical efficacy. In solid tumors, tumor stroma poses an additional hurdle through hindrance of infiltration and active inhibition. Our project aimed at generating chimeric co-stimulatory switch proteins (CSP) consisting of intracellular co-stimulatory domains (ICD) fused to extracellular protein domains (ECD) for which ligands are expressed in solid tumors. The ECD of CD40L was selected for combination with the ICD from the CD28 protein. With this approach, it was expected to not only provide co-stimulation and strengthen the TCR signaling, but also, through the CD40L ECD, facilitate the activation of tumor-resident antigen-presenting cells (APCs), modulate activation of tumor endothelium and induce TCR-MHC independent apoptotic effect on tumor cells. Since CD28 and CD40L belong to different classes of transmembrane proteins (type I and type II, respectively), creating a chimeric protein presented a structural and functional challenge. We present solutions to this challenge describing different CSP formats that were successfully expressed in human T cells along with an antigen-specific TCR. The level of surface expression of the CSPs depended on their distinct design and the state of T cell activation. In particular, CSPs were upregulated by TCR stimulation and downregulated following interaction with CD40 on target cells. Ligation of the CSP in the context of TCR-stimulation modulated intracellular signaling cascades and led to improved TCR-induced cytokine secretion and cytotoxicity. Moreover, the CD40L ECD exhibited activity as evidenced by effective maturation and activation of B cells and DCs. CD40L:CD28 CSPs are a new type of switch proteins designed to exert dual beneficial antitumor effect by acting directly on the gene-modified T cells and simultaneously on tumor cells and tumor-supporting cells of the TME. The observed effects suggest that they constitute a promising tool to be included in the engineering process of T cells to endow them with complementary features for improved performance in the tumor milieu.

77. PDGF Promotes Dermal Fibroblast Activation via a Novel Mechanism Mediated by Signaling Through MCHR1.

Front Immunol

2021 Nov 29

Takamura N, Renaud L, da Silveira WA

78. Impact of Graft-Resident Leucocytes on Treg Mediated Skin Graft Survival.

Front Immunol

2021 Nov 29

Steiner R, Weijler AM, Wekerle T

The importance and exact role of graft-resident leucocytes (also referred to as passenger leucocytes) in transplantation is controversial as these cells have been reported to either initiate or retard graft rejection. T cell activation to allografts is mediated via recognition of intact or processed donor MHC molecules on antigen-presenting cells (APC) as well as through interaction with donor-derived extracellular vesicles. Reduction of graft-resident leucocytes before transplantation is a well-known approach for prolonging organ survival without interfering with the recipient's immune system. As previously shown by our group, injecting mice with IL-2/anti-IL-2 complexes (IL-2cplx) to augment expansion of CD4 T regulatory cells (Tregs) induces tolerance towards islet allografts, and also to skin allografts when IL-2cplx treatment is supplemented with rapamycin and a short-term treatment of anti-IL-6. In this study, we investigated the mechanisms by which graft-resident leucocytes impact graft survival by studying the combined effects of IL-2cplx-mediated Treg expansion and passenger leucocyte depletion. For the latter, effective depletion of APC and T cells within the graft was induced by prior total body irradiation (TBI) of the graft donor. Surprisingly, substantial depletion of donor-derived leucocytes by TBI did not prolong graft survival in naïve mice, although it did result in augmented recipient leucocyte graft infiltration, presumably through irradiation-induced nonspecific inflammation. Notably, treatment with the IL-2cplx protocol prevented early inflammation of irradiated grafts, which correlated with an influx of Tregs into the grafts. This finding suggested there might be a synergistic effect of Treg expansion and graft-resident leucocyte depletion. In support of this idea, significant prolongation of skin graft survival was achieved if we combined graft-resident leucocyte depletion with the IL-2cplx protocol; this finding correlated along with a progressive shift in the composition of T cells subsets in the grafts towards a more tolerogenic environment. Donor-specific humoral responses remained unchanged, indicating minor importance of graft-resident leucocytes in anti-donor antibody development. These results demonstrate the importance of donor-derived leucocytes as well as Tregs in allograft survival, which might give rise to new clinical approaches.

79. Proteoform Analysis of Matrix Metalloproteinase-9/Gelatinase B and Discovery of Its Citrullination in Rheumatoid Arthritis Synovial Fluids.

Front Immunol

2021 Nov 29

Grillet B, Yu K, Ugarte-Berzal E

80. Conditional Deletion of Pdcd1 Identifies the Cell-Intrinsic Action of PD-1 on Functional CD8 T Cell Subsets for Antitumor Efficacy.

Front Immunol

2021 Nov 29

Raghavan S, Tovbis-Shifrin N, Kochel C

81. Progesterone Aggravates Lung Fibrosis in a Mouse Model of Systemic Sclerosis.

Front Immunol

2021 Nov 29

Vafashoar F, Mousavizadeh K, Poormoghim H

82. COVID-19 Vaccine-Related Thrombosis: A Systematic Review and Exploratory Analysis.

Front Immunol

2021 Nov 29

Bilotta C, Perrone G, Adelfio V

INTRODUCTION: The World Health Organization declared the coronavirus disease 2019 (COVID-19) pandemic on March 11, 2020. Two vaccine types were developed using two different technologies: viral vectors and mRNA. Thrombosis is one of the most severe and atypical adverse effects of vaccines. This study aimed to analyze published cases of thrombosis after COVID-19 vaccinations to identify patients' features, potential pathophysiological mechanisms, timing of appearance of the adverse events, and other critical issues. MATERIALS AND METHODS: We performed a systematic electronic search of scientific articles regarding COVID-19 vaccine-related thrombosis and its complications on the PubMed (MEDLINE) database and through manual searches. We selected 10 out of 50 articles from February 1 to May 5, 2021 and performed a descriptive analysis of the adverse events caused by the mRNA-based Pfizer and Moderna vaccines and the adenovirus-based AstraZeneca vaccine. RESULTS: In the articles on the Pfizer and Moderna vaccines, the sample consisted of three male patients with age heterogeneity. The time from vaccination to admission was ≤3 days in all cases; all patients presented signs of petechiae/purpura at admission, with a low platelet count. In the studies on the AstraZeneca vaccine, the sample consisted of 58 individuals with a high age heterogeneity and a high female prevalence. Symptoms appeared around the ninth day, and headache was the most common symptom. The platelet count was below the lower limit of the normal range. All patients except one were positive for PF4 antibodies. The cerebral venous sinus was the most affected site. Death was the most prevalent outcome in all studies, except for one study in which most of the patients remained alive. DISCUSSION: Vaccine-induced thrombotic thrombocytopenia (VITT) is an unknown nosological phenomenon secondary to inoculation with the COVID-19 vaccine. Several hypotheses have been formulated regarding its physiopathological mechanism. Recent studies have assumed a mechanism that is assimilable to heparin-induced thrombocytopenia, with protagonist antibodies against the PF4-polyanion complex. Viral DNA has a negative charge and can bind to PF4, causing VITT. New experimental studies have assumed that thrombosis is related to a soluble adenoviral protein spike variant, originating from splicing events, which cause important endothelial inflammatory events, and binding to endothelial cells expressing ACE2. CONCLUSION: Further studies are needed to better identify VITT's pathophysiological mechanisms and genetic, demographic, or clinical predisposition of high-risk patients, to investigate the correlation of VITT with the different vaccine types, and to test the significance of the findings.

83. Transcriptomic and Single-Cell Analysis Reveals Regulatory Networks and Cellular Heterogeneity in Mouse Primary Sjögren's Syndrome Salivary Glands.

Front Immunol

2021 Nov 29

Horeth E, Oyelakin A, Song EC

84. Editorial: Emerging Roles for Type 2-Associated Cells and Cytokines in Cancer Immunity.

Front Immunol

2021 Nov 26

Schiavoni G, Munitz A, Strid J.

85. Corrigendum: Ets-2 Propagates IL-6 Trans-Signaling Mediated Osteoclast-Like Changes in Human Rheumatoid Arthritis Synovial Fibroblast.

Front Immunol

2021 Nov 26

Singh AK, Haque M, Madarampalli B

86. How Times Have Changed! A Cornucopia of Antigens for Membranous Nephropathy.

Front Immunol

2021 Nov 26

Caza TN, Al-Rabadi LF, Beck LH Jr.

87. A Co-Association Network Analysis Reveals Putative Regulators for Health-Related Traits in Pigs.

Front Immunol

2021 Nov 26

Crespo-Piazuelo D, Ramayo-Caldas Y, González-Rodríguez O

In recent years, the increase in awareness of antimicrobial resistance together with the societal demand of healthier meat products have driven attention to health-related traits in livestock production. Previous studies have reported medium to high heritabilities for these traits and described genomic regions associated with them. Despite its genetic component, health- and immunity-related traits are complex and its study by association analysis with genomic markers may be missing some information. To analyse multiple phenotypes and gene-by-gene interactions, systems biology approaches, such as the association weight matrix (AWM), allows combining genome wide association study results with network inference algorithms. The present study aimed to identify gene networks, key regulators and candidate genes associated to immunocompetence in pigs by integrating multiple health-related traits, enriched for innate immune phenotypes, using the AWM approach. The co-association network analysis unveiled a network comprised of 3,636 nodes (genes) and 451,407 edges (interactions), including a total of 246 regulators. From these, five genes (ARNT2, BRMS1L, MED12L, SUPT3H and TRIM25) were selected as key regulators as they were associated with the maximum number of genes with the minimum overlapping (1,827 genes in total). The five regulators were involved in pathways related to immunity such as lymphocyte differentiation and activation, platelet activation and degranulation, megakaryocyte differentiation, FcγR-mediated phagocytosis and response to nitric oxide, among others, but also in immunometabolism. Furthermore, we identified genes co-associated with the key regulators previously reported as candidate genes (e.g., ANGPT1, CD4, CD36, DOCK1, PDE4B, PRKCE, PTPRC and SH2B3) for immunity traits in humans and pigs, but also new candidate ones (e.g., ACSL3, CXADR, HBB, MMP12, PTPN6, WLS) that were not previously described. The co-association analysis revealed new regulators associated with health-related traits in pigs. This approach also identified gene-by-gene interactions and candidate genes involved in pathways related to cell fate and metabolic and immune functions. Our results shed new light in the regulatory mechanisms involved in pig immunity and reinforce the use of the pig as biomedical model.

88. Strategies to Improve the Antitumor Effect of Immunotherapy for Hepatocellular Carcinoma.

Front Immunol

2021 Nov 26

Xing R, Gao J, Cui Q

Hepatocellular carcinoma (HCC), one of the most fatal malignancies in the world, is usually diagnosed in advanced stages due to late symptom manifestation with very limited therapeutic options, which leads to ineffective intervention and dismal prognosis. For a decade, tyrosine kinase inhibitors (TKIs) have offered an overall survival (OS) benefit when used in a first-line (sorafenib and lenvatinib) and second-line setting (regorafenib and cabozantinib) in advanced HCC, while long-term response remains unsatisfactory due to the onset of primary or acquired resistance. Recently, immunotherapy has emerged as a promising therapy in the treatment of several solid tumors, such as melanoma and non-small cell lung cancer. Moreover, as the occurrence of HCC is associated with immune tolerance and immunosurveillance escape, there is a potent rationale for employing immunotherapy in HCC. However, immunotherapy monotherapy, mainly including immune checkpoint inhibitors (ICIs) that target checkpoints programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and the cytotoxic T lymphocyte antigen-4 (CTLA-4), has a relatively low response rate. Thus, the multi-ICIs or the combination of immunotherapy with other therapies, like antiangiogenic drugs and locoregional therapies, has become a novel strategy to treat HCC. Combining different ICIs may have a synergistical effect attributed to the complementary effects of the two immune checkpoint pathways (CTLA-4 and PD-1/PD-L1 pathways). The incorporation of antiangiogenic drugs in ICIs can enhance antitumor immune responses via synergistically regulating the vasculature and the immune microenvironment of tumor. In addition, locoregional treatments can improve antitumor immunity by releasing the neoplasm antigens from killed tumor cells; in turn, this antitumor immune response can be intensified by immunotherapy. Therefore, the combination of locoregional treatments and immunotherapy may achieve greater efficacy through further synergistic effects for advanced HCC. This review aims to summarize the currently reported results and ongoing trials of the ICIs-based combination therapies for HCC to explore the rational combination strategies and further improve the survival of patients with HCC.

89. SMAC Mimetics as Therapeutic Agents in HIV Infection.

Front Immunol

2021 Nov 26

Molyer B, Kumar A, Angel JB.

90. Pharmacological Poly (ADP-Ribose) Polymerase Inhibitors Decrease Mycobacterium tuberculosis Survival in Human Macrophages.

Front Immunol

2021 Nov 26

van Doorn CLR, Steenbergen SAM, Walburg KV

91. Quercetin Preserves Oral Cavity Health by Mitigating Inflammation and Microbial Dysbiosis.

Front Immunol

2021 Nov 26

Mooney EC, Holden SE, Xia XJ

92. Two Duplicated Ptpn6 Homeologs Cooperatively and Negatively Regulate RLR-Mediated IFN Response in Hexaploid Gibel Carp.

Front Immunol

2021 Nov 26

Tong JF, Zhou L, Li S

93. Macrophages Are the Key Players in Promoting Hyper-Inflammatory Response in a Mouse Model of TB-IRIS.

Front Immunol

2021 Nov 26

Pal L, Nandani R, Kumar P

TB-IRIS is an abnormal inflammatory response in a subset of HIV-TB co-infected patients shortly after initiation of anti-retroviral therapy (ART). Therapy in these patients could have greatly improved the life expectancy as ART reconstitutes the function and number of CD4+ T cells and many patients see improvement in symptoms but paradoxically up to 54% of co-infected patients develop TB-IRIS. Different studies have indicated that both innate and adaptive immunity are involved in the pathology of IRIS but the role of macrophages in abnormal activation of CD4+ T cells is poorly understood. Since macrophages are one of the major antigen-presenting cells and are infected by M.tb at a high frequency, they are very much likely to be involved in the development of TB-IRIS. In this study, we have developed a mouse model of experimental IRIS, in which M.tb-infected T-cell knockout mice undergo a fatal inflammatory disease after CD4+ T cell reconstitution. Lung macrophages and blood monocytes from M.tb-infected TCRβ-/- mice showed upregulated expression of cell surface activation markers and also showed higher mRNA expression of inflammation-associated chemokines and matrix metalloproteases responsible for tissue damage. Furthermore, cytokine and TLR signaling feedback mechanism to control excessive inflammation was also found to be dysregulated in these macrophages under lymphopenic conditions. Previous studies have shown that hyperactive CD4+ T cells are responsible for disease induction and our study shows that somehow macrophages are in a higher activated state when infected with M.tb in an immune-deficient condition, which results in excessive activation of the adoptively transferred CD4+ T cells. Understanding of the mechanisms underlying the pathophysiology of TB-IRIS would facilitate identification of prospective biomarkers for disease development in HIV-TB co-infected patients before starting antiretroviral therapy.

94. Increased Ratio of CD14(++)CD80(+) Cells/CD14(++)CD163(+) Cells in the Infrapatellar Fat Pad of End-Stage Arthropathy Patients.

Front Immunol

2021 Nov 26

Ma S, Murakami K, Saito R

OBJECTIVES: This study sought to identify the ratio of M1/M2 cells in the infrapatellar fat pads (IFP) and subcutaneous fat tissues (SC) of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. The clinical features of OA and RA patients treated with or without biological disease-modifying anti-rheumatic drugs (bDMARDs) were also assessed. METHODS: IFP and SC were collected from patients with OA and RA who are undergoing total knee arthroplasty (TKA). CD14-positive cells were then isolated from these samples. Flow cytometry was used to determine the number of CD14++CD80+ cells and CD14++CD163+ cells. The expression levels of lipid transcription factors, such as sterol regulatory element-binding protein 1 (SREBP1) and liver X receptor alpha (LXRA), and inflammatory cytokines were also evaluated. RESULTS: Twenty OA patients and 22 RA patients were enrolled in this study. Ten of the RA patients (45.4%) received bDAMRDs before TKA. On average, a fivefold increase in the number of CD14-positive cells and lower expression levels of SREBP1C and LXRA were observed in OA IFP relative to OA SC; however, these results were not obtained from the RA samples. The median ratio of CD14++CD80+ cells/CD14++CD163+ cells of OA IFP was 0.87 (0.76-1.09, interquartile range), which is higher to that of OA SC with a lower ratio (p = 0.05835). CONCLUSIONS: The quantity and quality of CD14-positive cells differed between IFP and SC in arthropathy patients. To our knowledge, this is the first study to characterize the ratio of M1/M2 cells in the IFP and SC of end-stage OA and RA patients. The increased ratio of CD14++CD80+ cells/CD14++CD163+ cells in the IFP from patients with OA and RA treated with bDMARDs indicated that inflammation was localized in the IFP. As adipose tissue-derived innate immune cells were revealed as one of the targets for regulating inflammation, further analysis of these cells in the IFP may reveal new therapeutic strategies for inflammatory joint diseases.

95. Pediococcus pentosaceus Enhances Host Resistance Against Pathogen by Increasing IL-1β Production: Understanding Probiotic Effectiveness and Administration Duration.

Front Immunol

2021 Nov 26

Shan C, Li M, Liu Z

96. Roles of Emerging RNA-Binding Activity of cGAS in Innate Antiviral Response.

Front Immunol

2021 Nov 26

Ma Y, Wang X, Luo W

97. Complement Mediated Hemolytic Anemias in the COVID-19 Era: Case Series and Review of the Literature.

Front Immunol

2021 Nov 25

Fattizzo B, Pasquale R, Bellani V

The complex pathophysiologic interplay between SARS-CoV-2 infection and complement activation is the subject of active investigation. It is clinically mirrored by the occurrence of exacerbations of complement mediated diseases during COVID-19 infection. These include complement-mediated hemolytic anemias such as paroxysmal nocturnal hemoglobinuria (PNH), autoimmune hemolytic anemia (AIHA), particularly cold agglutinin disease (CAD), and hemolytic uremic syndrome (HUS). All these conditions may benefit from complement inhibitors that are also under study for COVID-19 disease. Hemolytic exacerbations in these conditions may occur upon several triggers including infections and vaccines and may require transfusions, treatment with complement inhibitors and/or immunosuppressors (i.e., steroids and rituximab for AIHA), and result in thrombotic complications. In this manuscript we describe four patients (2 with PNH and 2 with CAD) who experienced hemolytic flares after either COVID-19 infection or SARS-Cov2 vaccine and provide a review of the most recent literature. We report that most episodes occurred within the first 10 days after COVID-19 infection/vaccination and suggest laboratory monitoring (Hb and LDH levels) in that period. Moreover, in our experience and in the literature, hemolytic exacerbations occurring during COVID-19 infection were more severe, required greater therapeutic intervention, and carried more complications including fatalities, as compared to those developing after SARS-CoV-2 vaccine, suggesting the importance of vaccinating this patient population. Patient education remains pivotal to promptly recognize signs/symptoms of hemolytic flares and to refer to medical attention. Treatment choice should be based on the severity of the hemolytic exacerbation as well as of that of COVID-19 infection. Therapies include transfusions, complement inhibitor initiation/additional dose in the case of PNH, steroids/rituximab in patients with CAD and warm type AIHA, plasma exchange, hemodialysis and complement inhibitor in the case of atypical HUS. Finally, anti-thrombotic prophylaxis should be always considered in these settings, provided safe platelet counts.

98. Immunometabolites Drive Bacterial Adaptation to the Airway.

Front Immunol

2021 Nov 25

Tomlinson KL, Prince AS, Wong Fok Lung T.

99. T Cell Fitness and Autologous CAR T Cell Therapy in Haematologic Malignancy.

Front Immunol

2021 Nov 25

Mehta PH, Fiorenza S, Koldej RM

100. Subunit-Specific Reactivity of Autoantibodies Against Laminin-332 Reveals Direct Inflammatory Mechanisms on Keratinocytes.

Front Immunol

2021 Nov 25

Bao L, Li J, Solimani F

101. Case Report: Markedly Long-Term Preservation of Pancreatic β-Cell Function in a Subject With Elderly Onset of Type 1 Diabetes Mellitus Showing High-Titer Autoimmune Antibodies for Over 4 Years.

Front Immunol

2021 Nov 25

Shigemoto R, Anno T, Kawasaki F

102. Interferon Lambda Signaling in Macrophages Is Necessary for the Antiviral Response to Influenza.

Front Immunol

2021 Nov 25

Mallampalli RK, Adair J, Elhance A

103. The Role of Vasoactive Intestinal Peptide and Mast Cells in the Regulatory Effect of Lactobacillus casei ATCC 393 on Intestinal Mucosal Immune Barrier.

Front Immunol

2021 Nov 25

Song X, Pi S, Gao Y

104. The Impact of HBV Quasispecies Features on Immune Status in HBsAg+/HBsAb+ Patients With HBV Genotype C Using Next-Generation Sequencing.

Front Immunol

2021 Nov 25

Wang Y, Xiao X, Chen S

105. Comparison of Two Diagnostic Assays for Anti-Laminin 332 Mucous Membrane Pemphigoid.

Front Immunol

2021 Nov 25

Goletz S, Giurdanella F, Holtsche MM

106. Targeting Innate Immunity in Breast Cancer Therapy: A Narrative Review.

Front Immunol

2021 Nov 25

Ye Y, Xu C, Chen F

107. Inhibition of PI3Kδ Differentially Regulates Poly I:C- and Human Metapneumovirus-Induced PD-L1 and PD-L2 Expression in Human Bronchial Epithelial Cells.

Front Immunol

2021 Nov 25

Ogawa T, Kan-O K, Shiota A

Bronchial epithelial cells are front sentinels eliciting innate and adaptive immunity to respiratory viral pathogens. Recognition of viral double-stranded RNA induces antiviral interferon (IFN) responses in bronchial epithelial cells. Co-inhibitory molecules programmed cell death 1 ligand 1 (PD-L1) and ligand 2 (PD-L2) were also induced on bronchial epithelial cells, which bind programmed cell death 1 on T cell and inhibit the function of virus-specific cytotoxic T lymphocyte. A previous study showed that antiviral type I IFN increased PD-L1 and PD-L2 expression in cultured melanoma cells. However, it remains unknown whether antiviral IFNs affect PD-L1 and PD-L2 expression in bronchial epithelial cells. In addition, we previously reported that inhibition of PI3Kδ signaling enhanced antiviral IFN responses in human primary bronchial epithelial cells (PBECs). Here we assessed the effect of exogenous IFNs or a selective PI3Kδ inhibitor IC87114 on PD-L1 and PD-L2 in PBECs stimulated with a synthetic double-stranded RNA poly I:C or human metapneumovirus. Treatment with IFNβ or IFNλ increased PD-L1 and PD-L2, and IFNβ or IFNλ treatment plus poly I:C further increased both expressions. Treatment with IC87114 or transfection with siRNA targeting PI3K p110δ enhanced poly I:C-induced gene and protein expression of PD-L2, whereas IC87114 suppressed poly I:C-induced PD-L1. IC87114 enhanced poly I:C-induced gene expression of IFNβ, IFNλ, and IFN-regulated genes via increased TBK1 and IRF3 phosphorylation. Transfection with siIRF3 counteracted the enhancement of poly I:C-induced PD-L2 by IC87114, whereas IC87114 suppressed poly I:C-induced PD-L1 regardless of transfection with siNC or siIRF3. Similar effects of IC87114 on PD-L1 and PD-L2 expression were observed in human metapneumovirus-infected PBECs. We showed for the first time that type I and type III IFNs induced the expression of PD-L1 and PD-L2 in PBECs. Our findings suggest that during viral infections, inhibition of PI3Kδ differentially regulates PD-L1 and PD-L2 expression in bronchial epithelial cells.

108. Characterization of Pathogenesis and Inflammatory Responses to Experimental Parechovirus Encephalitis.

Front Immunol

2021 Nov 25

Jan MW, Su HL, Chang TH

109. Gain-of-Function Mutations R249C and S250C in Complement C2 Protein Increase C3 Deposition in the Presence of C-Reactive Protein.

Front Immunol

2021 Nov 25

Urban A, Kowalska D, Stasiłojć G

110. Neutrophils Orchestrate the Periodontal Pocket.

Front Immunol

2021 Nov 24

Vitkov L, Muñoz LE, Schoen J

111. Programmed Cell Death Pathways in the Pathogenesis of Idiopathic Inflammatory Myopathies.

Front Immunol

2021 Nov 24

Shi J, Tang M, Zhou S

112. Monomeric IgA Antagonizes IgG-Mediated Enhancement of DENV Infection.

Front Immunol

2021 Nov 24

Wegman AD, Fang H, Rothman AL

113. Predictable Roles of Peripheral IgM Memory B Cells for the Responses to Anti-PD-1 Monotherapy Against Advanced Non-Small Cell Lung Cancer.

Front Immunol

2021 Nov 24

Xia L, Guo L, Kang J

114. Thymic Function and T-Cell Receptor Repertoire Diversity: Implications for Patient Response to Checkpoint Blockade Immunotherapy.

Front Immunol

2021 Nov 24

Cardinale A, De Luca CD, Locatelli F

115. Recent Advances in Developmental Hematopoiesis: Diving Deeper With New Technologies.

Front Immunol

2021 Nov 24

Weijts B, Yvernogeau L, Robin C.

116. SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage.

Front Immunol

2021 Nov 24

Xia DY, Yuan JL, Jiang XC

Mounting evidence has suggested that modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state might be a potential therapeutic approach in the treatment of subarachnoid hemorrhage (SAH) injury. Our previous study has indicated that sirtuin 1 (SIRT1) could ameliorate early brain injury (EBI) in SAH by reducing oxidative damage and neuroinflammation. However, the effects of SIRT1 on microglial polarization and the underlying molecular mechanisms after SAH have not been fully illustrated. In the present study, we first observed that EX527, a potent selective SIRT1 inhibitor, enhanced microglial M1 polarization and nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation in microglia after SAH. Administration of SRT1720, an agonist of SIRT1, significantly enhanced SIRT1 expression, improved functional recovery, and ameliorated brain edema and neuronal death after SAH. Moreover, SRT1720 modulated the microglia polarization shift from the M1 phenotype and skewed toward the M2 phenotype. Additionally, SRT1720 significantly decreased acetylation of forkhead box protein O1, inhibited the overproduction of reactive oxygen species (ROS) and suppressed NLRP3 inflammasome signaling. In contrast, EX527 abated the upregulation of SIRT1 and reversed the inhibitory effects of SRT1720 on ROS-NLRP3 inflammasome activation and EBI. Similarly, in vitro, SRT1720 suppressed inflammatory response, oxidative damage, and neuronal degeneration, and improved cell viability in neurons and microglia co-culture system. These effects were associated with the suppression of ROS-NLRP3 inflammasome and stimulation of SIRT1 signaling, which could be abated by EX527. Altogether, these findings indicate that SRT1720, an SIRT1 agonist, can ameliorate EBI after SAH by shifting the microglial phenotype toward M2 via modulation of ROS-mediated NLRP3 inflammasome signaling.

117. Robust Antibody Levels in Both Diabetic and Non-Diabetic Individuals After BNT162b2 mRNA COVID-19 Vaccination.

Front Immunol

2021 Nov 24

Ali H, Alterki A, Sindhu S

The emergence of effective vaccines for COVID-19 has been welcomed by the world with great optimism. Given their increased susceptibility to COVID-19, the question arises whether individuals with type-2 diabetes mellitus (T2DM) and other metabolic conditions can respond effectively to the mRNA-based vaccine. We aimed to evaluate the levels of anti-SARS-CoV-2 IgG and neutralizing antibodies in people with T2DM and/or other metabolic risk factors (hypertension and obesity) compared to those without. This study included 262 people (81 diabetic and 181 non-diabetic persons) that took two doses of BNT162b2 (Pfizer-BioNTech) mRNA vaccine. Both T2DM and non-diabetic individuals had a robust response to vaccination as demonstrated by their high antibody titers. However, both SARS-CoV-2 IgG and neutralizing antibodies titers were lower in people with T2DM. The mean ( ± 1 standard deviation) levels were 154 ± 49.1 vs. 138 ± 59.4 BAU/ml for IgG and 87.1 ± 11.6 vs. 79.7 ± 19.5% for neutralizing antibodies in individuals without diabetes compared to those with T2DM, respectively. In a multiple linear regression adjusted for individual characteristics, comorbidities, previous COVID-19 infection, and duration since second vaccine dose, diabetics had 13.86 BAU/ml (95% CI: 27.08 to 0.64 BAU/ml, p=0.041) less IgG antibodies and 4.42% (95% CI: 8.53 to 0.32%, p=0.036) fewer neutralizing antibodies than non-diabetics. Hypertension and obesity did not show significant changes in antibody titers. Taken together, both type-2 diabetic and non-diabetic individuals elicited strong immune responses to SARS-CoV-2 BNT162b2 mRNA vaccine; nonetheless, lower levels were seen in people with diabetes. Continuous monitoring of the antibody levels might be a good indicator to guide personalized needs for further booster shots to maintain adaptive immunity. Nonetheless, it is important that people get their COVID-19 vaccination especially people with diabetes.

118. Dietary β-Carotene on Postpartum Uterine Recovery in Mice: Crosstalk Between Gut Microbiota and Inflammation.

Front Immunol

2021 Nov 24

Yang X, He Z, Hu R

119. Exploring the Prognostic Value, Immune Implication and Biological Function of H2AFY Gene in Hepatocellular Carcinoma.

Front Immunol

2021 Nov 24

Huang Y, Huang S, Ma L

120. Activation of Intracellular Complement in Lungs of Patients With Severe COVID-19 Disease Decreases T-Cell Activity in the Lungs.

Front Immunol

2021 Nov 24

Howell MC, Green R, McGill AR

121. Effectiveness of Regdanvimab Treatment in High-Risk COVID-19 Patients to Prevent Progression to Severe Disease.

Front Immunol

2021 Nov 23

Lee JY, Lee JY, Ko JH

OBJECTIVE: To evaluate clinical effectiveness of regdanvimab, a monoclonal antibody agent for treating coronavirus 2019 (COVID-19). METHODS: A retrospective cohort study was conducted at two general hospitals during the study period of December 2020 to May 2021. Mild COVID-19 patients with risk factors for disease progression admitted to the hospitals within seven days of symptom onset were enrolled and followed until discharge or referral. Multivariate analyses for disease progression were conducted in the total and propensity score (PS)-matched cohorts. RESULTS: A total of 778 mild COVID-19 patients were included and classified as the regdanvimab (n = 234) and supportive care (n = 544) groups. Significantly fewer patients required O2 supplementation via nasal prong in the regdanvimab group (8.1%) than in the supportive care group (18.4%, P < 0.001). The decreased risk for O2 support by regdanvimab treatment was noticed in the multivariate analysis of the total cohort (HR 0.570, 95% CI 0.343-0.946, P = 0.030), but it was not statistically significant in the PS-matched cohort (P = 0.057). Progression to severe disease was also significantly lower in the regdanvimab group (2.1%) than in the supportive care group (9.6%, P < 0.001). The significantly reduced risk for progression to severe disease by regdanvimab treatment was observed in the analysis of both the total cohort (HR 0.262, 95% CI 0.103-0.667, P = 0.005) and PS-matched cohort (HR 0.176, 95% CI 0.060-0.516, P = 0.002). Potential risk factors for progression were investigated in the supportive care group and SpO2 < 97% and CRP elevation >1.5 mg/dL were common risk factors for O2 support and progression to severe disease. Among the patients with any of these factors, regdanvimab treatment was associated with decreased risk for progression to severe disease with slightly lower HR (HR 0.202, 95% CI 0.062-0.657, P = 0.008) than that of the total cohort. CONCLUSION: Regdanvimab treatment was associated with a decreased risk of progression to severe disease.

122. Editorial: New Insights on Bruton's Tyrosine Kinase Inhibitors.

Front Immunol

2021 Nov 23

Smith CIE, Brown JR, Zain R.

123. A Novel Germline Heterozygous BCL11B Variant Causing Severe Atopic Disease and Immune Dysregulation.

Front Immunol

2021 Nov 23

Lu HY, Sertori R, Contreras AV

124. SIRT1: A Potential Therapeutic Target in Autoimmune Diseases.

Front Immunol

2021 Nov 23

Shen P, Deng X, Chen Z

125. Immune Cell Infiltration Analysis Demonstrates Excessive Mast Cell Activation in Psoriasis.

Front Immunol

2021 Nov 23

Zhang Y, Shi Y, Lin J

126. Leukocyte Membrane Enzymes Play the Cell Adhesion Game.

Front Immunol

2021 Nov 23

López-Cortés GI, Díaz-Alvarez L, Ortega E.

127. High Dimensional Immune Profiling Reveals Different Response Patterns in Active and Latent Tuberculosis Following Stimulation With Mycobacterial Glycolipids.

Front Immunol

2021 Nov 23

Silva CS, Sundling C, Folkesson E

128. Editorial: Neuroinflammation and Neuroautoimmunity in Peripheral Neuropathies: Old Players, New Roles.

Front Immunol

2021 Nov 23

Marinelli S, Maiarù M, Colciago A.

129. Commentary: Efficacy and Safety of Dupilumab in Moderate-to-Severe Bullous Pemphigoid.

Front Immunol

2021 Nov 23

Wang SH, Zuo YG.

130. m6A Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization in Acute Myeloid Leukemia.

Front Immunol

2021 Nov 23

Du A, Wu X, Gao Y

131. hPMSCs-Derived Exosomal miRNA-21 Protects Against Aging-Related Oxidative Damage of CD4(+) T Cells by Targeting the PTEN/PI3K-Nrf2 Axis.

Front Immunol

2021 Nov 23

Xiong Y, Xiong Y, Zhang H

132. Plasma MicroRNA Signature Panel Predicts the Immune Response After Antiretroviral Therapy in HIV-Infected Patients.

Front Immunol

2021 Nov 23

Lv JN, Li JQ, Cui YB

133. Identification of Immune-Related Gene Signatures in Lung Adenocarcinoma and Lung Squamous Cell Carcinoma.

Front Immunol

2021 Nov 23

Li N, Wang J, Zhan X.

Accumulating evidence indicates that immunotherapy helped to improve the survival and quality-of-life of patients with lung adenocarcinoma (LUAD) or lung squamous cell carcinoma (LUSC) besides chemotherapy and gene targeting treatment. This study aimed to develop immune-related gene signatures in LUAD and LUSC subtypes, respectively. LUAD and LUSC samples were divided into high- and low-abundance groups of immune cell infiltration (Immunity_H and Immunity_L) based on the abundance of immune cell infiltrations. The distribution of immune cells was significantly different between the high- and low-immunity subtypes in LUAD and LUSC samples. The differentially expressed genes (DEGs) between those two groups in LUAD and LUSC contain some key immune-related genes, such as PDL1, PD1, CTLA-4, and HLA families. The DEGs were enriched in multiple immune-related pathways. Furthermore, the seven-immune-related-gene-signature (CD1B, CHRNA6, CLEC12B, CLEC17A, CLNK, INHA, and SLC14A2) prognostic model-based high- and low-risk groups were significantly associated with LUAD overall survival and clinical characteristics. The eight-immune-related-gene-signature (C4BPB, FCAMR, GRAPL, MAP1LC3C, MGC2889, TRIM55, UGT1A1, and VIPR2) prognostic model-based high- and low-risk groups were significantly associated with LUSC overall survival and clinical characteristics. The prognostic models were tested as good ones by receiver operating characteristic, principal component analysis, univariate and multivariate analysis, and nomogram. The verifications of these two immune-related-gene-signature prognostic models showed consistency in the train and test cohorts of LUAD and LUSC. In addition, patients with LUAD in the low-risk group responded better to immunotherapy than those in the high-risk group. This study revealed two reliable immune-related-gene-signature models that were significantly associated with prognosis and tumor microenvironment cell infiltration in LUAD and LUSC, respectively. Evaluation of the integrated characterization of multiple immune-related genes and pathways could help to predict the response to immunotherapy and monitor immunotherapy strategies.

134. Dual Targeting by Inhibition of Phosphoinositide-3-Kinase and Mammalian Target of Rapamycin Attenuates the Neuroinflammatory Responses in Murine Hippocampal Cells and Seizures in C57BL/6 Mice.

Front Immunol

2021 Nov 23

Vyas P, Tulsawani R, Vohora D.

Emerging evidence suggests the association of seizures and inflammation; however, underlying cell signaling mechanisms are still not fully understood. Overactivation of phosphoinositide-3-kinases is associated with both neuroinflammation and seizures. Herein, we speculate the PI3K/Akt/mTOR pathway as a promising therapeutic target for neuroinflammation-mediated seizures and associated neurodegeneration. Firstly, we cultured HT22 cells for detection of the downstream cell signaling events activated in a lipopolysaccharide (LPS)-primed pilocarpine (PILO) model. We then evaluated the effects of 7-day treatment of buparlisib (PI3K inhibitor, 25 mg/kg p.o.), dactolisib (PI3K/mTOR inhibitor, 25 mg/kg p.o.), and rapamycin (mTORC1 inhibitor, 10 mg/kg p.o.) in an LPS-primed PILO model of seizures in C57BL/6 mice. LPS priming resulted in enhanced seizure severity and reduced latency. Buparlisib and dactolisib, but not rapamycin, prolonged latency to seizures and reduced neuronal loss, while all drugs attenuated seizure severity. Buparlisib and dactolisib further reduced cellular redox, mitochondrial membrane potential, cleaved caspase-3 and p53, nuclear integrity, and attenuated NF-κB, IL-1β, IL-6, TNF-α, and TGF-β1 and TGF-β2 signaling both in vitro and in vivo post-PILO and LPS+PILO inductions; however, rapamycin mitigated the same only in the PILO model. Both drugs protected against neuronal cell death demonstrating the contribution of this pathway in the seizure-induced neuronal pyknosis; however, rapamycin showed resistance in a combination model. Furthermore, LPS and PILO exposure enhanced pAkt/Akt and phospho-p70S6/total-p70S6 kinase activity, while buparlisib and dactolisib, but not rapamycin, could reduce it in a combination model. Partial rapamycin resistance was observed possibly due to the reactivation of the pathway by a functionally different complex of mTOR, i.e., mTORC2. Our study substantiated the plausible involvement of PI3K-mediated apoptotic and inflammatory pathways in LPS-primed PILO-induced seizures and provides evidence that its modulation constitutes an anti-inflammatory mechanism by which seizure inhibitory effects are observed. We showed dual inhibition by dactolisib as a promising approach. Targeting this pathway at two nodes at a time may provide new avenues for antiseizure therapies.

135. Successful Milk Oral Immunotherapy Promotes Generation of Casein-Specific CD137(+) FOXP3(+) Regulatory T Cells Detectable in Peripheral Blood.

Front Immunol

2021 Nov 23

Zhang Y, Li L, Genest G

BACKGROUND: Oral immunotherapy (OIT) is an emerging treatment for cow's milk protein (CMP) allergy in children. The mechanisms driving tolerance following OIT are not well understood. Regulatory T cells (TREG) cells are key inhibitors of allergic responses and promoters of allergen-specific tolerance. In an exploratory study, we sought to detect induction of allergen-specific TREG in a cohort of subjects undergoing OIT. METHODS: Pediatric patients with a history of allergic reaction to cow's milk and a positive Skin Pick Test (SPT) and/or CMP-specific IgE >0.35 kU, as well as a positive oral challenge to CMP underwent OIT with escalating doses of milk and were followed for up to 6 months. At specific milestones during the dose escalation and maintenance phases, casein-specific CD4+ T cells were expanded from patient blood by culturing unfractionated PBMCs with casein in vitro. The CD4+ T cell phenotypes were quantified by flow cytometry. RESULTS: Our culture system induced activated casein-specific FOXP3+Helios+ TREG cells and FOXP3- TEFF cells, discriminated by expression of CD137 (4-1BB) and CD154 (CD40L) respectively. The frequency of casein-specific TREG cells increased significantly with escalating doses of milk during OIT while casein-specific TEFF cell frequencies remained constant. Moreover, expanded casein-specific TREG cells expressed higher levels of FOXP3 compared to polyclonal TREG cells, suggesting a more robust TREG phenotype. The induction of casein-specific TREG cells increased with successful CMP desensitization and correlated with increased frequencies of casein-specific Th1 cells among OIT subjects. The level of casein-specific TREG cells negatively correlated with the time required to reach the maintenance phase of desensitization. CONCLUSIONS: Overall, effective CMP-OIT successfully promoted the expansion of casein-specific, functionally-stable FOXP3+ TREG cells while mitigating Th2 responses in children receiving OIT. Our exploratory study proposes that an in vitro TREG response to casein may correlate with the time to reach maintenance in CMP-OIT.

136. Identification and Validation of 17-lncRNA Related to Regulatory T Cell Heterogeneity as a Prognostic Signature for Head and Neck Squamous Cell Carcinoma.

Front Immunol

2021 Nov 22

Sun Q, Li Y, Yang X

137. Conditioned Medium of Human Amniotic Epithelial Cells Alleviates Experimental Allergic Conjunctivitis Mainly by IL-1ra and IL-10.

Front Immunol

2021 Nov 22

Wu B, Gao F, Lin J

138. CD247, a Potential T Cell-Derived Disease Severity and Prognostic Biomarker in Patients With Idiopathic Pulmonary Fibrosis.

Front Immunol

2021 Nov 22

Li Y, Chen S, Li X

139. Fish Paralog Proteins RNASEK-a and -b Enhance Type I Interferon Secretion and Promote Apoptosis.

Front Immunol

2021 Nov 22

Sun ZC, Jiang Z, Xu X

140. Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy in Children: A Retrospective Analysis of 35 Cases.

Front Immunol

2021 Nov 22

Fang H, Hu W, Jiang Z

OBJECTIVE: To analyze the clinical manifestations, imaging, electroencephalography, treatment, and prognosis of 35 cases of autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) in children. METHODS: Children hospitalized in the Department of Neurology, Hunan Children's Hospital, China, between January 2015 and June 2021, owing to autoimmune diseases of the central nervous system were subjected to a cell-based assay (CBA). The assay identified 40 children positive for GFAP-immunoglobulin (Ig)G antibodies in the serum and/or the cerebrospinal fluid. Based on clinical manifestations and imaging characteristics, five children who were only positive for GFAP-IgG antibodies in serum were excluded, and the remaining 35 children were diagnosed with autoimmune GFAP-A. The clinical data derived from the 35 children were retrospectively analyzed. RESULTS: A total of 35 children, including 23 males and 12 females with a mean age of 6.3 ± 0.6 years, manifested clinical symptoms of fever (62.9%), headache (42.9%), convulsions (42.9%), abnormal mental behavior (51.4%), disorders of consciousness (54.3%), visual disturbance (22.9%), ataxia (11.4%), paralysis (40%), and autonomic dysfunction (25.7%). One child exhibited only the clinical symptom of peripheral facial nerve palsy. Eleven out of 35 children were also positive for other antibodies. In addition to the common overlapping autoimmune syndromes, one case of autoimmune GFAP-A also manifested as Bickerstaff's brainstem encephalitis. Linear periventricular enhancement upon MRI was significantly less frequent in children (8.5%) than in adults. In pediatric patients, MRI contrast enhancement was principally seen in the meninges and brain lobes. Although repeated relapse (17.1%) and sequelae symptoms (20%) occurred in some cases, most children showed a favorable prognosis. Spearman's rank correlation showed that the antibody titer was not significantly associated with the severity of the initial disease conditions. CONCLUSIONS: The disease diagnosis in children seropositive for GFAP antibodies only should receive a comprehensive diagnosis based on their clinical symptoms, imaging, electroencephalographic characteristics, and treatment responses. Some patients with relapses should receive repeated gamma globulin and corticosteroid therapy or the addition of immunosuppressants to their therapeutic regimen, and slow-dose tapering of corticosteroids and extended treatment are recommended for patients with overlapping autoimmune syndromes.

141. Integrative Single-Cell RNA-Seq and ATAC-Seq Analysis of Peripheral Mononuclear Cells in Patients With Ankylosing Spondylitis.

Front Immunol

2021 Nov 22

Xu H, Yu H, Liu L

142. Transcriptional Profiling and Machine Learning Unveil a Concordant Biosignature of Type I Interferon-Inducible Host Response Across Nasal Swab and Pulmonary Tissue for COVID-19 Diagnosis.

Front Immunol

2021 Nov 22

Zhang C, Feng YG, Tam C

BACKGROUND: COVID-19, caused by SARS-CoV-2 virus, is a global pandemic with high mortality and morbidity. Limited diagnostic methods hampered the infection control. Since the direct detection of virus mainly by RT-PCR may cause false-negative outcome, host response-dependent testing may serve as a complementary approach for improving COVID-19 diagnosis. OBJECTIVE: Our study discovered a highly-preserved transcriptional profile of Type I interferon (IFN-I)-dependent genes for COVID-19 complementary diagnosis. METHODS: Computational language R-dependent machine learning was adopted for mining highly-conserved transcriptional profile (RNA-sequencing) across heterogeneous samples infected by SARS-CoV-2 and other respiratory infections. The transcriptomics/high-throughput sequencing data were retrieved from NCBI-GEO datasets (GSE32155, GSE147507, GSE150316, GSE162835, GSE163151, GSE171668, GSE182569). Mathematical approaches for homological analysis were as follows: adjusted rand index-related similarity analysis, geometric and multi-dimensional data interpretation, UpsetR, t-distributed Stochastic Neighbor Embedding (t-SNE), and Weighted Gene Co-expression Network Analysis (WGCNA). Besides, Interferome Database was used for predicting the transcriptional factors possessing IFN-I promoter-binding sites to the key IFN-I genes for COVID-19 diagnosis. RESULTS: In this study, we identified a highly-preserved gene module between SARS-CoV-2 infected nasal swab and postmortem lung tissue regulating IFN-I signaling for COVID-19 complementary diagnosis, in which the following 14 IFN-I-stimulated genes are highly-conserved, including BST2, IFIT1, IFIT2, IFIT3, IFITM1, ISG15, MX1, MX2, OAS1, OAS2, OAS3, OASL, RSAD2, and STAT1. The stratified severity of COVID-19 may also be identified by the transcriptional level of these 14 IFN-I genes. CONCLUSION: Using transcriptional and computational analysis on RNA-seq data retrieved from NCBI-GEO, we identified a highly-preserved 14-gene transcriptional profile regulating IFN-I signaling in nasal swab and postmortem lung tissue infected by SARS-CoV-2. Such a conserved biosignature involved in IFN-I-related host response may be leveraged for COVID-19 diagnosis.

143. The Impact of Inflammation on the Immune Responses to Transplantation: Tolerance or Rejection?

Front Immunol

2021 Nov 22

Ravindranath MH, El Hilali F, Filippone EJ.

144. Gene Expression Analysis of the Bone Marrow Microenvironment Reveals Distinct Immunotypes in Smoldering Multiple Myeloma Associated to Progression to Symptomatic Disease.

Front Immunol

2021 Nov 22

Isola I, Brasó-Maristany F, Moreno DF

BACKGROUND: We previously reported algorithms based on clinical parameters and plasma cell characteristics to identify patients with smoldering multiple myeloma (SMM) with higher risk of progressing who could benefit from early treatment. In this work, we analyzed differences in the immune bone marrow (BM) microenvironment in SMM to better understand the role of immune surveillance in disease progression and to identify immune biomarkers associated to higher risk of progression. METHODS: Gene expression analysis of BM cells from 28 patients with SMM, 22 patients with monoclonal gammopathy of undetermined significance (MGUS) and 22 patients with symptomatic MM was performed by using Nanostring Technology. RESULTS: BM cells in SMM compared to both MGUS and symptomatic MM showed upregulation of genes encoding for key molecules in cytotoxicity. However, some of these cytotoxic molecules positively correlated with inhibitory immune checkpoints, which may impair the effector function of BM cytotoxic cells. Analysis of 28 patients with SMM revealed 4 distinct clusters based on immune composition and activation markers. Patients in cluster 2 showed a significant increase in expression of cytotoxic molecules but also inhibitory immune checkpoints compared to cluster 3, suggesting the presence of cytotoxic cells with an exhausted phenotype. Accordingly, patients in cluster 3 had a significantly longer progression free survival. Finally, individual gene expression analysis showed that higher expression of TNF superfamily members (TNF, TNFAIP3, TNFRSF14) was associated with shorter progression free survival. CONCLUSIONS: Our results suggest that exhausted cytotoxic cells are associated to high-risk patients with SMM. Biomarkers overexpressed in patients with this immune gene profile in combination with clinical parameters and PC characterization may be useful to identify SMM patients with higher risk of progression.

145. Successful Immunotherapy for Pancreatic Cancer in a Patient With TSC2 and SMAD4 Mutations: A Case Report.

Front Immunol

2021 Nov 22

Ye Y, Zheng S.

146. In-Silico Tool for Predicting, Scanning, and Designing Defensins.

Front Immunol

2021 Nov 22

Kaur D, Patiyal S, Arora C

147. Performance Evaluation of Multiple Ultrasonographical Methods for the Detection of Primary Sjögren's Syndrome.

Front Immunol

2021 Nov 22

Xu S, Luo J, Zhu C

148. Immune Evasive Effects of SARS-CoV-2 Variants to COVID-19 Emergency Used Vaccines.

Front Immunol

2021 Nov 22

Zhang Y, Banga Ndzouboukou JL, Gan M

149. N6-Methyladenosine Methylation Analysis of Long Noncoding RNAs and mRNAs in IPEC-J2 Cells Treated With Clostridium perfringens beta2 Toxin.

Front Immunol

2021 Nov 22

Yang J, Yang Q, Zhang J

BACKGROUND: The n6-methyladenosine (m6A) modification is present widely in mRNAs and long non-coding RNAs (lncRNAs), and is related to the occurrence and development of certain diseases. However, the role of m6A methylation in Clostridium perfringens type C infectious diarrhea remains unclear. METHODS: Here, we treated intestinal porcine jejunum epithelial cells (IPEC-J2 cells) with Clostridium perfringens beta2 (CPB2) toxin to construct an in vitro model of Clostridium perfringens type C (C. perfringens type C) infectious diarrhea, and then used methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) to identify the methylation profiles of mRNAs and lncRNAs in IPEC-J2 cells. RESULTS: We identified 6,413 peaks, representing 5,825 m6A-modified mRNAs and 433 modified lncRNAs, of which 4,356 m6A modified mRNAs and 221 m6A modified lncRNAs were significantly differential expressed between the control group and CPB2 group. The motif GGACU was enriched significantly in both the control group and the CPB2 group. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation analysis showed that the differentially methylated modified mRNAs were mainly enriched in Hippo signaling pathway and Wnt signaling pathway. In addition, the target genes of the differentially m6A modified lncRNAs were related to defense response to virus and immune response. For example, ENSSSCG00000042575, ENSSSCG00000048701 and ENSSSCG00000048785 might regulate the defense response to virus, immune and inflammatory response to resist the harmful effects of viruses on cells. CONCLUSION: In summary, this study established the m6A transcription profile of mRNAs and lncRNAs in IPEC-J2 cells treated by CPB2 toxin. Further analysis showed that m6A-modified RNAs were related to defense against viruses and immune response after CPB2 toxin treatment of the cells. Threem6A-modified lncRNAs, ENSSSCG00000042575, ENSSSCG00000048785 and ENSSSCG00000048701, were most likely to play a key role in CPB2 toxin-treated IPEC-J2 cells. The results provide a theoretical basis for further research on the role of m6A modification in piglet diarrhea.

150. Cancer Evo-Dev: A Theory of Inflammation-Induced Oncogenesis.

Front Immunol

2021 Nov 22

Liu W, Deng Y, Li Z

Chronic inflammation is a prerequisite for the development of cancers. Here, we present the framework of a novel theory termed as Cancer Evolution-Development (Cancer Evo-Dev) based on the current understanding of inflammation-related carcinogenesis, especially hepatocarcinogenesis induced by chronic infection with hepatitis B virus. The interaction between genetic predispositions and environmental exposures, such as viral infection, maintains chronic non-resolving inflammation. Pollution, metabolic syndrome, physical inactivity, ageing, and adverse psychosocial exposure also increase the risk of cancer via inducing chronic low-grade smoldering inflammation. Under the microenvironment of non-resolving inflammation, pro-inflammatory factors facilitate the generation of somatic mutations and viral mutations by inducing the imbalance between the mutagenic forces such as cytidine deaminases and mutation-correcting forces including uracil-DNA glycosylase. Most cells with somatic mutations and mutated viruses are eliminated in survival competition. Only a small percentage of mutated cells survive, adapt to the hostile environment, retro-differentiate, and function as cancer-initiating cells via altering signaling pathways. These cancer-initiating cells acquire stem-ness, reprogram metabolic patterns, and affect the microenvironment. The carcinogenic process follows the law of "mutation-selection-adaptation". Chronic physical activity reduces the levels of inflammation via upregulating the activity and numbers of NK cells and lymphocytes and lengthening leukocyte telomere; downregulating proinflammatory cytokines including interleukin-6 and senescent lymphocytes especially in aged population. Anti-inflammation medication reduces the occurrence and recurrence of cancers. Targeting cancer stemness signaling pathways might lead to cancer eradication. Cancer Evo-Dev not only helps understand the mechanisms by which inflammation promotes the development of cancers, but also lays the foundation for effective prophylaxis and targeted therapy of various cancers.

151. Lumpfish (Cyclopterus lumpus) Is Susceptible to Renibacterium salmoninarum Infection and Induces Cell-Mediated Immunity in the Chronic Stage.

Front Immunol

2021 Nov 22

Gnanagobal H, Cao T, Hossain A

Renibacterium salmoninarum is a Gram-positive, intracellular pathogen that causes Bacterial Kidney Disease (BKD) in several fish species in freshwater and seawater. Lumpfish (Cyclopterus lumpus) is utilized as a cleaner fish to biocontrol sea lice infestation in Atlantic salmon (Salmo salar) farms. Atlantic salmon is susceptible to R. salmoninarum, and it can transfer the infection to other fish species. Although BKD outbreaks have not been reported in lumpfish, its susceptibility and immune response to R. salmoninarum is unknown. In this study, we evaluated the susceptibility and immune response of lumpfish to R. salmoninarum infection. Groups of lumpfish were intraperitoneally (i.p.) injected with either R. salmoninarum (1×107, 1×108, or 1×109 cells dose-1) or PBS (control). R. salmoninarum infection kinetics and mortality were followed for 98 days post-infection (dpi). Transcript expression levels of 33 immune-relevant genes were measured in head kidney (n = 6) of fish infected with 1×109 cells/dose and compared to the control at 28 and 98 dpi. Infected lumpfish displayed characteristic clinical signs of BKD. Lumpfish infected with high, medium, and low doses had a survival rate of 65%, 93%, and 95%, respectively. Mortality in the high-dose infected group stabilized after 50 dpi, but R. salmoninarum persisted in the fish tissues until 98 dpi. Cytokines (il1β, il8a, il8b), pattern recognition receptors (tlr5a), interferon-induced effectors (rsad2, mxa, mxb, mxc), and iron regulation (hamp) and acute phase reactant (saa5) related genes were up-regulated at 28 dpi. In contrast, cell-mediated adaptive immunity-related genes (cd4a, cd4b, ly6g6f, cd8a, cd74) were down-regulated at 28 dpi, revealing the immune suppressive nature of R. salmoninarum. However, significant upregulation of cd74 at 98 dpi suggests induction of cell-mediated immune response. This study showed that R. salmoninarum infected lumpfish in a similar fashion to salmonid fish species and caused a chronic infection, enhancing cell-mediated adaptive immune response.

152. Blockade of CC Chemokine Receptor Type 3 Diminishes Pain and Enhances Opioid Analgesic Potency in a Model of Neuropathic Pain.

Front Immunol

2021 Nov 2

Pawlik K, Ciechanowska A, Ciapała K

Neuropathic pain is a serious clinical issue, and its treatment remains a challenge in contemporary medicine. Thus, dynamic development in the area of animal and clinical studies has been observed. The mechanisms of neuropathic pain are still not fully understood; therefore, studies investigating these mechanisms are extremely important. However, much evidence indicates that changes in the activation and infiltration of immune cells cause the release of pronociceptive cytokines and contribute to neuropathic pain development and maintenance. Moreover, these changes are associated with low efficacy of opioids used to treat neuropathy. To date, the role of CC chemokine receptor type 3 (CCR3) in nociception has not been studied. Similarly, little is known about its endogenous ligands (C-C motif ligand; CCL), namely, CCL5, CCL7, CCL11, CCL24, CCL26, and CCL28. Our research showed that the development of hypersensitivity in rats following chronic constriction injury (CCI) of the sciatic nerve is associated with upregulation of CCL7 and CCL11 in the spinal cord and dorsal root ganglia (DRG). Moreover, our results provide the first evidence that single and repeated intrathecal administration of the CCR3 antagonist SB328437 diminishes mechanical and thermal hypersensitivity. Additionally, repeated administration enhances the analgesic properties of morphine and buprenorphine following nerve injury. Simultaneously, the injection of SB328437 reduces the protein levels of some pronociceptive cytokines, such as IL-6, CCL7, and CCL11, in parallel with a reduction in the activation and influx of GFAP-, CD4- and MPO-positive cells in the spinal cord and/or DRG. Moreover, we have shown for the first time that an inhibitor of myeloperoxidase-4-aminobenzoic hydrazide may relieve pain and simultaneously enhance morphine and buprenorphine efficacy. The obtained results indicate the important role of CCR3 and its modulation in neuropathic pain treatment and suggest that it represents an interesting target for future investigations.

153. Ets-2 Propagates IL-6 Trans-Signaling Mediated Osteoclast-Like Changes in Human Rheumatoid Arthritis Synovial Fibroblast.

Front Immunol

2021 Nov 2

Singh AK, Haque M, Madarampalli B

154. Comprehensive Multi-Omics Identification of Interferon-γ Response Characteristics Reveals That RBCK1 Regulates the Immunosuppressive Microenvironment of Renal Cell Carcinoma.

Front Immunol

2021 Nov 2

Xu W, Tao J, Zhu W

Interferon-gamma (IFN-γ) has a complex role in modulating the tumor microenvironment (TME) during renal cell carcinoma (RCC) development. To define the role of IFN-γ response genes in RCC progression, we characterized the differential gene expression, prognostic implications, and DNA variation profiles of selected IFN-γ response signatures, which exhibited a significant hazard ratio for the overall survival (OS) and progression-free survival (PFS) of papillary, chromophobia, and clear cell RCC (ccRCC) patients (n = 944). Prognostic nomograms were constructed to predict the outcomes for ccRCC patients, highlighting the prognostic implications of RANBP2-type and C3HC4-type zinc finger containing 1 (RBCK1). Interestingly, large-scale pan-cancer samples (n = 12,521) and three single-cell RNA datasets revealed that RBCK1 showed markedly differential expression between cancer and normal tissues and significantly correlated with tumor-infiltrating immune cells, tumor purity, and immune checkpoint molecules, such as PD-L1, CTLA-4, LAG-3, and TIGIT in pan-cancer samples. Notably, the TIDE score was significantly higher in the RBCK1high group compared with the RBCK1low group in both ccRCC and RCC cohorts. Besides, immunohistochemistry staining showed significantly elevated RBCK1 expression in tumors (n = 50) compared with kidney samples (n = 40) from a real-world cohort, Fudan University Shanghai Cancer Center (FUSCC, Shanghai). After RBCK1 expression was confirmed in ccRCC, we found a significantly decreased number of infiltrating CD4+ T cells, CD4+ FOXP3+ Treg cells, M1 macrophages, and CD56bight/dim NK cells in the immune-cold RBCK1high group. In addition to the distinct heterogeneous immune microenvironment, the increased expression of RBCK1 predicted a prominently worse prognosis than the RBCK1low group for 232 ccRCC patients in the FUSCC proteomic cohort. Furthermore, after transfected with siRNA in human ccRCC cells, extraordinarily decreased cell proliferation, migration capacities, and prominently elevated apoptosis tumor cell proportion were found in the siRNA groups compared with the negative control group. In conclusion, this study identified IFN-γ response clusters, which might be used to improve the prognostic accuracy of immune contexture in the ccRCC microenvironment. Immune-cold RBCK1high patients have pro-tumorigenic immune infiltration and significantly worse outcomes than RBCK1low patients based on results from multi-omics to real-world data. Our discovery of novel independent prognostic indicators for RCC highlights the association between tumor alterations and immune phenotype.

155. Herpes DNAemia and TTV Viraemia in Intensive Care Unit Critically Ill Patients: A Single-Centre Prospective Longitudinal Study.

Front Immunol

2021 Nov 2

Mallet F, Diouf L, Meunier B

INTRODUCTION: We analysed blood DNAemia of TTV and four herpesviruses (CMV, EBV, HHV6, and HSV-1) in the REAnimation Low Immune Status Marker (REALISM) cohort of critically ill patients who had presented with either sepsis, burns, severe trauma, or major surgery. The aim was to identify common features related to virus and injury-associated pathologies and specific features linking one or several viruses to a particular pathological context. METHODS: Overall and individual viral DNAemia were measured over a month using quantitative PCR assays from the 377 patients in the REALISM cohort. These patients were characterised by clinical outcomes [severity scores, mortality, Intensive Care Unit (ICU)-acquired infection (IAI)] and 48 parameters defining their host response after injury (cell populations, immune functional assays, and biomarkers). Association between viraemic event and clinical outcomes or immune markers was assessed using χ2-test or exact Fisher's test for qualitative variables and Wilcoxon test for continuous variables. RESULTS: The cumulative incidence of viral DNAemia increased from below 4% at ICU admission to 35% for each herpesvirus during the first month. EBV, HSV1, HHV6, and CMV were detected in 18%, 12%, 10%, and 9% of patients, respectively. The incidence of high TTV viraemia (>10,000 copies/ml) increased from 11% to 15% during the same period. Herpesvirus viraemia was associated with severity at admission; CMV and HHV6 viraemia correlated with mortality during the first week and over the month. The presence of individual herpesvirus during the first month was significantly associated (p < 0.001) with the occurrence of IAI, whilst herpesvirus DNAemia coupled with high TTV viraemia during the very first week was associated with IAI. Herpesvirus viraemia was associated with a lasting exacerbated host immune response, with concurrent profound immune suppression and hyper inflammation, and delayed return to immune homeostasis. The percentage of patients presenting with herpesvirus DNAemia was significantly higher in sepsis than in all other groups. Primary infection in the hospital and high IL10 levels might favour EBV and CMV reactivation. CONCLUSION: In this cohort of ICU patients, phenotypic differences were observed between TTV and herpesviruses DNAemia. The higher prevalence of herpesvirus DNAemia in sepsis hints at further studies that may enable a better in vivo understanding of host determinants of herpesvirus viral reactivation. Furthermore, our data suggest that EBV and TTV may be useful as additional markers to predict clinical deterioration in ICU patients.

156. Dendritic Cell Vaccination of Glioblastoma: Road to Success or Dead End.

Front Immunol

2021 Nov 2

Datsi A, Sorg RV.

157. Editorial: Inflammation in Healing and Regeneration of Cutaneous Wounds.

Front Immunol

2021 Nov 19

Cowin AJ, Bayat A, Murray RZ

158. CCR5 Receptor Occupancy Analysis Reveals Increased Peripheral Blood CCR5+CD4+ T Cells Following Treatment With the Anti-CCR5 Antibody Leronlimab.

Front Immunol

2021 Nov 19

Chang XL, Wu HL, Webb GM

CCR5 plays a central role in infectious disease, host defense, and cancer progression, thereby making it an ideal target for therapeutic development. Notably, CCR5 is the major HIV entry co-receptor, where its surface density correlates with HIV plasma viremia. The level of CCR5 receptor occupancy (RO) achieved by a CCR5-targeting therapeutic is therefore a critical predictor of its efficacy. However, current methods to measure CCR5 RO lack sensitivity, resulting in high background and overcalculation. Here, we report on two independent, flow cytometric methods of calculating CCR5 RO using the anti-CCR5 antibody, Leronlimab. We show that both methods led to comparable CCR5 RO values, with low background on untreated CCR5+CD4+ T cells and sensitive measurements of occupancy on both blood and tissue-resident CD4+ T cells that correlated longitudinally with plasma concentrations in Leronlimab-treated macaques. Using these assays, we found that Leronlimab stabilized cell surface CCR5, leading to an increase in the levels of circulating and tissue-resident CCR5+CD4+ T cells in vivo in Leronlimab-treated macaques. Weekly Leronlimab treatment in a chronically SIV-infected macaque led to increased CCR5+CD4+ T cells levels and fully suppressed plasma viremia, both concomitant with full CCR5 RO on peripheral blood CD4+ T cells, demonstrating that CCR5+CD4+ T cells were protected from viral replication by Leronlimab binding. Finally, we extended these results to Leronlimab-treated humans and found that weekly 700 mg Leronlimab led to complete CCR5 RO on peripheral blood CD4+ T cells and a statistically significant increase in CCR5+CD4+ T cells in peripheral blood. Collectively, these results establish two RO calculation methods for longitudinal monitoring of anti-CCR5 therapeutic antibody blockade efficacy in both macaques and humans, demonstrate that CCR5+CD4+ T cell levels temporarily increase with Leronlimab treatment, and facilitate future detailed investigations into the immunological impacts of CCR5 inhibition in multiple pathophysiological processes.

159. Avoiding Absolute Quantification Trap: A Novel Predictive Signature of Clinical Benefit to Anti-PD-1 Immunotherapy in Non-Small Cell Lung Cancer.

Front Immunol

2021 Nov 19

Liu C, Wang S, Zheng S

160. An Immunogenic Cell Death-Related Classification Predicts Prognosis and Response to Immunotherapy in Head and Neck Squamous Cell Carcinoma.

Front Immunol

2021 Nov 19

Wang X, Wu S, Liu F

161. Melanocortin 1 Receptor Deficiency in Hematopoietic Cells Promotes the Expansion of Inflammatory Leukocytes in Atherosclerotic Mice.

Front Immunol

2021 Nov 19

Kadiri JJ, Tadayon S, Thapa K

Melanocortin receptor 1 (MC1-R) is expressed in leukocytes, where it mediates anti-inflammatory actions. We have previously observed that global deficiency of MC1-R signaling perturbs cholesterol homeostasis, increases arterial leukocyte accumulation and accelerates atherosclerosis in apolipoprotein E knockout (Apoe-/-) mice. Since various cell types besides leukocytes express MC1-R, we aimed at investigating the specific contribution of leukocyte MC1-R to the development of atherosclerosis. For this purpose, male Apoe-/- mice were irradiated, received bone marrow from either female Apoe-/- mice or MC1-R deficient Apoe-/- mice (Apoe-/- Mc1re/e) and were analyzed for tissue leukocyte profiles and atherosclerotic plaque phenotype. Hematopoietic MC1-R deficiency significantly elevated total leukocyte counts in the blood, bone marrow and spleen, an effect that was amplified by feeding mice a cholesterol-rich diet. The increased leukocyte counts were largely attributable to expanded lymphocyte populations, particularly CD4+ T cells. Furthermore, the number of monocytes was elevated in Apoe-/- Mc1re/e chimeric mice and it paralleled an increase in hematopoietic stem cell count in the bone marrow. Despite robust leukocytosis, atherosclerotic plaque size and composition as well as arterial leukocyte counts were unaffected by MC1-R deficiency. To address this discrepancy, we performed an in vivo homing assay and found that MC1-R deficient CD4+ T cells and monocytes were preferentially entering the spleen rather than homing in peri-aortic lymph nodes. This was mechanistically associated with compromised chemokine receptor 5 (CCR5)-dependent migration of CD4+ T cells and a defect in the recycling capacity of CCR5. Finally, our data demonstrate for the first time that CD4+ T cells also express MC1-R. In conclusion, MC1-R regulates hematopoietic stem cell proliferation and tissue leukocyte counts but its deficiency in leukocytes impairs cell migration via a CCR5-dependent mechanism.

162. Pre-Existing Cross-Reactive Antibody Responses Do Not Significantly Impact Inactivated COVID-19 Vaccine-Induced Neutralization.

Front Immunol

2021 Nov 19

Wang J, Guo C, Cai L

Recent exposure to seasonal coronaviruses (sCoVs) may stimulate cross-reactive antibody responses against severe acute respiratory syndrome CoV 2 (SARS-CoV-2). However, previous studies have produced divergent results regarding protective or damaging immunity induced by prior sCoV exposure. It remains unknown whether pre-existing humoral immunity plays a role in vaccine-induced neutralization and antibody responses. In this study, we collected 36 paired sera samples from 36 healthy volunteers before and after immunization with inactivated whole-virion SARS-CoV-2 vaccines for COVID-19, and analyzed the distribution and intensity of pre-existing antibody responses at the epitope level pre-vaccination as well as the relationship between pre-existing sCoV immunity and vaccine-induced neutralization. We observed large amounts of pre-existing cross-reactive antibodies in the conserved regions among sCoVs, especially the S2 subunit. Excep t for a few peptides, the IgG and IgM fluorescence intensities against S, M and N peptides did not differ significantly between pre-vaccination and post-vaccination sera of vaccinees who developed a neutralization inhibition rate (%inhibition) <40 and %inhibition ≥40 after two doses of the COVID-19 vaccine. Participants with strong and weak pre-existing cross-reactive antibodies (strong pre-CRA; weak pre-CRA) had similar %inhibition pre-vaccination (10.9% ± 2.9% vs. 12.0% ± 2.2%, P=0.990) and post-vaccination (43.8% ± 25.1% vs. 44.6% ± 21.5%, P=0.997). Overall, the strong pre-CRA group did not show a significantly greater increase in antibody responses to the S protein linear peptides post-vaccination compared with the weak pre-CRA group. Therefore, we found no evidence for a significant impact of pre-existing antibody responses on inactivated vaccine-induced neutralization and antibody responses. Our research provides an important basis for inactivated SARS-CoV-2 vaccine use in the context of high sCoV seroprevalence.

163. SSTP1, a Host Defense Peptide, Exploits the Immunomodulatory IL6 Pathway to Induce Apoptosis in Cancer Cells.

Front Immunol

2021 Nov 19

Gopalakrishnan S, Uma SK, Mohan G

While the immunomodulatory pathways initiated in immune cells contribute to therapeutic response, their activation in cancer cells play a role in cancer progression. Also, many of the aberrantly expressed immunomodulators on cancer cells are considered as therapeutic targets. Here, we introduce host defense peptide (HDP), a known immuomodulator, as a therapeutic agent to target them. The cationic host defense peptides (HDPs), an integral part of the innate immune system, possess membranolytic activity, which imparts antimicrobial and antitumor efficacy to it. They act as immunomodulators by activating the immune cells. Though their antimicrobial function has been recently reassigned to immunoregulation, their antitumor activity is still attributed to its membranolytic activity. This membrane pore formation ability, which is proportional to the concentration of the peptide, also leads to side effects like hemolysis, limiting their therapeutic application. So, despite the identification of a variety of anticancer HDPs, their clinical utility is limited. Though HDPs are shown to exert the immunomodulatory activity through specific membrane targets on immune cells, their targets on cancer cells are unknown. We show that SSTP1, a novel HDP identified by shotgun cloning, binds to the active IL6/IL6Rα/gp130 complex on cancer cells, rearranging the active site residues. In contrast to the IL6 blockers inhibiting JAK/STAT activity, SSTP1 shifts the proliferative IL6/JAK/STAT signaling to the apoptotic IL6/JNK/AP1 pathway. In IL6Rα-overexpressing cancer cells, SSTP1 induces apoptosis at low concentration through JNK pathway, without causing significant membrane disruption. We highlight the importance of immunomodulatory pathways in cancer apoptosis, apart from its established role in immune cell regulation and cancer cell proliferation. Our study suggests that identification of the membrane targets for the promising anticancer HDPs might lead to the identification of new drugs for targeted therapy.

164. Data-Driven Analysis of COVID-19 Reveals Persistent Immune Abnormalities in Convalescent Severe Individuals.

Front Immunol

2021 Nov 19

Lim J, Puan KJ, Wang LW

165. Antibody or Anybody? Considering the Role of MRGPRX2 in Acute Drug-Induced Anaphylaxis and as a Therapeutic Target.

Front Immunol

2021 Nov 19

Mackay GA, Fernandopulle NA, Ding J

166. How to Prepare Spectral Flow Cytometry Datasets for High Dimensional Data Analysis: A Practical Workflow.

Front Immunol

2021 Nov 19

den Braanker H, Bongenaar M, Lubberts E.

167. The Chicken Embryo Model: A Novel and Relevant Model for Immune-Based Studies.

Front Immunol

2021 Nov 19

Garcia P, Wang Y, Viallet J

168. Immunomodulation in the Treatment of Periodontitis: Progress and Perspectives.

Front Immunol

2021 Nov 19

Yang B, Pang X, Li Z

169. Dynamic Process of Secondary Pulmonary Infection in Mice With Intracerebral Hemorrhage.

Front Immunol

2021 Nov 19

Zhang H, Huang Y, Li X

Stroke is a common central nervous system disease in clinical practice. Stroke patients often have infectious complications, such as pneumonia and infections of the urinary tract and gastrointestinal tract. Although it has been shown that translocation of the host gut microbiota to the lungs and immune dysfunction plays a vital role in the development of infection after ischemic stroke, the occurrence and mechanism of pulmonary infection at different time points after hemorrhagic cerebral remain unclear. In this study, the changes in the immune system and intestinal barrier function in mice during disease development were investigated at 1 day (M 1 d), 3 days (M 3 d) and 7 days (M 7 d) following hemorrhagic stroke to clarify the mechanism of secondary pulmonary infection. The experimental results revealed that after hemorrhagic stroke, model mice showed increased brain damage from day 1 to 3, followed by a trend of brain recovery from day 3 to 7 . After hemorrhagic stroke, the immune system was disturbed in model mice. Significant immunosuppression of the peripheral immune system was observed in the M 3 d group but improved in the M 7 d group. Staining of lung tissues with hematoxylin and eosin (H&E) and for inflammatory factors revealed considerable disease and immune disorders in the M 7 d group. Stroke seriously impaired intestinal barrier function in mice and significantly changed the small intestine structure. From 1 to 7 d after stroke, intestinal permeability was increased, whereas the levels of markers for intestinal tight junctions, mucus and immunoglobulin A were decreased. Analysis based on 16S rRNA suggested that the microflora in the lung and ileum was significantly altered after stroke. The composition of microflora in lung and ileum tissue was similar in the M 7d group, suggesting that intestinal bacteria had migrated to lung tissue and caused lung infection at this time point after hemorrhagic stroke. In stroke mice, the aggravation of intestinal barrier dysfunction and immune disorders after intracerebral hemorrhage, promoted the migration of enteric bacteria, and increased the risk of pneumonia poststroke. Our findings reveal the dynamic process of infection after hemorrhagic stroke and provide clues for the optimal timing of intervention for secondary pulmonary infection in stroke patients.

170. Pro- and Anti- Effects of Immunoglobulin A- Producing B Cell in Tumors and Its Triggers.

Front Immunol

2021 Nov 19

Zhong Z, Nan K, Weng M

171. Transcriptomic Remodelling of Fetal Endothelial Cells During Establishment of Inflammatory Memory.

Front Immunol

2021 Nov 19

Weiss E, Vlahos A, Kim B

172. Free Feeding of CpG-Oligodeoxynucleotide Particles Prophylactically Attenuates Allergic Airway Inflammation and Hyperresponsiveness in Mice.

Front Immunol

2021 Nov 19

Okajima T, Shigemori S, Namai F

173. Novel Effects of Combination Therapy Through Inhibition of Caspase-1/Gasdermin D Induced-Pyroptosis in Lupus Nephritis.

Front Immunol

2021 Nov 19

Cao H, Liang J, Liu J

OBJECTIVES: Combination therapy with mycophenolate mofetil, tacrolimus and steroids are effective in achieving complete remission in lupus nephritis (LN). Combination therapy uniquely downregulated caspase-1 compared with monotherapies, which can cleave gasdermin D (GSDMD) and was recently identified as the pyroptosis executioner. We therefore investigated whether combination therapy enabled the suppression of caspase-1/GSDMD-mediated pyroptosis in LN. METHODS: Expression and activation of GSDMD were detected in kidney specimens of the human and mouse with LN using immunohistochemical staining and immunoblotting. Primary podocytes isolated from MRL/lpr mice were incubated with LPS+ATP, and pretreated with monotherapy or combination therapy. Inhibition of caspase-1/GSDMD-induced pyroptosis by combination therapy were assessed in MRL/lpr mice and human specimens. Pyroptosis was examined using a FAM caspase-1 kit and flow cytometry. The correlation between pyroptosis in peripheral blood and the systemic lupus erythematosus disease activity index (SLEDAI) was analyzed. RESULTS: Kidney tissue specimens from LN patients and mice exhibited greatly increased expression levels and cleavage of GSDMD. In cultured podocytes, combination treatment significantly suppressed the activation of NLRP3 and caspase-1 and reduced GSDMD N-terminal levels. Combination therapy repressed disease progression through inhibition of caspase-1/GSDMD-mediated pyroptosis in both humans and MRL/lpr mice. Caspase-1/PI positive cell numbers in peripheral blood were positively correlated with SLE-DAI. LN patients with complete remission and partial remission had remarkably reduced caspase-1/PI positive cell numbers compared to baseline. Ac-FLTD-CMK, a GSDMD-derived inhibitor, prevented the development of LN. CONCLUSION: Combination therapy suppressed caspase-1/GSDMD-mediated pyroptosis in vitro and in vivo and reduced disease progression.

174. Cellular and Molecular Phenotypes of pConsensus Peptide (pCons) Induced CD8(+) and CD4(+) Regulatory T Cells in Lupus.

Front Immunol

2021 Nov 19

Singh RP, Hahn BH, Bischoff DS.

175. Corrigendum: Blockade of IL-6/IL-6R Signaling Attenuates Acute Antibody-Mediated Rejection in a Mouse Cardiac Transplantation Model.

Front Immunol

2021 Nov 18

Ma M, Sun Q, Li X

176. Role of CXCL5 in Regulating Chemotaxis of Innate and Adaptive Leukocytes in Infected Lungs Upon Pulmonary Influenza Infection.

Front Immunol

2021 Nov 18

Guo L, Li N, Yang Z

177. A Model of Minor Histocompatibility Antigens in Allogeneic Hematopoietic Cell Transplantation.

Front Immunol

2021 Nov 18

Martin PJ, Levine DM, Storer BE

178. Low-Dose Acetylsalicylic Acid Reduces T Cell Immune Activation: Potential Implications for HIV Prevention.

Front Immunol

2021 Nov 18

Lajoie J, Kowatsch MM, Mwangi LW

179. The Immune Landscape of Human Primary Lung Tumors Is Th2 Skewed.

Front Immunol

2021 Nov 18

Frafjord A, Buer L, Hammarström C

180. The Bacterial Mucosal Immunotherapy MV130 Protects Against SARS-CoV-2 Infection and Improves COVID-19 Vaccines Immunogenicity.

Front Immunol

2021 Nov 18

Del Fresno C, García-Arriaza J, Martínez-Cano S

181. Insights Into the Immune Response of the Black Soldier Fly Larvae to Bacteria.

Front Immunol

2021 Nov 18

Bruno D, Montali A, Mastore M

In insects, a complex and effective immune system that can be rapidly activated by a plethora of stimuli has evolved. Although the main cellular and humoral mechanisms and their activation pathways are highly conserved across insects, the timing and the efficacy of triggered immune responses can differ among different species. In this scenario, an insect deserving particular attention is the black soldier fly (BSF), Hermetia illucens (Diptera: Stratiomyidae). Indeed, BSF larvae can be reared on a wide range of decaying organic substrates and, thanks to their high protein and lipid content, they represent a valuable source of macromolecules useful for different applications (e.g., production of feedstuff, bioplastics, and biodiesel), thus contributing to the development of circular economy supply chains for waste valorization. However, decaying substrates bring the larvae into contact with different potential pathogens that can challenge their health status and growth. Although these life strategies have presumably contributed to shape the evolution of a sophisticated and efficient immune system in this dipteran, knowledge about its functional features is still fragmentary. In the present study, we investigated the processes underpinning the immune response to bacteria in H. illucens larvae and characterized their reaction times. Our data demonstrate that the cellular and humoral responses in this insect show different kinetics: phagocytosis and encapsulation are rapidly triggered after the immune challenge, while the humoral components intervene later. Moreover, although both Gram-positive and Gram-negative bacteria are completely removed from the insect body within a few hours after injection, Gram-positive bacteria persist in the hemolymph longer than do Gram-negative bacteria. Finally, the activity of two key actors of the humoral response, i.e., lysozyme and phenoloxidase, show unusual dynamics as compared to other insects. This study represents the first detailed characterization of the immune response to bacteria of H. illucens larvae, expanding knowledge on the defense mechanisms of this insect among Diptera. This information is a prerequisite to manipulating the larval immune response by nutritional and environmental factors to increase resistance to pathogens and optimize health status during mass rearing.

182. Proteomic Approaches to Defining Remission and the Risk of Relapse in Rheumatoid Arthritis.

Front Immunol

2021 Nov 18

O'Neil LJ, Hu P, Liu Q

183. Editorial: Ticks and Host Immunity - New Strategies for Controlling Ticks and Tick-Borne Pathogens.

Front Immunol

2021 Nov 18

Tabor AE, de Miranda Santos IKF, Boulanger N.

184. Janus Kinase Inhibitors in the Treatment of Vitiligo: A Review.

Front Immunol

2021 Nov 18

Qi F, Liu F, Gao L.

185. GII.P16-GII.2 Recombinant Norovirus VLPs Polarize Macrophages Into the M1 Phenotype for Th1 Immune Responses.

Front Immunol

2021 Nov 18

Han JC, Li QX, Fang JB

Norovirus (NoV) is a zoonotic virus that causes diarrhea in humans and animals. Outbreaks in nosocomial settings occur annually worldwide, endangering public health and causing serious social and economic burdens. The latter quarter of 2016 witnessed the emergence of the GII.P16-GII.2 recombinant norovirus throughout Asia. This genotype exhibits strong infectivity and replication characteristics, proposing its potential to initiate a pandemic. There is no vaccine against GII.P16-GII.2 recombinant norovirus, so it is necessary to design a preventive vaccine. In this study, GII.P16-GII.2 type norovirus virus-like particles (VLPs) were constructed using the baculovirus expression system and used to conduct immunizations in mice. After immunization of mice, mice were induced to produce memory T cells and specific antibodies, indicating that the VLPs induced specific cellular and humoral immune responses. Further experiments were then initiated to understand the underlying mechanisms involved in antigen presentation. Towards this, we established co-cultures between dendritic cells (DCs) or macrophages (Mø) and naïve CD4+T cells and simulated the antigen presentation process by incubation with VLPs. Thereafter, we detected changes in cell surface molecules, cytokines and related proteins. The results indicated that VLPs effectively promoted the phenotypic maturation of Mø but not DCs, as indicated by significant changes in the expression of MHC-II, costimulatory factors and related cytokines in Mø. Moreover, we found VLPs caused Mø to polarize to the M1 type and release inflammatory cytokines, thereby inducing naïve CD4+ T cells to perform Th1 immune responses. Therefore, this study reveals the mechanism of antigen presentation involving GII.P16-GII.2 recombinant norovirus VLPs, providing a theoretical basis for both understanding responses to norovirus infection as well as opportunities for vaccine development.

186. The Alternatively Spliced Isoforms of Key Molecules in the cGAS-STING Signaling Pathway.

Front Immunol

2021 Nov 18

Liang J, Hong Z, Sun B

187. Neuro-Immunity and Gut Dysbiosis Drive Parkinson's Disease-Induced Pain.

Front Immunol

2021 Nov 18

Roversi K, Callai-Silva N, Roversi K

188. Pattern-Recognition Receptor Agonist-Containing Immunopotentiator CVC1302 Boosts High-Affinity Long-Lasting Humoral Immunity.

Front Immunol

2021 Nov 18

Du L, Hou L, Yu X

189. Using the T Cell Receptor as a Biomarker in Type 1 Diabetes.

Front Immunol

2021 Nov 17

Nakayama M, Michels AW.

190. COVID-19, Pre-Eclampsia, and Complement System.

Front Immunol

2021 Nov 17

Agostinis C, Mangogna A, Balduit A

191. Mutation in Irf8 Gene (Irf8(R294C) ) Impairs Type I IFN-Mediated Antiviral Immune Response by Murine pDCs.

Front Immunol

2021 Nov 17

Das A, Chauhan KS, Kumar H

Plasmacytoid dendritic cells (pDCs) are the key producers of type I interferons (IFNs), thus playing a central role in initiating antiviral immune response. Besides robust type I IFN production, pDCs also act as antigen presenting cells post immunogenic stimulation. Transcription factor Irf8 is indispensable for the development of both pDC and cDC1 subset. However, the mechanism underlying the differential regulation by IRF8 in cDC1- and pDC-specific genomic architecture of developmental pathways still remains to be fully elucidated. Previous studies indicated that the Irf8R294C mutation specifically abrogates development of cDC1 without affecting that of pDC. In the present study using RNA-seq based approach, we have found that though the point mutation Irf8R294C did not affect pDC development, it led to defective type I IFN production, thus resulting in inefficient antiviral response. This observation unraveled the distinctive roles of IRF8 in these two subpopulations-regulating the development of cDC1 whereas modulating the functionality of pDCs without affecting development. We have reported here that Irf8R294C mutation also caused defect in production of ISGs as well as defective upregulation of costimulatory molecules in pDCs in response to NDV infection (or CpG stimulation). Through in vivo studies, we demonstrated that abrogation of type I IFN production was concomitant with reduced upregulation of costimulatory molecules in pDCs and increased NDV burden in IRF8R294C mice in comparison with wild type, indicating inefficient viral clearance. Further, we have also shown that Irf8R294C mutation abolished the activation of type I IFN promoter by IRF8, justifying the low level of type I IFN production. Taken together, our study signifies that the single point mutation in Irf8, Irf8R294C severely compromised type I IFN-mediated immune response by murine pDCs, thereby causing impairment in antiviral immunity.

192. Collagen 1a1 Expression by Airway Macrophages Increases In Fibrotic ILDs and Is Associated With FVC Decline and Increased Mortality.

Front Immunol

2021 Nov 17

Tsitoura E, Trachalaki A, Vasarmidi E

193. JAK2-STAT Epigenetically Regulates Tolerized Genes in Monocytes in the First Encounter With Gram-Negative Bacterial Endotoxins in Sepsis.

Front Immunol

2021 Nov 17

Morante-Palacios O, Lorente-Sorolla C, Ciudad L

194. Corrigendum: Mechanism of Rhinovirus Immunity and Asthma.

Front Immunol

2021 Nov 16

Yang Z, Mitländer H, Vuorinen T

195. High Prevalence of Genital Human Papillomavirus Infection in Patients With Primary Immunodeficiencies.

Front Immunol

2021 Nov 16

Gernert M, Kiesel M, Fröhlich M

196. Development and Application of the Placebo Response Model in Clinical Trials for Primary Sjögren's Syndrome.

Front Immunol

2021 Nov 16

Wang ZZ, Zheng QS, Liu HX

This study aimed to develop a placebo response model for pharmaceutical clinical trials of primary Sjogren's syndrome,and to quantitatively analyze the distribution and related factors influencing the placebo response to further optimize the design of clinical trials and evaluate the results of single-arm clinical trials. Public databases, including PubMed, Embase, and Cochrane Library were searched for reports on randomized placebo-controlled trials for Sjögren's syndrome which used the change from baseline in ESSDAI score as the primary outcome. The model-based meta-analysis method was used to evaluate the time course and the related influencing factors of the placebo response for ESSDAI in such clinical trials. A virtual placebo control group was constructed based on the final placebo response model to determine the treatment efficacy of belimumab and cyclosporine A for primary Sjögren's syndrome in a single-arm study. A total of 12 studies involving 450 subjects were included in the analysis. The established model described the time-course characteristics of the changes in ESSDAI score from the baseline in the 48 weeks placebo group. We found that the onset time of placebo response was approximately 12 weeks, and its efficacy plateaued at 48 weeks. The baseline ESSDAI score had a significant effect on the maximum value of the placebo response; the maximum value of the placebo response decreased by 0.552 for every 1 score rise in the baseline ESSDAI score. The efficacy of belimumab and cyclosporine A in the single-arm trial was comparable to that of the placebo response at the same baseline; no significant therapeutic advantage was observed. The placebo response model established in this study could provide a basis for designing clinical trials for primary Sjogren's syndrome in the future. It may also provide a reliable external efficacy control standard for single-arm clinical trials.

197. Regulation of T-Cell Immune Responses by Pro-Resolving Lipid Mediators.

Front Immunol

2021 Nov 16

Perez-Hernandez J, Chiurchiù V, Perruche S

198. Construction of Genomic Library and Screening of Edwardsiella tarda Immunogenic Proteins for Their Protective Efficacy Against Edwardsiellosis.

Front Immunol

2021 Nov 16

Bothammal P, Ganesh M, Vigneshwaran V

199. Corrigendum: Development of a Scrub Typhus Diagnostic Platform Incorporating Cell-Surface Display Technology.

Front Immunol

2021 Nov 16

Liao CC, Tsai CH, Lo HR

200. Characterization of Host lncRNAs in Response to Vibrio splendidus Infection and Function as Efficient miRNA Sponges in Sea Cucumber.

Front Immunol

2021 Nov 16

Zhang S, Shao Y, Li C.

201. Impact of Patient Age on Clinical Efficacy and Toxicity of Checkpoint Inhibitor Therapy.

Front Immunol

2021 Nov 16

Wong SK, Nebhan CA, Johnson DB.

202. Role of the Extracellular Traps in Central Nervous System.

Front Immunol

2021 Nov 16

Wu X, Zeng H, Cai L

203. Reversion Mosaicism in Primary Immunodeficiency Diseases.

Front Immunol

2021 Nov 16

Miyazawa H, Wada T.

204. Impaired Functional T-Cell Response to SARS-CoV-2 After Two Doses of BNT162b2 mRNA Vaccine in Older People.

Front Immunol

2021 Nov 16

Demaret J, Corroyer-Simovic B, Alidjinou EK

Long-term care facility (LTCF) older residents display physiological alterations of cellular and humoral immunity that affect vaccine responses. Preliminary reports suggested a low early postvaccination antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The aim of this study was to focus on the specific T-cell response. We quantified S1-specific IgG, neutralizing antibody titers, total specific IFNγ-secreting T cells by ELISpot, and functionality of CD4+- and CD8+-specific T cells by flow cytometry, after two doses of the BNT162b2 vaccine in younger and older people, with and without previous COVID-19 infection (hereafter referred to as COVID-19-recovered and COVID-19-naive subjects, respectively). Frailty, nutritional, and immunosenescence parameters were collected at baseline in COVID-19-naive older people. We analyzed the immune response in 129 young adults (median age 44.0 years) and 105 older residents living in a LCTF (median age 86.5 years), 3 months after the first injection. Humoral and cellular memory responses were dramatically impaired in the COVID-19-naive older (n = 54) compared with the COVID-19-naive younger adults (n = 121). Notably, older participants' neutralizing antibodies were 10 times lower than the younger's antibody titers (p < 0.0001) and LCTF residents also had an impaired functional T-cell response: the frequencies of IFNγ+ and IFNγ+IL-2+TNFα+ cells among specific CD4+ T cells, and the frequency of specific CD8+ T cells were lower in COVID-19-naive older participants than in COVID-19-naive young adults (p < 0.0001 and p = 0.0018, respectively). However, COVID-19-recovered older participants (n = 51) had greater antibody and T-cell responses, including IFNγ+ and IFNγ+IL-2+TNFα+-specific CD4+ T cells (p < 0.0001), as well as TNFα+-specific CD8+ T cells (p < 0.001), than COVID-19-naive older adults. We also observed that "inflammageing" and particularly high plasma levels of TNFα was associated to poor antibody response in the older participants. In conclusion, our results show that the COVID-19-naive older people had low counts and impaired specific CD4+ and CD8+ T cells, in addition to impaired antibody response, and that specific studies are warranted to assess the efficiency of SARS-CoV-2 mRNA-based vaccines, as in other immunocompromised subjects. Our study also shows that, despite their physiological alterations of immunity, vaccination is highly efficient in boosting the prior natural memory response in COVID-19-recovered older people.

205. A New Formulation of Probiotics Attenuates Calcipotriol-Induced Dermatitis by Inducing Regulatory Dendritic Cells.

Front Immunol

2021 Nov 16

Xu B, Ling S, Xu X

206. Potential Applications of Fluorescence-Activated Cell Sorting (FACS) and Droplet-Based Microfluidics in Promoting the Discovery of Specific Antibodies for Characterizations of Fish Immune Cells.

Front Immunol

2021 Nov 16

Fei C, Nie L, Zhang J

Akin to their mammalian counterparts, teleost fish possess a complex assortment of highly specialized immune cells that are capable of unleashing potent innate immune responses to eradicate or mitigate incoming pathogens, and also differentiate into memory lymphocytes to provide long-term protection. Investigations into specific roles and functions of fish immune cells depend on the precise separation of each cell type. Commonly used techniques, for example, density gradient centrifugation, rely on immune cells to have differing sizes or densities and thus fail to separate between similar cell types (e.g. T and B lymphocytes). Furthermore, a continuously growing database of teleost genomic information has revealed an inventory of cellular markers, indicating the possible presence of immune cell subsets in teleost fish. This further complicates the interpretation of results if subsets of immune cells are not properly separated. Consequently, monoclonal antibodies (mAbs) against specific cellular markers are required to precisely identify and separate novel subsets of immune cells in fish. In the field of fish immunology, mAbs are largely generated using the hybridoma technology, resulting in the development of mAbs against specific cellular markers in different fish species. Nevertheless, this technology suffers from being labour-intensive, time-consuming and most importantly, the inevitable loss of diversities of antibodies during the fusion of antibody-expressing B lymphocytes and myeloma cells. In light of this, the focus of this review is to discuss the potential applications of fluorescence-activated cell sorting and droplet-based microfluidics, two emerging technologies capable of screening and identifying antigen-specific B lymphocytes in a high-throughput manner, in promoting the development of valuable reagents for fish immunology studies. Our main goal is to encourage the incorporation of alternative technologies into the field of fish immunology to promote the production of specific antibodies in a high-throughput and cost-effective way, which could better allow for the precise separation of fish immune cells and also facilitate the identification of novel immune cell subsets in teleost fish.

207. Type 1 Innate Lymphoid Cells Limit the Antitumoral Immune Response.

Front Immunol

2021 Nov 16

Vienne M, Etiennot M, Escalière B

208. Development of a Flow Cytometry Assay to Predict Immune Checkpoint Blockade-Related Complications.

Front Immunol

2021 Nov 16

Schilling HL, Glehr G, Kapinsky M

209. Epigenetic Modulation of Class-Switch DNA Recombination to IgA by miR-146a Through Downregulation of Smad2, Smad3 and Smad4.

Front Immunol

2021 Nov 16

Casali P, Li S, Morales G

IgA is the predominant antibody isotype at intestinal mucosae, where it plays a critical role in homeostasis and provides a first line of immune protection. Dysregulation of IgA production, however, can contribute to immunopathology, particularly in kidneys in which IgA deposition can cause nephropathy. Class-switch DNA recombination (CSR) to IgA is directed by TGF-β signaling, which activates Smad2 and Smad3. Activated Smad2/Smad3 dimers are recruited together with Smad4 to the IgH α locus Iα promoter to activate germline Iα-Cα transcription, the first step in the unfolding of CSR to IgA. Epigenetic factors, such as non-coding RNAs, particularly microRNAs, have been shown to regulate T cells, dendritic cells and other immune elements, as well as modulate the antibody response, including CSR, in a B cell-intrinsic fashion. Here we showed that the most abundant miRNA in resting B cells, miR-146a targets Smad2, Smad3 and Smad4 mRNA 3'UTRs and keeps CSR to IgA in check in resting B cells. Indeed, enforced miR-146a expression in B cells aborted induction of IgA CSR by decreasing Smad levels. By contrast, upon induction of CSR to IgA, as directed by TGF-β, B cells downregulated miR-146a, thereby reversing the silencing of Smad2, Smad3 and Smad4, which, once expressed, led to recruitment of Smad2, Smad3 and Smad4 to the Iα promoter for activation of germline Iα-Cα transcription. Deletion of miR-146a in miR-146a-/- mice significantly increased circulating levels of steady state total IgA, but not IgM, IgG or IgE, and heightened the specific IgA antibody response to OVA. In miR-146a-/- mice, the elevated systemic IgA levels were associated with increased IgA+ B cells in intestinal mucosae, increased amounts of fecal free and bacteria-bound IgA as well as kidney IgA deposition, a hallmark of IgA nephropathy. Increased germline Iα-Cα transcription and CSR to IgA in miR-146a-/- B cells in vitro proved that miR-146a-induced Smad2, Smad3 and Smad4 repression is B cell intrinsic. The B cell-intrinsic role of miR-146a in the modulation of CSR to IgA was formally confirmed in vivo by construction and OVA immunization of mixed bone marrow μMT/miR-146a-/- chimeric mice. Thus, by inhibiting Smad2, Smad3 and Smad4 expression, miR-146a plays an important and B cell intrinsic role in modulation of CSR to IgA and the IgA antibody response.

210. The NF-κB Transcription Factor c-Rel Modulates Group 2 Innate Lymphoid Cell Effector Functions and Drives Allergic Airway Inflammation.

Front Immunol

2021 Nov 16

Mindt BC, Krisna SS, Duerr CU

211. A Serum Biomarker Panel of exomiR-451a, exomiR-25-3p and Soluble TWEAK for Early Diagnosis of Rheumatoid Arthritis.

Front Immunol

2021 Nov 15

Rodríguez-Muguruza S, Altuna-Coy A, Castro-Oreiro S

BACKGROUND: The etiology of rheumatoid arthritis (RA) remains poorly understood. Early and accurate diagnosis still difficult to achieve. Inflammatory related molecules released into the circulation such cytokines and exosome-derived microRNAs (exomiRNAs) could be good candidates for early diagnosis of autoimmune diseases. We sought to discover a serum biomarker panel for the early detection of RA based on exomiRNAs and inflammatory markers. METHODS: A 179 miRNAs-microarray panel was analyzed in a pilot study (4 early RA and 4 controls). Validation of deregulated exomiRNAs was performed in a larger cohort (24 patients with early RA and 24 controls). miRNet software was used to predict exomiRNA gene-targets interactions. Potentially altered pathways were analyzed by Reactome pathway database search. STRING database was used to predict protein-protein interaction networks. Enzyme-linked immunosorbent assay was used to measure serum levels of sTWEAK and sCD163. Signature biomarker candidates were statistical analyzed. RESULTS: We detected 11 differentially expressed exomiRNAs in early RA pilot study. Validation analysis revealed that 6/11 exomiRNAs showed strong agreement with the pilot microarray data (exomiR-144-3p, -25-3p, -15a-5p, -451a, -107 and -185-5p). sTWEAK and sCD163 biomarkers were significantly elevated in the serum of patients with early RA. Receiver operating characteristic (ROC) analysis showed that the best panel to diagnose early RA contained exomiR-451a, exomiR-25-3p and sTWEAK, and could correctly classify 95.6% of patients, with an area under the ROC curve of 0.983 and with 100% specificity and 85.7% sensitivity. The YWHAB gene was identified as a common target of the putative miRNA-regulated pathways. CONCLUSION: A novel serum biomarker panel composed of exomiR-451a, exomiR-25-3p and serum levels of sTWEAK may have use in the early clinical diagnosis of RA. A new predicted exomiRNA-target gene YHWAB has been identified and may have a relevant role in the development of RA.

212. Intramuscular Vaccination With the HSV-1(VC2) Live-Attenuated Vaccine Strain Confers Protection Against Viral Ocular Immunopathogenesis Associated With γδT Cell Intracorneal Infiltration.

Front Immunol

2021 Nov 15

Nabi R, Lewin AC, Collantes TM

213. The Latest Developments in Immunomodulation of Mesenchymal Stem Cells in the Treatment of Intrauterine Adhesions, Both Allogeneic and Autologous.

Front Immunol

2021 Nov 15

Chen JM, Huang QY, Zhao YX

214. Understanding the Connection Between Common Stroke Comorbidities, Their Associated Inflammation, and the Course of the Cerebral Ischemia/Reperfusion Cascade.

Front Immunol

2021 Nov 15

Przykaza Ł.

215. Epithelial Aryl Hydrocarbon Receptor Protects From Mucus Production by Inhibiting ROS-Triggered NLRP3 Inflammasome in Asthma.

Front Immunol

2021 Nov 15

Hu X, Shen Y, Zhao Y

BACKGROUND: Despite long-standing recognition in the significance of mucus overproduction in asthma, its etiology remains poorly understood. Muc5ac is a secretory mucin that has been associated with reduced pulmonary function and asthma exacerbations. OBJECTIVES: We sought to investigate the immunological pathway that controls Muc5ac expression and allergic airway inflammation in asthma. METHODS: Cockroach allergen-induced Muc5ac expression and aryl hydrocarbon receptor (AhR) signaling activation was examined in the human bronchial epithelial cells (HBECs) and mouse model of asthma. AhR regulation of Muc5ac expression, mitochondrial ROS (Mito-ROS) generation, and NLRP3 inflammasome was determined by AhR knockdown, the antagonist CH223191, and AhR-/- mice. The role of NLRP3 inflammasome in Muc5ac expression and airway inflammation was also investigated. RESULTS: Cockroach allergen induced Muc5ac overexpression in HBECs and airways of asthma mouse model. Increased expression of AhR and its downstream genes CYP1A1 and CYP1B1 was also observed. Mice with AhR deletion showed increased allergic airway inflammation and MUC5AC expression. Moreover, cockroach allergen induced epithelial NLRP3 inflammasome activation (e.g., NLRP3, Caspase-1, and IL-1β), which was enhanced by AhR knockdown or the antagonist CH223191. Furthermore, AhR deletion in HBECs led to enhanced ROS generation, particularly Mito-ROS, and inhibition of ROS or Mito-ROS subsequently suppressed the inflammasome activation. Importantly, inhibition of the inflammasome with MCC950, a NLRP3-specifc inhibitor, attenuated allergic airway inflammation and Muc5ac expression. IL-1β generated by the activated inflammasomes mediated cockroach allergen-induced Muc5ac expression in HBECs. CONCLUSIONS: These results reveal a previously unidentified functional axis of AhR-ROS-NLRP3 inflammasome in regulating Muc5ac expression and airway inflammation.

216. XAV-19, a Swine Glyco-Humanized Polyclonal Antibody Against SARS-CoV-2 Spike Receptor-Binding Domain, Targets Multiple Epitopes and Broadly Neutralizes Variants.

Front Immunol

2021 Nov 15

Vanhove B, Marot S, So RT

217. The Roles of Exosomes in Immunoregulation and Autoimmune Thyroid Diseases.

Front Immunol

2021 Nov 15

Zou J, Peng H, Liu Y.

218. Molecular Tuning of Actin Dynamics in Leukocyte Migration as Revealed by Immune-Related Actinopathies.

Front Immunol

2021 Nov 15

Kamnev A, Lacouture C, Fusaro M

219. Obesity Prolongs the Inflammatory Response in Mice After Severe Trauma and Attenuates the Splenic Response to the Inflammatory Reflex.

Front Immunol

2021 Nov 15

Gärtner F, Gihring A, Roth A

220. Therapeutic Potential of a Novel Bifidobacterium Identified Through Microbiome Profiling of RA Patients With Different RF Levels.

Front Immunol

2021 Nov 15

Jeong Y, Jhun J, Lee SY

221. IL-21 Rescues the Defect of IL-10-Producing Regulatory B Cells and Improves Allergic Asthma in DOCK8 Deficient Mice.

Front Immunol

2021 Nov 15

Jiang J, Qin T, Zhang L

222. Epstein-Barr Virus and the Origin of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome.

Front Immunol

2021 Nov 15

Ruiz-Pablos M, Paiva B, Montero-Mateo R

223. Pulmonary Eosinophils at the Center of the Allergic Space-Time Continuum.

Front Immunol

2021 Nov 15

Schetters STT, Schuijs MJ.

224. Acute Phase Proteins Are Baseline Predictors of Tuberculosis Treatment Failure.

Front Immunol

2021 Nov 15

Kumar NP, Moideen K, Nancy A

225. Stigmatization in Patients With Psoriasis: A Mini Review.

Front Immunol

2021 Nov 15

Zhang H, Yang Z, Tang K

226. Clinical and Immunological Features of Human BCL10 Deficiency.

Front Immunol

2021 Nov 12

Garcia-Solis B, Van Den Rym A, Pérez-Caraballo JJ

227. Epigallocatechin-3-Gallate as a Novel Vaccine Adjuvant.

Front Immunol

2021 Nov 12

Cheong Y, Kim M, Ahn J

228. Metallothionein 3-Zinc Axis Suppresses Caspase-11 Inflammasome Activation and Impairs Antibacterial Immunity.

Front Immunol

2021 Nov 12

Chowdhury D, Gardner JC, Satpati A

229. Novel Assay Platform to Evaluate Intracellular Killing of Mycobacterium tuberculosis: In Vitro and In Vivo Validation.

Front Immunol

2021 Nov 12

Horváti K, Fodor K, Pályi B

One of the main hallmarks of tuberculosis (TB) is the ability of the causative agent to transform into a stage of dormancy and the capability of long persistence in the host phagocytes. It is believed that approximately one-third of the population of the world is latently infected with Mycobacterium tuberculosis (Mtb), and 5%-10% of these individuals can develop clinical manifestations of active TB even decades after the initial infection. In this latent, intracellular form, the bacillus is shielded by an extremely robust cell wall and becomes phenotypically resistant to most antituberculars. Therefore, there is a clear rationale to develop novel compounds or carrier-conjugated constructs of existing drugs that are effective against the intracellular form of the bacilli. In this paper, we describe an experimental road map to define optimal candidates against intracellular Mtb and potential compounds effective in the therapy of latent TB. To validate our approach, isoniazid, a first-line antitubercular drug was employed, which is active against extracellular Mtb in the submicromolar range, but ineffective against the intracellular form of the bacteria. Cationic peptide conjugates of isoniazid were synthesized and employed to study the host-directed drug delivery. To measure the intracellular killing activity of the compounds, Mtb-infected MonoMac-6 human monocytic cells were utilized. We have assessed the antitubercular activity, cytotoxicity, membrane interactions in combination with internalization efficacy, localization, and penetration ability on interface and tissue-mimicking 3D models. Based on these in vitro data, most active compounds were further evaluated in vivo in a murine model of TB. Intraperitoneal infectious route was employed to induce a course of slowly progressive and systemic disease. The well-being of the animals, monitored by the body weight, allows a prolonged experimental setup and provides a great opportunity to test the long-term activity of the drug candidates. Having shown the great potency of this simple and suitable experimental design for antimicrobial research, the proposed novel assay platform could be used in the future to develop further innovative and highly effective antituberculars.

230. A Bioactive Extract Rich in Triterpenic Acid and Polyphenols from Olea europaea Promotes Systemic Immunity and Protects Atlantic Salmon Smolts Against Furunculosis.

Front Immunol

2021 Nov 12

Salomón R, Furones MD, Reyes-López FE

231. Anti-TLR7 Antibody Protects Against Lupus Nephritis in NZBWF1 Mice by Targeting B Cells and Patrolling Monocytes.

Front Immunol

2021 Nov 11

Murakami Y, Fukui R, Tanaka R

232. Immunogenicity and Protective Potential of Mucosal Vaccine Formulations Based on Conserved Epitopes of Influenza A Viruses Fused to an Innovative Ring Nanoplatform in Mice and Chickens.

Front Immunol

2021 Nov 11

Calzas C, Mao M, Turpaud M

Current inactivated vaccines against influenza A viruses (IAV) mainly induce immune responses against highly variable epitopes across strains and are mostly delivered parenterally, limiting the development of an effective mucosal immunity. In this study, we evaluated the potential of intranasal formulations incorporating conserved IAV epitopes, namely the long alpha helix (LAH) of the stalk domain of hemagglutinin and three tandem repeats of the ectodomain of the matrix protein 2 (3M2e), as universal mucosal anti-IAV vaccines in mice and chickens. The IAV epitopes were grafted to nanorings, a novel platform technology for mucosal vaccination formed by the nucleoprotein (N) of the respiratory syncytial virus, in fusion or not with the C-terminal end of the P97 protein (P97c), a recently identified Toll-like receptor 5 agonist. Fusion of LAH to nanorings boosted the generation of LAH-specific systemic and local antibody responses as well as cellular immunity in mice, whereas the carrier effect of nanorings was less pronounced towards 3M2e. Mice vaccinated with chimeric nanorings bearing IAV epitopes in fusion with P97c presented modest LAH- or M2e-specific IgG titers in serum and were unable to generate a mucosal humoral response. In contrast, N-3M2e or N-LAH nanorings admixed with Montanide™ gel (MG) triggered strong specific humoral responses, composed of serum type 1/type 2 IgG and mucosal IgG and IgA, as well as cellular responses dominated by type 1/type 17 cytokine profiles. All mice vaccinated with the [N-3M2e + N-LAH + MG] formulation survived an H1N1 challenge and the combination of both N-3M2e and N-LAH nanorings with MG enhanced the clinical and/or virological protective potential of the preparation in comparison to individual nanorings. Chickens vaccinated parenterally or mucosally with N-LAH and N-3M2e nanorings admixed with Montanide™ adjuvants developed a specific systemic humoral response, which nonetheless failed to confer protection against heterosubtypic challenge with a highly pathogenic H5N8 strain. Thus, while the combination of N-LAH and N-3M2e nanorings with Montanide™ adjuvants shows promise as a universal mucosal anti-IAV vaccine in the mouse model, further experiments have to be conducted to extend its efficacy to poultry.

233. Distinct CD4(-)CD8(-) (Double-Negative) Memory T-Cell Subpopulations Are Associated With Indeterminate and Cardiac Clinical Forms of Chagas Disease.

Front Immunol

2021 Nov 11

Passos LSA, Koh CC, Magalhães LMD

234. Effects of β-Blockers on the Sympathetic and Cytokines Storms in Covid-19.

Front Immunol

2021 Nov 11

Al-Kuraishy HM, Al-Gareeb AI, Mostafa-Hedeab G

235. A Novel Serum tsRNA for Diagnosis and Prediction of Nephritis in SLE.

Front Immunol

2021 Nov 11

Yang P, Zhang X, Chen S

236. Solid Tumor Microenvironment Can Harbor and Support Functional Properties of Memory T Cells.

Front Immunol

2021 Nov 11

Sullivan PM, Reed SJ, Kalia V

Robust T cell responses are crucial for effective anti-tumor responses and often dictate patient survival. However, in the context of solid tumors, both endogenous T cell responses and current adoptive T cell therapies are impeded by the immunosuppressive tumor microenvironment (TME). A multitude of inhibitory signals, suppressive immune cells, metabolites, hypoxic conditions and limiting nutrients are believed to render the TME non-conducive to sustaining productive T cell responses. In this study we conducted an in-depth phenotypic and functional comparison of tumor-specific T cells and tumor-nonspecific bystander memory T cells within the same TME. Using two distinct TCR transgenic and solid-tumor models, our data demonstrate that despite exposure to the same cell-extrinsic factors of the TME, the tumor-nonspecific bystander CD8 T cells retain the complete panoply of memory markers, and do not share the same exhaustive phenotype as tumor-reactive T cells. Compared to tumor-specific T cells, bystander memory CD8 T cells in the TME also retain functional effector cytokine production capabilities in response to ex vivo cognate antigenic stimulation. Consistent with these results, bystander memory T cells isolated from tumors showed enhanced recall responses to secondary bacterial challenge in a T cell transplant model. Importantly, the tumor-resident bystander memory cells could also efficiently utilize the available resources within the TME to elaborate in situ recall effector functions following intra-tumoral peptide antigen injection. Additionally, CRISPR-Cas9 gene deletion studies showed that CXCR3 was critical for the trafficking of both tumor antigen-specific and bystander memory T cells to solid tumors. Collectively, these findings that T cells can persist and retain their functionality in distinct solid tumor environments in the absence of cognate antigenic stimulation, support the notion that persistent antigenic signaling is the central driver of T cell exhaustion within the TME. These studies bear implications for programming more efficacious TCR- and CAR-T cells with augmented therapeutic efficacy and longevity through regulation of antigen and chemokine receptors.

237. MicroRNA-21 Regulates Diametrically Opposed Biological Functions of Regulatory T Cells.

Front Immunol

2021 Nov 11

Sun J, Liu R, He X

238. The Expression of CD28 and Its Synergism on the Immune Response of Flounder (Paralichthys olivaceus) to Thymus-Dependent Antigen.

Front Immunol

2021 Nov 11

Xing J, Liu W, Tang X

CD28 is well known as a critical T-cell costimulatory receptor involved in T cell activation by binding to its ligands. In this study, CD28 was cloned, and its expression profiles were characterized in flounder (Paralichthys olivaceus); variations of CD28+ cells after being stimulated with different types of antigens and the function of the CD28 costimulatory pathway on T-cell activation were investigated in vitro. fCD28 consists of four exons and three introns, and the full-length cDNA of fCD28 was 675-bp encoded 224 amino acids. The conserved motif (121TFPPPF126) binding to the CD80/86 ligand exists in the Ig-superfamily homology domain. The high expression of fCD28 is in gills, PBLs, head kidney, and spleen. CD28+ cells were co-localized with CD4+ T lymphocytes but not on IgM+ B lymphocyte cells. Moreover, the expression of CD28 was significantly varied in flounder after being stimulated by keyhole limpet hemocyanin (KLH) at both the transcriptional and cellular levels, while no significant differences were observed between lipopolysaccharide (LPS) stimulation and the control group. Notably, treatment of PBLs cultured in vitro with CD28 molecule-specific antibody (anti-CD28 Abs) and PHA produced more cell colonies and stimulated the proliferation of cultured leukocytes compared to PHA stimulation alone and the control group, and a higher level of IL-2 was detected in the culture medium. Meanwhile, anti-CD28 Abs increased the percent of CD28+ cells (10.41 ± 1.35%), CD4+ T lymphocytes (18.32 ± 2.15%), and CD28+/CD4+ double-positive cells (6.24 ± 1.52%). This effect also resulted in significant variations in the genes of cell membrane-bound molecules, cytokines, and related signaling pathways in cultured leukocytes, with significant changes in the genes of interleukin-2 (IL-2) and nuclear factor of activated T cells (NFAT) in the early stages of culture, and the expression of other molecules increased over time. These results proved the localization of the CD28 molecule on T lymphocytes in flounder, and anti-CD28 may act as the B7 ligand involved in T cell activation after antigen stimulation. These data provide a basis for a more in-depth study of the mechanism of the CD28 costimulatory pathway in T cell activation.

239. Interaction Between Commensal Bacteria, Immune Response and the Intestinal Barrier in Inflammatory Bowel Disease.

Front Immunol

2021 Nov 11

Chen Y, Cui W, Li X

240. Aging of the Hematopoietic Stem Cell Niche: New Tools to Answer an Old Question.

Front Immunol

2021 Nov 11

Matteini F, Mulaw MA, Florian MC.

241. Co-Exposure of Cardiomyocytes to IFN-γ and TNF-α Induces Mitochondrial Dysfunction and Nitro-Oxidative Stress: Implications for the Pathogenesis of Chronic Chagas Disease Cardiomyopathy.

Front Immunol

2021 Nov 11

Nunes JPS, Andrieux P, Brochet P

Infection by the protozoan Trypanosoma cruzi causes Chagas disease cardiomyopathy (CCC) and can lead to arrhythmia, heart failure and death. Chagas disease affects 8 million people worldwide, and chronic production of the cytokines IFN-γ and TNF-α by T cells together with mitochondrial dysfunction are important players for the poor prognosis of the disease. Mitochondria occupy 40% of the cardiomyocytes volume and produce 95% of cellular ATP that sustain the life-long cycles of heart contraction. As IFN-γ and TNF-α have been described to affect mitochondrial function, we hypothesized that IFN-γ and TNF-α are involved in the myocardial mitochondrial dysfunction observed in CCC patients. In this study, we quantified markers of mitochondrial dysfunction and nitro-oxidative stress in CCC heart tissue and in IFN-γ/TNF-α-stimulated AC-16 human cardiomyocytes. We found that CCC myocardium displayed increased levels of nitro-oxidative stress and reduced mitochondrial DNA as compared with myocardial tissue from patients with dilated cardiomyopathy (DCM). IFN-γ/TNF-α treatment of AC-16 cardiomyocytes induced increased nitro-oxidative stress and decreased the mitochondrial membrane potential (ΔΨm). We found that the STAT1/NF-κB/NOS2 axis is involved in the IFN-γ/TNF-α-induced decrease of ΔΨm in AC-16 cardiomyocytes. Furthermore, treatment with mitochondria-sparing agonists of AMPK, NRF2 and SIRT1 rescues ΔΨm in IFN-γ/TNF-α-stimulated cells. Proteomic and gene expression analyses revealed that IFN-γ/TNF-α-treated cells corroborate mitochondrial dysfunction, transmembrane potential of mitochondria, altered fatty acid metabolism and cardiac necrosis/cell death. Functional assays conducted on Seahorse respirometer showed that cytokine-stimulated cells display decreased glycolytic and mitochondrial ATP production, dependency of fatty acid oxidation as well as increased proton leak and non-mitochondrial oxygen consumption. Together, our results suggest that IFN-γ and TNF-α cause direct damage to cardiomyocytes' mitochondria by promoting oxidative and nitrosative stress and impairing energy production pathways. We hypothesize that treatment with agonists of AMPK, NRF2 and SIRT1 might be an approach to ameliorate the progression of Chagas disease cardiomyopathy.

242. Circulating Exosome Involves in the Pathogenesis of Autoimmune Thyroid Diseases Through Immunomodulatory Proteins.

Front Immunol

2021 Nov 11

Jia X, Zhai T, Zhang JA.

243. Are HIV-1-Specific Antibody Levels Potentially Useful Laboratory Markers to Estimate HIV Reservoir Size? A Review.

Front Immunol

2021 Nov 11

Zaongo SD, Sun F, Chen Y.

244. Expanded Hemodialysis Therapy Ameliorates Uremia-Induced Systemic Microinflammation and Endothelial Dysfunction by Modulating VEGF, TNF-α and AP-1 Signaling.

Front Immunol

2021 Nov 11

Catar R, Moll G, Kamhieh-Milz J

ABSTRACT: Systemic chronic microinflammation and altered cytokine signaling, with adjunct cardiovascular disease (CVD), endothelial maladaptation and dysfunction is common in dialysis patients suffering from end-stage renal disease and associated with increased morbidity and mortality. New hemodialysis filters might offer improvements. We here studied the impact of novel improved molecular cut-off hemodialysis filters on systemic microinflammation, uremia and endothelial dysfunction. Human endothelial cells (ECs) were incubated with uremic serum obtained from patients treated with two different hemodialysis regimens in the Permeability Enhancement to Reduce Chronic Inflammation (PERCI-II) crossover clinical trial, comparing High-Flux (HF) and Medium Cut-Off (MCO) membranes, and then assessed for their vascular endothelial growth factor (VEGF) production and angiogenesis. Compared to HF membranes, dialysis with MCO membranes lead to a reduction in proinflammatory mediators and reduced endothelial VEGF production and angiogenesis. Cytokine multiplex screening identified tumor necrosis factor (TNF) superfamily members as promising targets. The influence of TNF-α and its soluble receptors (sTNF-R1 and sTNF-R2) on endothelial VEGF promoter activation, protein release, and the involved signaling pathways was analyzed, revealing that this detrimental signaling was indeed induced by TNF-α and mediated by AP-1/c-FOS signaling. In conclusion, uremic toxins, in particular TNF-signaling, promote endothelial maladaptation, VEGF expression and aberrant angiogenesis, which can be positively modulated by dialysis with novel MCO membranes. TRANSLATIONAL PERSPECTIVE AND GRAPHICAL ABSTRACT: Systemic microinflammation, altered cytokine signaling, cardiovascular disease, and endothelial maladaptation/dysfunction are common clinical complications in dialysis patients suffering from end-stage renal disease. We studied the impact of novel improved medium-cut-off hemodialysis filters on uremia and endothelial dysfunction. We can show that uremic toxins, especially TNF-signaling, promote endothelial maladaptation, VEGF expression and aberrant angiogenesis, which can be positively modulated by dialysis with novel improved medium-cut-off membranes.

245. Emerging Concepts in Immune Thrombotic Thrombocytopenic Purpura.

Front Immunol

2021 Nov 11

Laghmouchi A, Graça NAG, Voorberg J.

246. Real-Life Indications of Interleukin-1 Blocking Agents in Hereditary Recurrent Fevers: Data From the JIRcohort and a Literature Review.

Front Immunol

2021 Nov 11

Vinit C, Georgin-Lavialle S, Theodoropoulou A

BACKGROUND: Interleukin (IL)-1 inhibitors represent the main treatment in patients with colchicine-resistant/intolerant familial Mediterranean fever (crFMF), mevalonate kinase deficiency (MKD), and tumor necrosis factor receptor-associated periodic syndrome (TRAPS). However, the reasons for the use of IL-1 inhibitors in these diseases are still not completely clarified. OBJECTIVE: Identify real-life situations that led to initiating anakinra or canakinumab treatment in hereditary recurrent fevers (HRFs), combining data from an international registry and an up-to-date literature review. PATIENTS AND METHODS: Data were extracted from the JIRcohort, in which clinical information (demographic data, treatment, disease activity, and quality of life) on patients with FMF, MKD, and TRAPS was retrospectively collected. A literature search was conducted using Medline, EMBASE, and Cochrane databases. RESULTS: Complete data of 93 patients with HRF (53.8% FMF, 31.2% MKD, and 15.1% TRAPS) were analyzed. Data from both the registry and the literature review confirmed that the main reasons for use of IL-1 blockers were the following: failure of previous treatment (n = 57, 61.3% and n = 964, 75.3%, respectively), persistence of disease activity with frequent attacks (n = 44, 47.3% and n = 1,023, 79.9%) and/or uncontrolled inflammatory syndrome (n = 46, 49.5% and n = 398, 31.1%), severe disease complication or associated comorbidities (n = 38, 40.9% and n = 390, 30.4%), and worsening of patients' quality of life (n = 36, 38.7% and n = 100, 7,8%). No reasons were specified for 12 (16.4%) JIRcohort patients and 154 (12%) patients in the literature. CONCLUSION: In the absence of standardized indications for IL-1 inhibitors in crFMF, MKD, and TRAPS, these results could serve as a basis for developing a treat-to-target strategy that would help clinicians codify the therapeutic escalation with IL-1 inhibitors.

247. Glutathione Metabolism Is a Regulator of the Acute Inflammatory Response of Monocytes to (1→3)-β-D-Glucan.

Front Immunol

2021 Nov 11

Ramendra R, Mancini M, Ayala JM

248. The Trend of TIM3 Expression on T Cells in Patients With Nontuberculous Mycobacterial Lung Disease: From Immune Cell Dysfunction to Clinical Severity.

Front Immunol

2021 Nov 10

Wang PH, Wu MF, Hsu CY

249. SARS-CoV-2 Nsp5 Activates NF-κB Pathway by Upregulating SUMOylation of MAVS.

Front Immunol

2021 Nov 10

Li W, Qiao J, You Q

Front Immunol

2021 Nov 10

Gilbert C, Lefeuvre C, Preisser L

SARS-CoV-2 coronavirus infection induces heterogeneous symptoms, ranging from asymptomatic to lethal forms. Severe forms usually occur in the elderly and/or individuals with comorbidities. Children generally remain asymptomatic to primary infection, suggesting that they may have an effective local innate immune response. IFN-I and -III have non-redundant protective roles against SARS-CoV-2, although sometimes damaging the host. The expression and role of anti-viral peptides during SARS-CoV-2 infection have thus far been little studied. We aimed to identify the innate immune molecules present at the SARS-CoV-2 entry point. We analyzed the mRNA levels of type I (IFN-α and -β) and type III (IFN-λ1-3) interferons and selected antiviral peptides (i.e., β-defensins 1-3, α-defensins [HNP1-3, HD5] pentraxin-3, surfactant protein D, the cathelicidin LL-37 and interleukin-26) in nasopharyngeal swabs from 226 individuals of various ages, either infected with SARS-CoV-2 (symptomatic or asymptomatic) or negative for the virus. We observed that infection induced selective upregulation of IFN-λ1 expression in pediatric subjects (≤15 years), whereas IFN-α, IFN-β, IFN-λ2/λ3, and β-defensin 1-3 expression was unaffected. Conversely, infection triggered upregulation of IFN-α, IFN-β, IFN-λ2/λ3, and β-defensin 1-3 mRNA expression in adults (15-65 years) and the elderly (≥ 65 years), but without modulation of IFN-λ1. The expression of these innate molecules was not associated with gender or symptoms. Expression of the interferon-stimulated genes IFITM1 and IFITM3 was upregulated in SARS-CoV-2-positive subjects and reached similar levels in the three age groups. Finally, age-related differences in nasopharyngeal innate immunity were also observed in SARS-CoV-2-negative subjects. This study shows that the expression patterns of IFN-I/-III and certain anti-viral molecules in the nasopharyngeal mucosa of SARS-CoV-2-infected subjects differ with age and suggests that susceptibility to SARS-CoV-2 may be related to intrinsic differences in the nature of mucosal anti-viral innate immunity.

251. Basic Predictive Risk Factors for Cytokine Storms in COVID-19 Patients.

Front Immunol

2021 Nov 10

Shcherbak SG, Anisenkova AY, Mosenko SV

OBJECTIVE: A critical role in coronavirus disease 2019 (COVID-19) pathogenesis is played by immune dysregulation that leads to a generalized uncontrolled multisystem inflammatory response, caused by overproduction of proinflammatory cytokines, known as "a cytokine storm" (CS), strongly associated with a severe course of disease. The aim of this study is to identify prognostic biomarkers for CS development in COVID-19 patients and integrate them into a prognostic score for CS-associated risk applicable to routine clinical practice. MATERIALS AND METHODS: The authors performed a review of 458 medical records from COVID-19 patients (241 men and 217 women aged 60.0 ± 10.0) who received treatment in the St. Petersburg State Budgetary Institution of Healthcare City Hospital 40 (City Hospital 40, St. Petersburg), from Apr. 18, 2020 to Nov. 21, 2020. The patients were split in two groups: one group included 100 patients with moderate disease symptoms; the other group included 358 patients with progressive moderately severe, severe, and extremely severe disease. The National Early Warning Score (NEWS) score was used alongside with clinical assessment, chest computed tomographic (CT) scans, electrocardiography (ECG), and lab tests, like ferritin, C-reactive protein (CRP), interleukin (IL)-6, lactate dehydrogenase (LDH), and D-dimer. RESULTS: The basic risk factors for cytokine storms in COVID-19 patients are male gender, age over 40 years, positive test result for replicative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA, absolute lymphocyte count, dynamics in the NEWS score, as well as LDH, D-dimer, ferritin, and IL-6 levels. These clinical and instrumental findings can be also used as laboratory biomarkers for diagnosis and dynamic monitoring of cytokine storms. The suggested prognostic scale (including the NEWS score dynamics; serum IL-6 greater than 23 pg/ml; serum CRP 50 mg/L or greater; absolute lymphocyte count less than 0.72 × 109/L; positive test result for replicative coronavirus (SARS-CoV-2) RNA; age 40 years and over) is a useful tool to identify patients at a high risk for cytokine storm, requiring an early onset of anti-inflammatory therapy.

252. Editorial: The Role of Natural Killer Cells in Autoimmune Diseases.

Front Immunol

2021 Nov 1

Fierabracci A, Delfino DV, Markiewicz MA

253. Targeting Macrophage Dysregulation for Viral Infections: Novel Targets for Immunomodulators.

Front Immunol

2021 Nov 1

Reece MD, Taylor RR, Song C

254. How to Prevent and Mitigate Hypersensitivity Reactions to Biologicals Induced by Anti-Drug Antibodies?

Front Immunol

2021 Nov 1

Vultaggio A, Perlato M, Nencini F

255. Case Report: Interferon- γ Rescues Monocytic Human Leukocyte Antigen Receptor (mHLA-DR) Function in a COVID-19 Patient With ARDS and Superinfection With Multiple MDR 4MRGN Bacterial Strains.

Front Immunol

2021 Nov 1

Grimm C, Dickel S, Grundmann J

BACKGROUND: CD14+ monocytes present antigens to adaptive immune cells via monocytic human leukocyte antigen receptor (mHLA-DR), which is described as an immunological synapse. Reduced levels of mHLA-DR can display an acquired immune defect, which is often found in sepsis and predisposes for secondary infections and fatal outcomes. Monocytic HLA-DR expression is reliably induced by interferon- γ (IFNγ) therapy. CASE REPORT: We report a case of multidrug-resistant superinfected COVID-19 acute respiratory distress syndrome (ARDS) on extracorporeal membrane oxygenation (ECMO) support. The resistance profiles of the detected Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii and Citrobacter freundii isolates were equipped with resistance to all four antibiotic classes including carbapenems (4MRGN) and Cefiderocol in the case of K. pneumoniae. A causal therapeutic antibiotic strategy was not available. Therefore, we measured the immune status of the patient aiming to identify a potential acquired immune deficiency. Monocyte HLA-DR expression identified by FACS analysis revealed an expression level of 34% positive monocytes and suggested severe immunosuppression. We indicated IFNγ therapy, which resulted in a rapid increase in mHLA-DR expression (96%), rapid resolution of invasive bloodstream infection, and discharge from the hospital on day 70. DISCUSSION: Superinfection is a dangerous complication of COVID-19 pneumonia, and sepsis-induced immunosuppression is a risk factor for it. Immunosuppression is expressed by a disturbed antigen presentation of monocytes to cells of the adaptive immune system. The case presented here is remarkable as no validated antibiotic regimen existed against the detected bacterial pathogens causing bloodstream infection and severe pneumonia in a patient suffering from COVID-19 ARDS. Possible restoration of the patient's own immunity by IFNγ was a plausible option to boost the patient's immune system, eliminate the identified 4MRGNs, and allow for lung recovery. This led to the conclusion that immune status monitoring is useful in complicated COVID-19-ARDS and that concomitant IFNγ therapy may support antibiotic strategies. CONCLUSION: After a compromised immune system has been detected by suppressed mHLA-DR levels, the immune system can be safely reactivated by IFNγ.

256. Case Report: Serial Cases: Prolongation of High Immunoglobulin G Level in Repetitive COVID-19 Convalescence Plasma Donor in Saiful Anwar Hospital Malang, Indonesia.

Front Immunol

2021 Nov 1

Nurarifah N, Brahmantyo HP, Wardhani SO

257. Editorial: Immunity and Inflammatory Response in Kidney Stone Disease.

Front Immunol

2021 Nov 1

Thongboonkerd V, Yasui T, Khan SR.

258. Chimeric Antigen Receptor T-Cell Therapy in Lung Cancer: Potential and Challenges.

Front Immunol

2021 Nov 1

Xiao BF, Zhang JT, Zhu YG

259. Immune Profiling of Cord Blood From Preterm and Term Infants Reveals Distinct Differences in Pro-Inflammatory Responses.

Front Immunol

2021 Nov 1

Anderson J, Thang CM, Thanh LQ

260. Role of microRNA Shuttled in Small Extracellular Vesicles Derived From Mesenchymal Stem/Stromal Cells for Osteoarticular Disease Treatment.

Front Immunol

2021 Nov 1

Lara-Barba E, Araya MJ, Hill CN

261. DC-SIGN Mediates the Interaction Between Neutrophils and Leishmania amazonensis-Infected Dendritic Cells to Promote DC Maturation and Parasite Elimination.

Front Immunol

2021 Nov 1

Tiburcio R, Melo LD, Nunes S

262. Nlrx1-Regulated Defense and Metabolic Responses to Aspergillus fumigatus Are Morphotype and Cell Type Specific.

Front Immunol

2021 Nov 1

Kastelberg B, Ayubi T, Tubau-Juni N

The Nlr family member X1 (Nlrx1) is an immuno-metabolic hub involved in mediating effective responses to virus, bacteria, fungi, cancer, and auto-immune diseases. We have previously shown that Nlrx1 is a critical regulator of immune signaling and mortality in several models of pulmonary fungal infection using the clinically relevant fungus Aspergillus fumigatus. In the absence of Nlrx1, hosts produce an enhanced Th2 response primarily by CD103+ dendritic cell populations resulting in enhanced mortality via immunopathogenesis as well as enhanced fungal burden. Here, we present our subsequent efforts showcasing loss of Nlrx1 resulting in a decreased ability of host cells to process A. fumigatus conidia in a cell-type-specific manner by BEAS-2B airway epithelial cells, alveolar macrophages, bone marrow-derived macrophages, but not bone marrow-derived neutrophils. Furthermore, loss of Nlrx1 results in a diminished ability to generate superoxide and/or generic reactive oxygen species during specific responses to fungal PAMPs, conidia, and hyphae. Analysis of glycolysis and mitochondrial function suggests that Nlrx1 is needed to appropriately shut down glycolysis in response to A. fumigatus conidia and increase glycolysis in response to hyphae in BEAS-2B cells. Blocking glycolysis and pentose phosphate pathway (PPP) via 2-DG and NADPH production through glucose-6-phosphate dehydrogenase inhibitor resulted in significantly diminished conidial processing in wild-type BEAS-2B cells to the levels of Nlrx1-deficient BEAS-2B cells. Our findings suggest a need for airway epithelial cells to generate NADPH for reactive oxygen species production in response to conidia via PPP. In context to fungal pulmonary infections, our results show that Nlrx1 plays significant roles in host defense via PPP modulation of several aspects of metabolism, particularly glycolysis, to facilitate conidia processing in addition to its critical role in regulating immune signaling.

Newmer生物

Newmer生物