生信网-文献期刊

Front Immunol

2021 Oct 8

Song J, Deng T.

2. Innate Lymphoid Cells in Skin Homeostasis and Malignancy.

Front Immunol

2021 Oct 8

Wagner M, Koyasu S.

3. Alternative Complement Pathway Inhibition Does Not Abrogate Meningococcal Killing by Serum of Vaccinated Individuals.

Front Immunol

2021 Oct 8

Ispasanie E, Muri L, Schubart A

4. CD11c+CD163+ Cells and Signal Transducer and Activator of Transcription 3 (STAT3) Expression Are Common in Melanoma Leptomeningeal Disease.

Front Immunol

2021 Oct 8

Najem H, Marisetty A, Horbinski C

5. Plasma EVs Display Antigen-Presenting Characteristics in Patients With Allergic Rhinitis and Promote Differentiation of Th2 Cells.

Front Immunol

2021 Oct 8

Fang SB, Zhou ZR, Peng YQ

6. COVID-19 Is a Multi-Organ Aggressor: Epigenetic and Clinical Marks.

Front Immunol

2021 Oct 8

Kgatle MM, Lawal IO, Mashabela G

7. Pandemic Preparedness Against Influenza: DNA Vaccine for Rapid Relief.

Front Immunol

2021 Oct 8

Andersen TK, Bodin J, Oftung F

8. γδT Cells Are Required for CD8(+) T Cell Response to Vaccinia Viral Infection.

Front Immunol

2021 Oct 8

Dai R, Huang X, Yang Y.

9. IL-27 Mediates Pro-Inflammatory Effects via the ERK Signaling Pathway During Preterm Labor.

Front Immunol

2021 Oct 8

Huang D, Ran Y, Liu Z

10. Functional Effects of Receptor-Binding Domain Mutations of SARS-CoV-2 B.1.351 and P.1 Variants.

Front Immunol

2021 Oct 7

Bayarri-Olmos R, Jarlhelt I, Johnsen LB

11. Partners in Crime: Beta-Cells and Autoimmune Responses Complicit in Type 1 Diabetes Pathogenesis.

Front Immunol

2021 Oct 7

Toren E, Burnette KS, Banerjee RR

12. Blocking of EphA2 on Endometrial Tumor Cells Reduces Susceptibility to Vδ1 Gamma-Delta T-Cell-Mediated Killing.

Front Immunol

2021 Oct 7

Hudecek R, Kohlova B, Siskova I

BACKGROUND: Endometriosis is a common gynecological disease characterized by the presence of endometrial tissue outside the uterus causing chronic inflammation, severe pain, and infertility. However, the innate immunity of gamma-delta (γδ) T lymphocytes in endometriosis has not been characterized. Women with endometriosis present numerous endocrine and immune dysfunctions and elevated risk for endometrial, ovarian, and breast cancers. The tyrosine kinase EphA2 is often overexpressed in cancer including endometrial carcinoma. METHODS: We analyzed Vδ1 and Vδ2 γδ T cells in peripheral blood and paired peritoneal fluid samples in endometriosis patients (n = 19) and compared the counts with that of age- and sex-matched healthy donors (n = 33) using flow cytometry. Vδ1 and Vδ2 T cells isolated from healthy donors were used against KLE, RL-95, and Ishikawa endometrial tumor cells in 4 h flow cytometric cytotoxicity assays. The EphA2 blocking studies were performed using antibody, small-molecule inhibitor ALW-II-41-27, and the CRISPR/Cas9. RESULTS: We determined Vδ1 T cells substantially reduced in patients' peripheral blood (p < 0.01) and peritoneal fluid (p < 0.001). No differences were found for circulating Vδ2 T cells compared with peritoneal fluid samples. We observed inherent cytotoxic reactivity of Vδ1 and Vδ2 γδ T lymphocytes against endometrial tumor cells. Importantly, we found reduced specific lysis of EphA2-positive cell lines KLE and RL-95 by Vδ1 T cells in the EphA2 antibody blocking studies and by the EphA2 inhibitor. Furthermore, Vδ1 T-cell-mediated killing was significantly decreased in RL-95 cell EPHA2 knockout. Finally, potent cytolytic activity exerted by Vδ1 T cells was significantly reduced in EPHA2 knockouts in renal A-498 and colon HT-29 carcinoma cell lines. CONCLUSIONS: We determined variable levels of Vδ1 and Vδ2 γδ T cells in endometriosis patients. We observed inherent cytotoxic reactivity of γδ T-cell subsets against endometrial cell lines. Specifically, we found that blocking of EphA2 expression resulted in significant inhibition of endometrial tumor killing mediated by Vδ1 γδ T cells. These results suggest that EphA2 is involved in tumor cell lysis and contributes to susceptibility to Vδ1 γδ T cells cytotoxic reactivity.

13. Diphtheria And Tetanus Vaccination History Is Associated With Lower Odds of COVID-19 Hospitalization.

Front Immunol

2021 Oct 7

Monereo-Sánchez J, Luykx JJ, Pinzón-Espinosa J

14. VISTA Blockade Aggravates Bone Loss in Experimental Murine Apical Periodontitis.

Front Immunol

2021 Oct 7

Yang F, Zhang Y, Chen Z

15. Clinical and Imaging Features of Patients With Encephalitic Symptoms and Myelin Oligodendrocyte Glycoprotein Antibodies.

Front Immunol

2021 Oct 7

Wang J, Qiu Z, Li D

BACKGROUND: Myelin oligodendrocyte glycoprotein-antibody (MOG-ab)-associated disease (MOGAD) has highly heterogenous clinical and imaging presentations, in which encephalitis is an important phenotype. In recent years, some atypical presentations in MOG-ab-associated encephalitis (MOG-E) have been increasingly reported but have not yet been described well. The aim of the study was to describe the clinical and imaging features of patients with MOG-E in our center. Atypical phenotypes would be reported, which is expected to expand the spectrum of MOGAD. METHODS: We reviewed medical records of 59 patients with MOGAD diagnosed in our center and identified cases who had ever experienced encephalitic symptoms. Three hundred ten patients with autoimmune encephalitis (AE) were also reviewed, and cases with positive MOG-ab were identified. Besides, patients with chronically progressive encephalitis were identified from 13 MOG-E and 310 AE patients. We collected demographic, clinical, laboratory, radiological, and outcome data to explore clinical and imaging characteristics in MOG-E, especially in the atypical phenotype of chronically progressive encephalitis. RESULTS: We identified 13 patients (7 males, 6 females) with MOG-E. The median age at onset was 33 years (range 13~62 years). Most (9/13, 69.2%) of patients showed acute or subacute onset of encephalitic symptoms. Brain MRI abnormalities were observed in all patients. The most common lesion locations on MRI were cortical/subcortical (11/13, 84.6%), deep/periventricular white matter (10/13, 76.9%) and corpus callosum (4/13, 30.8%). Brain MRI patterns were categorized into four phenotypes. The most common pattern was cortical encephalitis with leptomeningeal enhancement/brain atrophy (10/13, 76.9%). Eight (8/13, 61.5%) patients had a good response to immunotherapy. Four (4/13, 30.8%) patients with chronically progressive course were identified from MOG-E cohort. They showed leukodystrophy-like pattern, multifocal hazy lesions, or cortical encephalitis on MRI. With immunotherapy, they only showed mild or no improvement. We also identified four (4/310, 1.3%) patients with chronically progressive course from AE cohort. They had better outcomes than counterparts in MOG-E. CONCLUSIONS: This study demonstrates that encephalitic presentations in MOGAD had complex clinical patterns. Chronically progressive encephalitis may be a new phenotype of MOGAD. We recommend to test MOG-ab in subacute and chronic progressive dementia with leukodystrophy-like MRI lesions.

16. Editorial: The Bidirectional Communication Between Neurons and Immune Cells in the Development of Psychiatric, Neurological and Immune-Mediated Disorders.

Front Immunol

2021 Oct 7

Gentile A, D'Acquisto F, Leposavić G.

17. SERS Sensing of Bacterial Endotoxin on Gold Nanoparticles.

Front Immunol

2021 Oct 7

Verde A, Mangini M, Managò S

Engineered gold nanoparticles (AuNPs) find application in several fields related to human activities (i.e., food and cosmetic industry or water purification) including medicine, where they are employed for diagnosis, drug delivery and cancer therapy. As for any material/reagent for human use, the safety of AuNPs needs accurate evaluation. AuNPs are prone to contamination by bacterial endotoxin (lipopolysaccharide, LPS), a potent elicitor of inflammatory responses in mammals. It is therefore important, when assessing AuNP immunosafety and immune-related effects, to discriminate between inflammatory effects intrinsic to the NPs from those caused by an undeliberate and undetected LPS contamination. Detection of LPS contamination in AuNP preparations poses different problems when using the current LPS detection assays, given the general interference of NPs, similar to other particulate agents, with the assay reagents and endpoints. This leads to time-consuming search for optimal assay conditions for every NP batch, with unpredictable results, and to the use in parallel of different assays, each with its weaknesses and unpredictability. Thus, the development of highly sensitive, quantitative and accurate assays able to detect of LPS on AuNPs is very important, in view of their medical applications. Surface-enhanced Raman spectroscopy (SERS) is a label-free, sensitive, chemical-specific, nondestructive and fast technique that can be used to directly obtain molecular fingerprint information and a quantitative analysis of LPS adsorbed on AuNPs. Within this study, we describe the use of SERS for the label-free identification and quantitative evaluation - down to few attograms - of the LPS adsorbed on the surface of 50 nm AuNPs. We thus propose SERS as an efficient tool to detect LPS on the AuNP surface, and as the basis for the development of a new sensitive and specific LPS-detection sensor based on the use of AuNPs and SERS.

18. Serum LAG-3 Predicts Outcome and Treatment Response in Hepatocellular Carcinoma Patients With Transarterial Chemoembolization.

Front Immunol

2021 Oct 7

Guo M, Qi F, Rao Q

19. Neuroinflammatory Triangle Presenting Novel Pharmacological Targets for Ischemic Brain Injury.

Front Immunol

2021 Oct 7

Shaheryar ZA, Khan MA, Adnan CS

20. Determinants of Ligand Specificity and Functional Plasticity in Type I Interferon Signaling.

Front Immunol

2021 Oct 7

Kirby D, Parmar B, Fathi S

The Type I Interferon family of cytokines all act through the same cell surface receptor and induce phosphorylation of the same subset of response regulators of the STAT family. Despite their shared receptor, different Type I Interferons have different functions during immune response to infection. In particular, they differ in the potency of their induced anti-viral and anti-proliferative responses in target cells. It remains not fully understood how these functional differences can arise in a ligand-specific manner both at the level of STAT phosphorylation and the downstream function. We use a minimal computational model of Type I Interferon signaling, focusing on Interferon-α and Interferon-β. We validate the model with quantitative experimental data to identify the key determinants of specificity and functional plasticity in Type I Interferon signaling. We investigate different mechanisms of signal discrimination, and how multiple system components such as binding affinity, receptor expression levels and their variability, receptor internalization, short-term negative feedback by SOCS1 protein, and differential receptor expression play together to ensure ligand specificity on the level of STAT phosphorylation. Based on these results, we propose phenomenological functional mappings from STAT activation to downstream anti-viral and anti-proliferative activity to investigate differential signal processing steps downstream of STAT phosphorylation. We find that the negative feedback by the protein USP18, which enhances differences in signaling between Interferons via ligand-dependent refractoriness, can give rise to functional plasticity in Interferon-α and Interferon-β signaling, and explore other factors that control functional plasticity. Beyond Type I Interferon signaling, our results have a broad applicability to questions of signaling specificity and functional plasticity in signaling systems with multiple ligands acting through a bottleneck of a small number of shared receptors.

21. Sarcoidosis Following Hematopoietic Stem Cell Transplantation: Clinical Characteristics and HLA Associations.

Front Immunol

2021 Oct 7

Wurm-Kuczera RI, Buentzel J, Koenig JFL

PURPOSE: Extrinsic factors and genetic predisposition contribute to the etiology of sarcoidosis, converging in a phenotype of altered immune response associated with multisystemic inflammatory granulomatous tissue infiltration. Immunological reconstitution after hematopoietic stem cell transplantation (HSCT) may represent a unique window for the pathogenesis of the disease. We describe the incidence, clinicopathological features, and HLA associations of sarcoidosis after HSCT in a single-center cohort of patients, together with data from previously published cases. METHODS: We retrospectively analyzed clinical characteristics and HLA haplotypes from allogeneic (allo) or autologous (auto) HSCT patients from January 2001 through May 2021 at the University Medicine Goettingen (UMG), and data from previously published cases. RESULTS: A total number of 19 patients was identified. These included 4 patients from our center (3 allo HSCT and 1 auto HSCT) and 15 patients from the literature review. Thirteen patients had received an allo HSCT, and six patients had received an auto HSCT. Sarcoidosis occurred after a median interval of 20 (after allo HSCT) and 7 (after auto HSCT) months, respectively. The predominant HLA allele associated with sarcoidosis was HLA DRB1*03:01. Sarcoidosis involved the respiratory tract in 15 patients (three unknown, one without pulmonary involvement), and it was associated with graft-versus-host disease in 7 of 13 patients receiving allo HSCT. None of the donors or patients had a history of sarcoidosis before transplantation. Disease manifestations resolved with standard glucocorticoid treatment without long-term sequelae. CONCLUSION: Sarcoidosis may occur at low frequency during reconstitution of the immune system after HSCT. HLA allele associations reflect the associations observed in the general population, particularly with DRB1*03:01. Further insights into the interplay between Tcell reconstitution and the development of sarcoidosis could also provide novel approaches to an improved understanding of the pathogenesis in sarcoidosis.

22. Functionally Mature CD1c(+) Dendritic Cells Preferentially Accumulate in the Inflammatory Arthritis Synovium.

Front Immunol

2021 Oct 7

Canavan M, Marzaioli V, Bhargava V

23. Enhanced Gut-Homing Dynamics and Pronounced Exhaustion of Mucosal and Blood CD4(+) T Cells in HIV-Infected Immunological Non-Responders.

Front Immunol

2021 Oct 7

Lorvik KB, Meyer-Myklestad MH, Kushekar K

24. Altering the Immunogenicity of Hemagglutinin Immunogens by Hyperglycosylation and Disulfide Stabilization.

Front Immunol

2021 Oct 7

Thornlow DN, Macintyre AN, Oguin TH

25. Anti-Carbamylated Fibrinogen Antibodies Might Be Associated With a Specific Rheumatoid Phenotype and Include a Subset Recognizing In Vivo Epitopes of Its γ Chain One of Which Is Not Cross Reactive With Anti-Citrullinated Protein Antibodies.

Front Immunol

2021 Oct 7

Brevet P, Lattard C, Guillou C

26. Serum Biomarker Profile Including CCL1, CXCL10, VEGF, and Adenosine Deaminase Activity Distinguishes Active From Remotely Acquired Latent Tuberculosis.

Front Immunol

2021 Oct 7

Delemarre EM, van Hoorn L, Bossink AWJ

27. Comprehensive B-Cell Immune Repertoire Analysis of Anti-NMDAR Encephalitis and Anti-LGI1 Encephalitis.

Front Immunol

2021 Oct 7

Feng J, Fan S, Sun Y

28. Low GNG12 Expression Predicts Adverse Outcomes: A Potential Therapeutic Target for Osteosarcoma.

Front Immunol

2021 Oct 6

Yuan J, Yuan Z, Ye A

BACKGROUND: G protein subunit gamma 12 (GNG12) is observed in some types of cancer, but its role in osteosarcoma is unknown. This study hypothesized that GNG12 may be a potential biomarker and therapeutic target. We aimed to identify an association between GNG12 and osteosarcoma based on the Gene Expression Omnibus and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) databases. METHODS: Osteosarcoma samples in GSE42352 and TARGET database were selected as the test cohorts. As the external validation cohort, 78 osteosarcoma specimens from The Second Affiliated Hospital of Nanchang University were collected. Patients with osteosarcoma were divided into high and low GNG12 mRNA-expression groups; differentially expressed genes were identified as GNG12-related genes. The biological function of GNG12 was annotated using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, gene set enrichment analysis, and immune infiltration analysis. Gene expression correlation analysis and competing endogenous RNA regulatory network construction were used to determine potential biological regulatory relationships of GNG12. Overall survival, Kaplan-Meier analysis, and log-rank tests were calculated to determine GNG12 reliability in predicting survival prognosis. RESULTS: GNG12 expression decreased in osteosarcoma samples. GNG12 was a highly effective biomarker for osteosarcoma [area under the receiver operating characteristic (ROC) curve (AUC) = 0.920], and the results of our Kaplan-Meier analysis indicated that overall survival and progression-free survival differed significantly between low and high GNG-expression group (p < 0.05). Functional analyses indicated that GNG12 may promote osteosarcoma through regulating the endoplasmic reticulum. Expression correlation analysis and competing endogenous RNA network construction showed that HOTTIP/miR-27a-3p may regulate GNG12 expression. Furthermore, the subunit suppresses adaptive immunity via inhibiting M1 and M2 macrophage infiltration. GNG12 was inhibited in metastatic osteosarcoma compared with non-metastatic osteosarcoma, and its expression predicted survival of patients (1, 3, and 5-year AUCs were 0.961, 0.826, and 0.808, respectively). CONCLUSION: This study identified GNG12 as a potential biomarker for osteosarcoma prognosis, highlighting its potential as an immunotherapy target.

Front Immunol

2021 Oct 6

Coleman C, Doyle-Meyers LA, Russell-Lodrigue KE

30. Activation of iNKT Cells Facilitates Liver Repair After Hepatic Ischemia Reperfusion Injury Through Acceleration of Macrophage Polarization.

Front Immunol

2021 Oct 6

Goto T, Ito Y, Satoh M

Macrophage polarization is critical for liver tissue repair following acute liver injury. However, the underlying mechanisms of macrophage phenotype switching are not well defined. Invariant natural killer T (iNKT) cells orchestrate tissue inflammation and tissue repair by regulating cytokine production. Herein, we examined whether iNKT cells played an important role in liver repair after hepatic ischemia-reperfusion (I/R) injury by affecting macrophage polarization. To this end, we subjected male C57BL/6 mice to hepatic I/R injury, and mice received an intraperitoneal (ip) injection of α-galactosylceramide (α-GalCer) or vehicle. Compared with that of the vehicle, α-GalCer administration resulted in the promotion of liver repair accompanied by acceleration of macrophage differentiation and by increases in the numbers of Ly6Chigh pro-inflammatory macrophages and Ly6Clow reparative macrophages. iNKT cells activated with α-GalCer produced interleukin (IL)-4 and interferon (IFN)-γ. Treatment with anti-IL-4 antibodies delayed liver repair, which was associated with an increased number of Ly6Chigh macrophages and a decreased number of Ly6Clow macrophages. Treatment with anti-IFN-γ antibodies promoted liver repair, associated with reduced the number of Ly6Chigh macrophages, but did not change the number of Ly6Clow macrophages. Bone marrow-derived macrophages up-regulated the expression of genes related to both a pro-inflammatory and a reparative phenotype when co-cultured with activated iNKT cells. Anti-IL-4 antibodies increased the levels of pro-inflammatory macrophage-related genes and decreased those of reparative macrophage-related genes in cultured macrophages, while anti-IFN-γ antibodies reversed the polarization of macrophages. Cd1d-deficient mice showed delayed liver repair and suppressed macrophage switching, compared with that in wild-type mice. These results suggest that the activation of iNKT cells by α-GalCer facilitated liver repair after hepatic I/R injury by both IL-4-and IFN-γ-mediated acceleration of macrophage polarization. Therefore, the activation of iNKT cells may represent a therapeutic tool for liver repair after hepatic I/R injury.

31. Interleukin-4 Programmed Macrophages Suppress Colitis and Do Not Enhance Infectious-Colitis, Inflammation-Associated Colon Cancer or Airway Hypersensitivity.

Front Immunol

2021 Oct 6

Callejas BE, Blyth GAD, Jendzjowsky N

32. Stigmasterol Restores the Balance of Treg/Th17 Cells by Activating the Butyrate-PPARγ Axis in Colitis.

Front Immunol

2021 Oct 6

Wen S, He L, Zhong Z

33. Depletion of T cells via Inducible Caspase 9 Increases Safety of Adoptive T-Cell Therapy Against Chronic Hepatitis B.

Front Immunol

2021 Oct 6

Klopp A, Schreiber S, Kosinska AD

34. Infections and Multiple Sclerosis: From the World to Sardinia, From Sardinia to the World.

Front Immunol

2021 Oct 6

Frau J, Coghe G, Lorefice L

35. Identification of Diagnostic Signatures and Immune Cell Infiltration Characteristics in Rheumatoid Arthritis by Integrating Bioinformatic Analysis and Machine-Learning Strategies.

Front Immunol

2021 Oct 6

Yu R, Zhang J, Zhuo Y

BACKGROUND: Rheumatoid arthritis (RA) refers to an autoimmune rheumatic disease that imposes a huge burden on patients and society. Early RA diagnosis is critical to preventing disease progression and selecting optimal therapeutic strategies more effectively. In the present study, the aim was at examining RA's diagnostic signatures and the effect of immune cell infiltration in this pathology. METHODS: Gene Expression Omnibus (GEO) database provided three datasets of gene expressions. Firstly, this study adopted R software for identifying differentially expressed genes (DEGs) and conducting functional correlation analyses. Subsequently, we integrated bioinformatic analysis and machine-learning strategies for screening and determining RA's diagnostic signatures and further verify by qRT-PCR. The diagnostic values were assessed through receiver operating characteristic (ROC) curves. Moreover, this study employed cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT) website for assessing the inflammatory state of RA, and an investigation was conducted on the relationship of diagnostic signatures and infiltrating immune cells. RESULTS: On the whole, 54 robust DEGs received the recognition. Lymphocyte-specific protein 1 (LSP1), Granulysin (GNLY), and Mesenchymal homobox 2 (MEOX2) (AUC = 0.955) were regarded as RA's diagnostic markers and showed their statistically significant difference by qRT-PCR. As indicated from the immune cell infiltration analysis, resting NK cells, neutrophils, activated NK cells, T cells CD8, memory B cells, and M0 macrophages may be involved in the development of RA. Additionally, all diagnostic signatures might be different degrees of correlation with immune cells. CONCLUSIONS: In conclusion, LSP1, GNLY, and MEOX2 are likely to be available in terms of diagnosing and treating RA, and the infiltration of immune cells mentioned above may critically impact RA development and occurrence.

36. Nonspecific Regulation of the Number of Immunocompetent Cells Under the Influence of DT Toxoid in Children With Glomerulonephritis.

Front Immunol

2021 Oct 6

Kostinov MP, Akhmatova NK, Magarshak OO

BACKGROUND: Studies aimed at identifying the mechanisms of the immunoregulatory effect of vaccination with diphtheria and tetanus toxoid on the parameters of adaptive immunity in children with kidney pathology are limited. The study aimed to study the effect of revaccination against diphtheria and tetanus on the proliferation and differentiation of immunocompetent cells, the formation of specific antibodies, and the course of the disease in children with glomerulonephritis (GN). METHODS: The study included 45 children with glomerulonephritis (GN) aged 5 to 15 years, in remission from 6 months up to 4 years. Of these, 25 children were revaccinated with DT toxoid (Diphtheria-Tetanus toxoid with reduced antigenic content) and 20 were in the control group (not vaccinated). The frequency of development of local and systemic reactions and the course of GN were assessed. The subpopulation structure of lymphocytes was studied in dynamics after 1-6-12 months by flow cytometry and IgG levels to diphtheria and tetanus were studied by ELISA. RESULTS: In 92% of children with GN, the post-vaccination period was uneventful. 8% showed a rise in temperature up to 37.3°C, without the development of local reactions. During the year, none of the patients had an exacerbation of GN or a concomitant disease. After revaccination with DT toxoid, a significant increase in IgG antibodies against diphtheria and tetanus was revealed, which persisted after 12 months - 7.5 [5.1-10.8] IU/mL (p <0.001) and 7.2 [4.8-10.7] IU/mL (p <0.001), respectively. In the post-vaccination period, a multidirectional change in the concentration of T-lymphocytes was noted: with an initially increased level, their percentage after revaccination with DT toxoid decreases from 83 (81-86) % to 78 (76-80)% after a month (p = 0.04) and up to 75 (69-79)% after 12 months (p<0.001). In the control group, such a decrease was not observed. A similar picture was observed for T-helpers, cytotoxic T-lymphocytes, and in patients with an initially low percentage of cytotoxic T-lymphocytes, on the contrary, its increase was noted (p<0.001), which is comparable with the value of this parameter in the group of children with initially normal value (H = 0.54, p = 0.76). The same patterns were observed in the change in the content of B-cells: one month after revaccination, the relative level of B-cells in patients with an initially lowered value increased (p = 0.02) and remained for 12 months (p<0.001). CONCLUSION: Revaccination with DT toxoid in children with GN not only does not cause undesirable changes in the system of immunocompetent cells but also has an immunomodulatory effect, which contributes to the favorable maintenance of the remission period of the disease.

37. Predator-Prey Dynamics of Intra-Host Simian Immunodeficiency Virus Evolution Within the Untreated Host.

Front Immunol

2021 Oct 6

Rife Magalis B, Autissier P, Williams KC

The dynamic nature of the SIV population during disease progression in the SIV/macaque model of AIDS and the factors responsible for its behavior have not been documented, largely owing to the lack of sufficient spatial and temporal sampling of both viral and host data from SIV-infected animals. In this study, we detail Bayesian coalescent inference of the changing collective intra-host viral effective population size (Ne ) from various tissues over the course of infection and its relationship with what we demonstrate is a continuously changing immune cell repertoire within the blood. Although the relative contribution of these factors varied among hosts and time points, the adaptive immune response best explained the overall periodic dynamic behavior of the effective virus population. Data exposing the nature of the relationship between the virus and immune cell populations revealed the plausibility of an eco-evolutionary mathematical model, which was able to mimic the large-scale oscillations in Ne through virus escape from relatively few, early immunodominant responses, followed by slower escape from several subdominant and weakened immune populations. The results of this study suggest that SIV diversity within the untreated host is governed by a predator-prey relationship, wherein differing phases of infection are the result of adaptation in response to varying immune responses. Previous investigations into viral population dynamics using sequence data have focused on single estimates of the effective viral population size (Ne ) or point estimates over sparse sampling data to provide insight into the precise impact of immune selection on virus adaptive behavior. Herein, we describe the use of the coalescent phylogenetic frame- work to estimate the relative changes in Ne over time in order to quantify the relationship with empirical data on the dynamic immune composition of the host. This relationship has allowed us to expand on earlier simulations to build a predator-prey model that explains the deterministic behavior of the virus over the course of disease progression. We show that sequential viral adaptation can occur in response to phases of varying immune pressure, providing a broader picture of the viral response throughout the entire course of progression to AIDS.

38. Stamp2 Protects From Maladaptive Structural Remodeling and Systolic Dysfunction in Post-Ischemic Hearts by Attenuating Neutrophil Activation.

Front Immunol

2021 Oct 6

Mollenhauer M, Bokredenghel S, Geißen S

39. Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosis.

Front Immunol

2021 Oct 6

Ó Maoldomhnaigh C, Cox DJ, Phelan JJ

In order to mount an appropriate immune response to infection, the macrophage must alter its metabolism by increasing aerobic glycolysis and concomitantly decreasing oxidative phosphorylation; a process known as the Warburg effect. Consequently, lactate, the end-product of glycolysis, accumulates in the extracellular environment. The subsequent effect of lactate on surrounding macrophages is poorly understood. Mycobacterium tuberculosis (Mtb), the causative organism of Tuberculosis (TB), is phagocytosed by macrophages in the airways. Mtb infected macrophages upregulate aerobic glycolysis and effector functions to try to kill the bacteria. Our lab has previously shown that human macrophages produce lactate in response to infection with Mtb. Although lactate has largely been considered a waste product of aerobic glycolysis, we hypothesised that the presence of extracellular lactate would impact subsequent immunometabolic responses and modulate macrophage function. We demonstrate that the presence of exogenous lactate has an immediate effect on the cellular metabolism of resting human macrophages; causing a decrease in extracellular acidification rate (ECAR; analogous to the rate of glycolysis) and an increase in the oxygen consumption rate (OCR; analogous to oxidative phosphorylation). When lactate-treated macrophages were stimulated with Mtb or LPS, glycolysis proceeds to increase immediately upon stimulation but oxidative phosphorylation remains stable compared with untreated cells that display a decrease in OCR. This resulted in a significantly reduced ECAR/OCR ratio early in response to stimulation. Since altered metabolism is intrinsically linked to macrophage function, we examined the effect of lactate on macrophage cytokine production and ability to kill Mtb. Lactate significantly reduced the concentrations of TNF and IL-1β produced by human macrophages in response to Mtb but did not alter IL-10 and IL-6 production. In addition, lactate significantly improved bacillary clearance in human macrophages infected with Mtb, through a mechanism that is, at least in part, mediated by promoting autophagy. These data indicate that lactate, the product of glycolysis, has a negative feedback effect on macrophages resulting in an attenuated glycolytic shift upon subsequent stimulation and reduced pro-inflammatory cytokine production. Interestingly, this pro-resolution effect of lactate is associated with increased capacity to kill Mtb.

40. Targeting Cbx3/HP1γ Induces LEF-1 and IL-21R to Promote Tumor-Infiltrating CD8 T-Cell Persistence.

Front Immunol

2021 Oct 6

Le PT, Ha N, Tran NK

41. TNF Patterns and Tumor Microenvironment Characterization in Head and Neck Squamous Cell Carcinoma.

Front Immunol

2021 Oct 6

Long Q, Huang C, Meng Q

42. Methyltransferase-Deficient Avian Flaviviruses Are Attenuated Due to Suppression of Viral RNA Translation and Induction of a Higher Innate Immunity.

Front Immunol

2021 Oct 6

Wu X, Zhang Y, Wang M

43. Advances in Universal CAR-T Cell Therapy.

Front Immunol

2021 Oct 6

Lin H, Cheng J, Mu W

44. Mechanism of Rhinovirus Immunity and Asthma.

Front Immunol

2021 Oct 6

Yang Z, Mitländer H, Vuorinen T

45. Teriflunomide Treatment of Multiple Sclerosis Selectively Modulates CD8 Memory T Cells.

Front Immunol

2021 Oct 5

Tilly G, Cadoux M, Garcia A

BACKGROUND AND OBJECTIVES: Inhibition of de novo pyrimidine synthesis in proliferating T and B lymphocytes by teriflunomide, a pharmacological inhibitor of dihydroorotate dehydrogenase (DHODH), has been shown to be an effective therapy to treat patients with MS in placebo-controlled phase 3 trials. Nevertheless, the underlying mechanism contributing to the efficacy of DHODH inhibition has been only partially elucidated. Here, we aimed to determine the impact of teriflunomide on the immune compartment in a longitudinal high-dimensional follow-up of patients with relapse-remitting MS (RRMS) treated with teriflunomide. METHODS: High-dimensional spectral flow cytometry was used to analyze the phenotype and the function of innate and adaptive immune system of patients with RRMS before and 12 months after teriflunomide treatment. In addition, we assessed the impact of teriflunomide on the migration of memory CD8 T cells in patients with RRMS, and we defined patient immune metabolic profiles. RESULTS: We found that 12 months of treatment with teriflunomide in patients with RRMS does not affect the B cell or CD4 T cell compartments, including regulatory TREG follicular helper TFH cell and helper TH cell subsets. In contrast, we observed a specific impact of teriflunomide on the CD8 T cell compartment, which was characterized by decreased homeostatic proliferation and reduced production of TNFα and IFNγ. Furthermore, we showed that DHODH inhibition also had a negative impact on the migratory velocity of memory CD8 T cells in patients with RRMS. Finally, we showed that the susceptibility of memory CD8 T cells to DHODH inhibition was not related to impaired metabolism. DISCUSSION: Overall, these findings demonstrate that the clinical efficacy of teriflunomide results partially in the specific susceptibility of memory CD8 T cells to DHODH inhibition in patients with RRMS and strengthens active roles for these T cells in the pathophysiological process of MS.

46. Editorial: Targeting Leukocyte Trafficking: Insights and Future Directions.

Front Immunol

2021 Oct 5

Sumagin R, Henson SM, Morrison VL

47. Identification of a Novel Serological Marker in Seronegative Rheumatoid Arthritis Using the Peptide Library Approach.

Front Immunol

2021 Oct 5

Bason C, Barbieri A, Martinelli N

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation mainly affecting the joints leading to cartilage and bone destruction. The definition of seropositive or seronegative RA is based on the presence or absence of rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPAs). Other autoantibodies have been identified in the last decade such as antibodies directed against carbamylated antigens, peptidyl-arginine deiminase type 4 and v-Raf murine sarcoma viral oncogene homologue B. In order to identify relevant autoantigens, we screened a random peptide library (RPL) with pooled IgGs obtained from 50 patients with seronegative RA. Patients' sera were then used in an ELISA test to identify the most frequently recognized peptide among those obtained by screening the RPL. Sera from age- and sex-matched healthy subjects were used as controls. We identified a specific peptide (RA-peptide) recognized by RA patients' sera, but not by healthy subjects or by patients with other immune-mediated diseases. The majority of sera from seronegative and seropositive RA patients (73.8% and 63.6% respectively) contained IgG antibodies directed against the RA-peptide. Interestingly, this peptide shares homology with some self-antigens, such as Protein-tyrosine kinase 2 beta, B cell scaffold protein, Liprin-alfa1 and Cytotoxic T lymphocyte protein 4. Affinity purified anti-RA-peptide antibodies were able to cross react with these autoantigens. In conclusion, we identified a peptide that is recognized by seropositive and, most importantly, by seronegative RA patients' sera, but not by healthy subjects, conferring to this epitope a high degree of specificity. This peptide shares also homology with other autoantigens which can be recognized by autoantibodies present in seronegative RA sera. These newly identified autoantibodies, although present also in a percentage of seropositive RA patients, may be considered as novel serum biomarkers for seronegative RA, which lacks the presence of RF and/or ACPAs.

48. A Comprehensive Review on the Role of Genetic Factors in Neuromyelitis Optica Spectrum Disorder.

Front Immunol

2021 Oct 5

Ghafouri-Fard S, Azimi T, Taheri M.

49. Case Report: Sustained Remission Due to PD-1-Inhibition in a Metastatic Melanoma Patient With Depleted B Cells.

Front Immunol

2021 Oct 5

Wulfken LM, Becker JC, Hayajneh R

50. Oncolytic Viro-Immunotherapy: An Emerging Option in the Treatment of Gliomas.

Front Immunol

2021 Oct 5

Zeng J, Li X, Sander M

51. The Immune System and the Antiviral Responses in Chinese Giant Salamander, Andrias davidianus.

Front Immunol

2021 Oct 5

Jiang N, Fan Y, Zhou Y

52. Suppression of Transmembrane Tumor Necrosis Factor Alpha Processing by a Specific Antibody Protects Against Colitis-Associated Cancer.

Front Immunol

2021 Oct 5

Ba H, Jiang R, Zhang M

53. Characteristics of Anti-Contactin1 Antibody-Associated Autoimmune Nodopathies With Concomitant Membranous Nephropathy.

Front Immunol

2021 Oct 5

Xu Q, Liu S, Zhang P

BACKGROUND: The concurrence of anti-contactin 1 (CNTN1) antibody-associated chronic inflammatory demyelinating polyneuropathy (CIDP) and membranous nephropathy (MN) has previously been reported in the literature. CIDP with autoantibodies against paranodal proteins are defined as autoimmune nodopathies (AN) in the latest research. In view of the unclear relationship between CIDP and MN, we performed a case study and literature review to investigate the clinical characteristics of anti-CNTN antibody-associated AN with MN. METHODS: We detected antibodies against NF155, NF186, CNTN1, CNTN2, CASPR1 and PLA2R in blood samples of a patient with clinically manifested MN and concomitant peripheral neuropathy via double immunofluorescence staining and conducted a quantitative measurement of anti-PLA2R IgG antibodies via enzyme-linked immunosorbent assay (ELISA). Case reports of anti-CNTN1 antibody-associated AN, anti-CNTN1 antibody-associated AN with MN, and CIDP with MN were retrieved through a literature search for a comparative analysis of clinical characteristics. The cases were grouped according to the chronological order of CIDP and MN onset for the comparison of clinical characteristics. RESULTS: A 57-year-old man with anti-PLA2R positive MN was admitted to the hospital due to limb numbness, weakness, and proprioceptive sensory disorder. He was diagnosed with anti-CNTN1 antibody-associated AN and recovered well after immunotherapy. Our literature search returned 22 cases of CIDP with MN that occurred before, after, or concurrently with CIDP. Good responses were achieved with early single-agent or combination immunotherapy, but eight out of the 22 patients with CIDP and concomitant MN ultimately developed different motor sequelae. Five patients had anti-CNTN1 antibody-associated AN with MN. Among these patients, males accounted for the majority of cases (male:female=4:1), the mean age at onset was late (60.2 ± 15.7 years, range 43-78 years), and 40% had acute to subacute onset. Clinical manifestations included sensory-motor neuropathy, sensory ataxia caused by proprioceptive impairment, and elevated cerebrospinal fluid protein levels. CONCLUSION: The age at onset of CIDP with MN was earlier than that of anti-CNTN1 antibody-associated AN. MN may occur before, after or concurrently with CIDP. The early detection and isotyping of anti-CNTN1 and anti-PLA2R antibodies and the monitoring of isotype switching may be essential for suspected CIDP patients.

54. Multi-Omics Data Analyses Identify B7-H3 as a Novel Prognostic Biomarker and Predict Response to Immune Checkpoint Blockade in Head and Neck Squamous Cell Carcinoma.

Front Immunol

2021 Oct 5

Lin W, Xu Y, Gao J

55. Regulatory T Cells: Regulation of Identity and Function.

Front Immunol

2021 Oct 5

Grover P, Goel PN, Greene MI.

56. NK Cell Reconstitution After Autologous Hematopoietic Stem Cell Transplantation: Association Between NK Cell Maturation Stage and Outcome in Multiple Myeloma.

Front Immunol

2021 Oct 5

Orrantia A, Terrén I, Astarloa-Pando G

57. Blood Transcriptomes of Anti-SARS-CoV-2 Antibody-Positive Healthy Individuals Who Experienced Asymptomatic Versus Clinical Infection.

Front Immunol

2021 Oct 5

Sfikakis PP, Verrou KM, Ampatziadis-Michailidis G

58. Unsatisfied Reporting Quality of Clinical Trials Evaluating Immune Checkpoint Inhibitor Therapy in Cancer.

Front Immunol

2021 Oct 5

Chen C, Zhou Y, Zhang X

BACKGROUND: More and more immune-oncology trials have been conducted for treating various cancers, yet it is unclear what the reporting quality of immune-oncology trials is,and characteristics associated with higher reporting quality. OBJECTIVE: This study aims to evaluate the reporting quality of immune-oncology trials. METHODS: The PubMed and Cochrane library were searched to identify all English publications of clinical trials assessing immunotherapy for cancer. Reporting quality of immune-oncology trials was evaluated by a quality score with 11 points derived from the Trial Reporting in Immuno-Oncology (TRIO) statement, which contained two parts: an efficacy score of 6 points and toxicity score of 5 point. Linear regression was used to identify characteristics associated with higher scores. RESULTS: Of the 10,169 studies screened, 298 immune-oncology trial reports were enrolled. The mean quality score, efficacy score, and toxicity score were 6.46, 3.61, and 2.85, respectively. The most common well-reported items were response evaluation criteria (96.0%) and toxicity grade (98.7%), followed by Kaplan-Meier survival analyses (80.5%). Treatment details beyond progression (12.8%) and toxicity onset time and duration (7.7%) were poorly reported. Multivariate regression revealed that higher impact factor (IF) (IF >20 vs. IF <5, p < 0.001), specific tumor type (p = 0.018 for lung, p = 0.021 for urinary system, vs. pan cancer), and a certain kind of immune checkpoint blocking agent (p < 0.001 for anti-PD-1 or multiagents, vs. anti-CTLA-4) were independent predictors of higher-quality score. Similar independent predictive characteristics were revealed for high-efficacy score. Only IF >20 had a significant high-toxicity score (p < 0.001). CONCLUSION: Immune-oncology trial reports presented an unsatisfied quality score, especially in the reporting of treatment details beyond progression and toxicity onset time and duration. High IF journals have better reporting quality. Future improvement of trial reporting was warranted to the benefit-risk assessment of immunotherapy.

59. Strong Association of the Myriad Discrete Speckled Nuclear Pattern With Anti-SS-A/Ro60 Antibodies: Consensus Experience of Four International Expert Centers.

Front Immunol

2021 Oct 5

Röber N, Dellavance A, Ingénito F

60. Reducing Hinge Flexibility of CAR-T Cells Prolongs Survival In Vivo With Low Cytokines Release.

Front Immunol

2021 Oct 5

Zhang A, Sun Y, Du J

61. GM-CSF Nitration Is a New Driver of Myeloid Suppressor Cell Activity in Tumors.

Front Immunol

2021 Oct 5

Calì B, Agnellini AHR, Cioccarelli C

62. Neutrophil Dynamics Affect Mycobacterium tuberculosis Granuloma Outcomes and Dissemination.

Front Immunol

2021 Oct 5

Hult C, Mattila JT, Gideon HP

63. Multiplexed Microsphere-Based Flow Cytometric Assay to Assess Strain Transcending Antibodies to Plasmodium vivax Duffy Binding Protein II Reveals an Efficient Tool to Identify Binding-Inhibitory Antibody Responders.

Front Immunol

2021 Oct 5

Alves JRS, de Araújo FF, Pires CV

64. IFNγ-Producing γ/δ T Cells Accumulate in the Fetal Brain Following Intrauterine Inflammation.

Front Immunol

2021 Oct 4

Lewis EL, Tulina N, Anton L

65. Corrigendum: Plasma Markers of Disrupted Gut Permeability in Severe COVID-19 Patients.

Front Immunol

2021 Oct 4

Giron LB, Dweep H, Yin X

66. Interaction Between Chronic Endometritis Caused Endometrial Microbiota Disorder and Endometrial Immune Environment Change in Recurrent Implantation Failure.

Front Immunol

2021 Oct 4

Chen P, Chen P, Guo Y

67. Humoral and Cellular Response Following Vaccination With the BNT162b2 mRNA COVID-19 Vaccine in Patients Affected by Primary Immunodeficiencies.

Front Immunol

2021 Oct 4

Amodio D, Ruggiero A, Sgrulletti M

68. Case Report: Successful Treatment of Refractory Interstitial Lung Disease With Cyclosporine A and Pirfenidone in a Child With SLE.

Front Immunol

2021 Oct 4

Deng L, Chen Y, Hu X

Interstitial lung disease (ILD) as an initial manifestation of lupus is rare, especially in young children. Here, we report a case of a 3-year-old boy who presented with fever, shortness of breath, and facial erythema. Clinical examination suggested a diagnosis of active systemic lupus erythematosus (SLE) with butterfly rash, anemia, positive antinuclear antibody, positive anti-double-stranded DNA, and hypocomplementemia. On retrospective review of the patient's records, multiple chest computed tomography (CT) images showed non-specific interstitial pneumonia + organizing pneumonia pattern, with no further autoimmune work-up during the visit to a respiratory department. In our opinion, persistent interstitial pneumonia may be a clue to connective tissue disease. The patient received steroid treatment for 1 year, and the radiological and immunological resolution was noted. However, he still suffered from cough and dyspnea. After a 1-year follow-up, he was hospitalized again for SLE relapse. While continuing corticosteroid therapy, the patient was given combination therapy consisting of cyclosporine A (CsA) and monthly-pulse cyclophosphamide for 6 months, and decreased proteinuria was noted. However, the patient's respiratory symptoms and pulmonary radiologic findings did not improve significantly. With continued steroid therapy, the patient was started on a daily regimen of CsA and pirfenidone. Both drugs were sufficiently effective to allow gradual reduction of steroid dosage. After 2 years of treatment, marked improvements in symptoms, pulmonary function and chest CT images were observed. Our experience with this case emphasizes that prompt work-up for connective tissue disease (CTD) should be considered in young children with ILD, and pirfenidone might be a useful add-on therapy with immunosuppressive agents for refractory CTD-ILD in pediatric patients. Nevertheless, further clinical trials including larger numbers of patients need to assess the efficiency and safety of this combination therapy for refractory CTD-ILD.

69. Modulation of the Complement System by Neoplastic Disease of the Central Nervous System.

Front Immunol

2021 Oct 4

Yarmoska SK, Alawieh AM, Tomlinson S

70. From Cellular Infiltration Assessment to a Functional Gene Set-Based Prognostic Model for Breast Cancer.

Front Immunol

2021 Oct 4

Li H, Huang Y, Sharma A

BACKGROUND: Cancer heterogeneity is a major challenge in clinical practice, and to some extent, the varying combinations of different cell types and their cross-talk with tumor cells that modulate the tumor microenvironment (TME) are thought to be responsible. Despite recent methodological advances in cancer, a reliable and robust model that could effectively investigate heterogeneity with direct prognostic/diagnostic clinical application remained elusive. RESULTS: To investigate cancer heterogeneity, we took advantage of single-cell transcriptome data and constructed the first indication- and cell type-specific reference gene expression profile (RGEP) for breast cancer (BC) that can accurately predict the cellular infiltration. By utilizing the BC-specific RGEP combined with a proven deconvolution model (LinDeconSeq), we were able to determine the intrinsic gene expression of 15 cell types in BC tissues. Besides identifying significant differences in cellular proportions between molecular subtypes, we also evaluated the varying degree of immune cell infiltration (basal-like subtype: highest; Her2 subtype: lowest) across all available TCGA-BRCA cohorts. By converting the cellular proportions into functional gene sets, we further developed a 24 functional gene set-based prognostic model that can effectively discriminate the overall survival (P = 5.9 × 10-33, n = 1091, TCGA-BRCA cohort) and therapeutic response (chemotherapy and immunotherapy) (P = 6.5 × 10-3, n = 348, IMvigor210 cohort) in the tumor patients. CONCLUSIONS: Herein, we have developed a highly reliable BC-RGEP that adequately annotates different cell types and estimates the cellular infiltration. Of importance, the functional gene set-based prognostic model that we have introduced here showed a great ability to screen patients based on their therapeutic response. On a broader perspective, we provide a perspective to generate similar models in other cancer types to identify shared factors that drives cancer heterogeneity.

71. Agonistic Activation of Cytosolic DNA Sensing Receptors in Woodchuck Hepatocyte Cultures and Liver for Inducing Antiviral Effects.

Front Immunol

2021 Oct 4

Suresh M, Li B, Huang X

Immune modulation for the treatment of chronic hepatitis B (CHB) has gained more traction in recent years, with an increasing number of compounds designed for targeting different host pattern recognition receptors (PRRs). These agonistic molecules activate the receptor signaling pathway and trigger an innate immune response that will eventually shape the adaptive immunity for control of chronic infection with hepatitis B virus (HBV). While definitive recognition of HBV nucleic acids by PRRs during viral infection still needs to be elucidated, several viral RNA sensing receptors, including toll-like receptors 7/8/9 and retinoic acid inducible gene-I-like receptors, are explored preclinically and clinically as possible anti-HBV targets. The antiviral potential of viral DNA sensing receptors is less investigated. In the present study, treatment of primary woodchuck hepatocytes generated from animals with CHB with HSV-60 or poly(dA:dT) agonists resulted in increased expression of interferon-gamma inducible protein 16 (IFI16) or Z-DNA-binding protein 1 (ZBP1/DAI) and absent in melanoma 2 (AIM2) receptors and their respective adaptor molecules and effector cytokines. Cytosolic DNA sensing receptor pathway activation correlated with a decline in woodchuck hepatitis virus (WHV) replication and secretion in these cells. Combination treatment with HSV-60 and poly(dA:dT) achieved a superior antiviral effect over monotreatment with either agonist that was associated with an increased expression of effector cytokines. The antiviral effect, however, could not be enhanced further by providing additional type-I interferons (IFNs) exogenously, indicating a saturated level of effector cytokines produced by these receptors following agonism. In WHV-uninfected woodchucks, a single poly(dA:dT) dose administered via liver-targeted delivery was well-tolerated and induced the intrahepatic expression of ZBP1/DAI and AIM2 receptors and their effector cytokines, IFN-β and interleukins 1β and 18. Receptor agonism also resulted in increased IFN-γ secretion of peripheral blood cells. Altogether, the effect on WHV replication and secretion following in vitro activation of IFI16, ZBP1/DAI, and AIM2 receptor pathways suggested an antiviral benefit of targeting more than one cytosolic DNA receptor. In addition, the in vivo activation of ZBP1/DAI and AIM2 receptor pathways in liver indicated the feasibility of the agonist delivery approach for future evaluation of therapeutic efficacy against HBV in woodchucks with CHB.

72. Molecular and Cellular Mechanisms Modulating Trained Immunity by Various Cell Types in Response to Pathogen Encounter.

Front Immunol

2021 Oct 4

Acevedo OA, Berrios RV, Rodríguez-Guilarte L

73. Identification of Differential Responses of Goat PBMCs to PPRV Virulence Using a Multi-Omics Approach.

Front Immunol

2021 Oct 4

Eloiflin RJ, Auray G, Python S

74. Induction of High Levels of Specific Humoral and Cellular Responses to SARS-CoV-2 After the Administration of Covid-19 mRNA Vaccines Requires Several Days.

Front Immunol

2021 Oct 4

Gil-Manso S, Carbonell D, López-Fernández L

75. Integrated Proteotranscriptomics of Human Myometrium in Labor Landscape Reveals the Increased Molecular Associated With Inflammation Under Hypoxia Stress.

Front Immunol

2021 Oct 4

Chen L, Wang L, Luo Y

76. Adipsin of the Alternative Complement Pathway Is a Potential Predictor for Preeclampsia in Early Pregnancy.

Front Immunol

2021 Oct 4

Liu M, Luo X, Xu Q

77. Commonalities Between ARDS, Pulmonary Fibrosis and COVID-19: The Potential of Autotaxin as a Therapeutic Target.

Front Immunol

2021 Oct 4

Ntatsoulis K, Karampitsakos T, Tsitoura E

78. In Vivo Mouse Models for Hepatitis B Virus Infection and Their Application.

Front Immunol

2021 Oct 29

Du Y, Broering R, Li X

79. Is Immune Therapy Plus Chemotherapy More Effective Than Immune Therapy Alone for Unresectable Recurrent Nasopharyngeal Carcinoma?

Front Immunol

2021 Oct 29

Zhou X, Niu X, Liu P

OBJECTIVE: To evaluate whether the combination of immune checkpoint inhibitor (ICI) with chemotherapy is more effective than ICI alone in the treatment of recurrent, locoregionally advanced, unresectable nasopharyngeal carcinoma (RAU-NPC), which has progressed after second line chemotherapy. METHODS AND MATERIALS: Patients with RAU-NPC that progressed after second chemotherapy were prescribed ICI once every 3 weeks, either alone or combined with chemotherapy at the discretion of treating physicians, until confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. The primary endpoint was the objective response rate (ORR). The secondary endpoints included safety, duration of response (DOR), and progression-free survival (PFS). RESULTS: From June 2016 to July 2021, 28 patients were enrolled in this study.21 patients received ICI plus chemotherapy, and 7 patients received ICI alone. Altogether, there were 7 (25%) complete response (CR) and 12 (42.8%) partial response (PR), respectively. Stable disease (SD) and progressive disease (PD) were defined in 4 (14.3%) and 5 (17.8%) cases, respectively. The ORR was 19 out of 28 (67.8%). The disease control rate (DCR) was 23 out of 28 (82.1%).Two patients (28.6%) in the ICI alone group and five (23.8%) in the combination group achieved CR (P=0.801). 2 patient (28.6%) in the ICI alone group and 10 (47.6%) in the combination group achieved PR (P=0.378). With a median follow-up of 16 months (2-61 months), five patients terminated ICI due to disease progression, one patient was lost to follow-up, and the remaining 22 patients continued with ICI. Neither the median PFS nor the median DOR was reached. All observed adverse events were defined as ≤ Grade 2. CONCLUSION: ICI alone or combined with chemotherapy demonstrated promising antitumor activity in RAU-NPC patients that progressed after second line chemotherapy, with a low toxicity profile. Compared with ICI alone, chemotherapy plus ICI did not improve CR or PR in our study.

80. The Risk of Severe Infections Following Rituximab Administration in Patients With Autoimmune Kidney Diseases: Austrian ABCDE Registry Analysis.

Front Immunol

2021 Oct 29

Odler B, Windpessl M, Krall M

81. Anti-BCMA CAR-T Cell Therapy in Relapsed/Refractory Multiple Myeloma Patients With Extramedullary Disease: A Single Center Analysis of Two Clinical Trials.

Front Immunol

2021 Oct 29

Que Y, Xu M, Xu Y

BACKGROUND: The prognosis of relapsed/refractory multiple myeloma (RRMM) patients with the extramedullary disease was significantly poor. Extramedullary multiple myeloma (EMM) patients gained limited benefits from traditional drugs. Anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy seems to be a promising approach to treat RRMM patients. However, very few clinical studies are designed for EMM. Our study aimed to compare and assess the safety, efficacy, and pharmacokinetics of anti-BCMA CAR-T cell therapy in EMM and non-EMM. METHODS: The results from published anti-BCMA CAR-T clinical trials, in which raw data of EMM patients were available, were reviewed and summarized. Two trials conducted in our clinical centers were analyzed and presented with detailed data. RESULTS: According to published anti-BCMA CAR-T clinical trials, the ORR of EMM ranged from 57% to 100%, with the complete remission (CR) rate of 29% to 60%. Between February 22, 2017, and September 26, 2019, a total of 61 subjects (EMM 25; non-EMM 36) received anti-BCMA CAR-T cell infusion. The data-cutoff date was April 1, 2021. There were no statistical differences between EMM and non-EMM groups in adverse events (AEs), including cytokine release syndrome (CRS). The most common AEs of grade ≥ 3 in both groups were hematologic toxicities. There was no significant difference in the objective response rate (ORR) and ≥ complete remission (CR) rate between both groups. However, the ≥ CR rate of the EMM group was lower than the non-EMM group receiving the fully human anti-BCMA CAR-T cell therapy (p = 0.026). The median progression-free survival (PFS) for EMM and the non-EMM group was 121 days and 361 days, respectively (p = 0.001). The median overall survival (OS) for EMM and the non-EMM group was 248 days and 1024 days, respectively (p = 0.005). The Cmax and AUC0-28d for EMM group were lower than non-EMM group (Cmax, p = 0.016; AUC0-28d, p = 0.016). Extramedullary disease was an independent prognostic risk factor for PFS (hazard ratio, 2.576; 95% CI, 1.343 to 4.941; p = 0.004) and OS (hazard ratio, 2.312; 95% CI, 1.165 to 4.592; p = 0.017) in RRMM patients receiving anti-BCMA CAR-T cell therapy. CONCLUSIONS: Based on our results, EMM patients could benefit from the two anti-BCMA CAR products, although they had a shorter PFS and OS compared with non-EMM patients. CLINICAL TRIAL REGISTRATION: http://www.chictr.org.cn, identifier ChiCTR-OPC-16009113 and ChiCTR1800018137.

82. Humanized Anti-CD19 CAR-T Cell Therapy and Sequential Allogeneic Hematopoietic Stem Cell Transplantation Achieved Long-Term Survival in Refractory and Relapsed B Lymphocytic Leukemia: A Retrospective Study of CAR-T Cell Therapy.

Front Immunol

2021 Oct 29

Chen W, Ma Y, Shen Z

Early response could be obtained in most patients with relapsed or refractory B cell lymphoblastic leukemia (R/R B-ALL) treated with chimeric antigen receptor T-cell (CAR-T) therapy, but relapse occurs in some patients. There is no consensus on treatment strategy post CAR-T cell therapy. In this retrospective study of humanized CD19-targeted CAR-T cell (hCART19s) therapy for R/R B-ALL, we analyzed the patients treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) or received a second hCART19s infusion, and summarized their efficacy and safety. We retrospectively studied 28 R/R B-ALL patients treated with hCART19s in the Affiliated Hospital of Xuzhou Medical University from 2016 to 2020. After the first hCART19s infusion, 10 patients received allo-HSCT (CART+HSCT group), 7 patients received a second hCART19s infusion (CART2 group), and 11 patients did not receive HSCT or a second hCART19s infusion (CART1 group). The safety, efficacy, and long-term survival were analyzed. Of the 28 patients who received hCART19s treatment, 1 patient could not be evaluated for efficacy, and 25 (92.6%) achieved complete remission (CR) with 20 (74.7%) achieving minimal residual disease (MRD) negativity. Seven (25%) patients experienced grade 3-4 CRS, and one died from grade 5 CRS. No patient experienced ≥3 grade ICANS. The incidence of second CR is higher in the CART+HSCT group compared to the CART2 group (100% vs. 42.9%, p=0.015). The median follow-up time was 1,240 days (range: 709-1,770). Significantly longer overall survival (OS) and leukemia-free survival (LFS) were achieved in the CART+HSCT group (median OS and LFS: not reached, p=0.006 and 0.001, respectively) compared to the CART2 group (median OS: 482; median LFS: 189) and the CART1 group (median OS: 236; median LFS: 35). In the CART+HSCT group, the incidence of acute graft-versus-host disease (aGVHD) was 30% (3/10), and transplantation-related mortality was 30% (3/10). No chronic GVHD occurred. Multivariate analysis results showed that blasts ≥ 20% in the bone marrow and MRD ≥ 65.6% are independent factors for inferior OS and LFS, respectively, while receiving allo-HSCT is an independent factor associated with both longer OS and LFS. In conclusion, early allo-HSCT after CAR-T therapy can achieve long-term efficacy, and the adverse events are controllable.

83. Immunotherapy With 5, 15-DPP Mediates Macrophage M1 Polarization and Modulates Subsequent Mycobacterium tuberculosis Infectivity in rBCG30 Immunized Mice.

Front Immunol

2021 Oct 29

Ahmad F, Umar MS, Khan N

84. Sustained Post-Developmental T-Bet Expression Is Critical for the Maintenance of Type One Innate Lymphoid Cells In Vivo.

Front Immunol

2021 Oct 29

Schroeder JH, Roberts LB, Meissl K

85. Self-Organizing Maps for Cellular In Silico Staining and Cell Substate Classification.

Front Immunol

2021 Oct 29

Yuan E, Matusiak M, Sirinukunwattana K

86. Single-Cell Analysis of Antigen-Specific CD8+ T-Cell Transcripts Reveals Profiles Specific to mRNA or Adjuvanted Protein Vaccines.

Front Immunol

2021 Oct 29

Meldgaard TS, Blengio F, Maffione D

87. Adeno-Associated Viruses (AAV) and Host Immunity - A Race Between the Hare and the Hedgehog.

Front Immunol

2021 Oct 29

Rapti K, Grimm D.

88. Comprehensive of N1-Methyladenosine Modifications Patterns and Immunological Characteristics in Ovarian Cancer.

Front Immunol

2021 Oct 29

Liu J, Chen C, Wang Y

BACKGROUND: recently, many researches have concentrated on the relevance between N1-methyladenosine (m1A) methylation modifications and tumor progression and prognosis. However, it remains unknown whether m1A modification has an effect in the prognosis of ovarian cancer (OC) and its immune infiltration. METHODS: Based on 10 m1A modulators, we comprehensively assessed m1A modification patterns in 474 OC patients and linked them to TME immune infiltration characteristics. m1Ascore computed with principal component analysis algorithm was applied to quantify m1A modification pattern in OC patients. m1A regulators protein and mRNA expression were respectively obtained by HPA website and RT-PCR in clinical OC and normal samples. RESULTS: We finally identified three different m1A modification patterns. The immune infiltration features of these m1A modification patterns correspond to three tumor immune phenotypes, including immune-desert, immune-inflamed and immune-excluded phenotypes. The results demonstrate individual tumor m1A modification patterns can predict patient survival, stage and grade. The m1Ascore was calculated to quantify individual OC patient's m1A modification pattern. A high m1Ascore is usually accompanied by a better survival advantage and a lower mutational load. Research on m1Ascore in the treatment of OC patients showed that patients with high m1Ascore showed marked therapeutic benefits and clinical outcomes in terms of chemotherapy and immunotherapy. Lastly, we obtained four small molecule drugs that may potentially ameliorate prognosis. CONCLUSION: This research demonstrates that m1A methylation modification makes an essential function in the prognosis of OC and in shaping the immune microenvironment. Comprehensive evaluation of m1A modifications improves our knowledge of immune infiltration profile and provides a more efficient individualized immunotherapy strategy for OC patients.

89. PIV and PILE Score at Baseline Predict Clinical Outcome of Anti-PD-1/PD-L1 Inhibitor Combined With Chemotherapy in Extensive-Stage Small Cell Lung Cancer Patients.

Front Immunol

2021 Oct 29

Zeng R, Liu F, Fang C

OBJECTIVES: The objective of this study is to evaluate whether PIV (Pan-Immune-Inflammation Value) and PILE [a score derived from PIV, lactate dehydrogenase (LDH), and Eastern Cooperative Oncology Group Performance Status (ECOG PS)] can predict clinical outcome of anti-PD-1/PD-L1 inhibitor combined with chemotherapy in patients with extensive-stage (ES) small cell lung cancer (SCLC). METHODS: A total of 53 patients with ES-SCLC in the control group of clinical trial (NCT03041311) were included in this study. PIV was calculated as follows: (neutrophil count × platelet count × monocyte count)/lymphocyte count. The PILE scores were composited based on PIV, LDH levels, and ECOG PS. The Kaplan-Meier method and Cox hazards regression models were used for survival analyses. Moreover, the predictive ability of PIV and PILE was validated in an independent real-world group consisting of 84 patients. RESULTS: Patients in the low PIV group (PIV < median) had longer progression-free survival (PFS) and overall survival (OS) than those in the high PIV group (PIV ≥ median), along with the HR, which was 2.157 and 2.359, respectively (PFS HR 95% CI: 1.181-3.940, p = 0.012; OS HR 95% CI: 1.168-4.762, p = 0.020). High PILE score was observed relating to worse treatment efficacy (disease control rate (DCR): 84.21% vs. 100%, p = 0.047; durable clinical benefit (DCB) rate: 10% vs. 48.5%, p = 0.060) and poor clinical outcome (median PFS: 4.75 vs. 5.53 m, p = 0.043; median OS: 7.13 vs. 15.93 m, p = 0.002). Similar results were obtained about the predictive and prognostic abilities of PIV and PILE scores in the validation group. CONCLUSIONS: High PIV and high PILE were correlated with worse clinical outcomes in ES-SCLC patients treated with anti-PD-1/PD-L1 inhibitor combined with chemotherapy, reflecting that PIV and PILE might be useful to identify patients unlikely to benefit from anti-PD-1/PD-L1 therapy.

90. Macrophage Selenoproteins Restrict Intracellular Replication of Francisella tularensis and Are Essential for Host Immunity.

Front Immunol

2021 Oct 29

Markley RL, Restori KH, Katkere B

The essential micronutrient Selenium (Se) is co-translationally incorporated as selenocysteine into proteins. Selenoproteins contain one or more selenocysteines and are vital for optimum immunity. Interestingly, many pathogenic bacteria utilize Se for various biological processes suggesting that Se may play a role in bacterial pathogenesis. A previous study had speculated that Francisella tularensis, a facultative intracellular bacterium and the causative agent of tularemia, sequesters Se by upregulating Se-metabolism genes in type II alveolar epithelial cells. Therefore, we investigated the contribution of host vs. pathogen-associated selenoproteins in bacterial disease using F. tularensis as a model organism. We found that F. tularensis was devoid of any Se utilization traits, neither incorporated elemental Se, nor exhibited Se-dependent growth. However, 100% of Se-deficient mice (0.01 ppm Se), which express low levels of selenoproteins, succumbed to F. tularensis-live vaccine strain pulmonary challenge, whereas 50% of mice on Se-supplemented (0.4 ppm Se) and 25% of mice on Se-adequate (0.1 ppm Se) diet succumbed to infection. Median survival time for Se-deficient mice was 8 days post-infection while Se-supplemented and -adequate mice was 11.5 and >14 days post-infection, respectively. Se-deficient macrophages permitted significantly higher intracellular bacterial replication than Se-supplemented macrophages ex vivo, corroborating in vivo observations. Since Francisella replicates in alveolar macrophages during the acute phase of pneumonic infection, we hypothesized that macrophage-specific host selenoproteins may restrict replication and systemic spread of bacteria. F. tularensis infection led to an increased expression of several macrophage selenoproteins, suggesting their key role in limiting bacterial replication. Upon challenge with F. tularensis, mice lacking selenoproteins in macrophages (TrspM) displayed lower survival and increased bacterial burden in the lung and systemic tissues in comparison to WT littermate controls. Furthermore, macrophages from TrspM mice were unable to restrict bacterial replication ex vivo in comparison to macrophages from littermate controls. We herein describe a novel function of host macrophage-specific selenoproteins in restriction of intracellular bacterial replication. These data suggest that host selenoproteins may be considered as novel targets for modulating immune response to control a bacterial infection.

91. The Dynamic Immunological Parameter Landscape in Coronavirus Disease 2019 Patients With Different Outcomes.

Front Immunol

2021 Oct 29

Tang G, Huang M, Luo Y

92. Machine Learning-Based Single Cell and Integrative Analysis Reveals That Baseline mDC Predisposition Correlates With Hepatitis B Vaccine Antibody Response.

Front Immunol

2021 Oct 29

Aevermann BD, Shannon CP, Novotny M

93. Editorial: The Roles of Checkpoint Inhibitors in Inflammatory Diseases.

Front Immunol

2021 Oct 28

von Knethen A, Rodriguez-Barbosa JI.

94. Editorial: Mouse Models of B Cell Malignancies.

Front Immunol

2021 Oct 28

Perez-Chacon G, Vincent-Fabert C, Zapata JM.

95. Functional Activity of the Complement System in Hospitalized COVID-19 Patients: A Prospective Cohort Study.

Front Immunol

2021 Oct 28

Charitos P, Heijnen IAFM, Egli A

AIMS: Although the exact factors promoting disease progression in COVID-19 are not fully elucidated, unregulated activation of the complement system (CS) seems to play a crucial role in the pathogenesis of acute lung injury (ALI) induced by SARS-CoV-2. In particular, the lectin pathway (LP) has been implicated in previous autopsy studies. The primary purpose of our study is to investigate the role of the CS in hospitalized COVID-19 patients with varying degrees of disease severity. METHODS: In a single-center prospective observational study, 154 hospitalized patients with PCR-confirmed SARS-CoV-2 infection were included. Serum samples on admission to the COVID-19 ward were collected for analysis of CS pathway activities and concentrations of LP proteins [mannose-binding lectin (MBL) and ficolin-3 (FCN-3)] & C1 esterase inhibitor (C1IHN). The primary outcome was mechanical ventilation or in-hospital death. RESULTS: The patients were predominately male and had multiple comorbidities. ICU admission was required in 16% of the patients and death (3%) or mechanical ventilation occurred in 23 patients (15%). There was no significant difference in LP activity, MBL and FCN-3 concentrations according to different peak disease severities. The median alternative pathway (AP) activity was significantly lower (65%, IQR 50-94) in patients with death/invasive ventilation compared to patients without (87%, IQR 68-102, p=0.026). An optimal threshold of <65.5% for AP activity was derived from a ROC curve resulting in increased odds for death or mechanical ventilation (OR 4,93; 95% CI 1.70-14.33, p=0.003) even after adjustment for confounding factors. Classical pathway (CP) activity was slightly lower in patients with more severe disease (median 101% for death/mechanical ventilation vs 109%, p=0.014). C1INH concentration correlated positively with length of stay, inflammatory markers and disease severity on admission but not during follow-up. CONCLUSION: Our results point to an overactivated AP in critically ill COVID-19 patients in vivo leading to complement consumption and consequently to a significantly reduced AP activity in vitro. The LP does not seem to play a role in the progression to severe COVID-19. Apart from its acute phase reaction the significance of C1INH in COVID-19 requires further studies.

96. CTNNB1 Alternation Is a Potential Biomarker for Immunotherapy Prognosis in Patients With Hepatocellular Carcinoma.

Front Immunol

2021 Oct 28

Chen L, Zhou Q, Liu J

BACKGROUND: The emergence of immune checkpoint inhibitors (ICIs) marks the beginning of a new era of immunotherapy for hepatocellular carcinoma (HCC), however, not all patients respond successfully to this treatment. A major challenge for HCC immunotherapy is the development of ways to screen for those patients that would benefit from this type of treatment and determine the optimal treatment plan for individual patients. Therefore, it is important to find a biomarker which allows for the stratification of HCC patients, which distinguishes responders from non-responders, thereby further improving the clinical benefits for those undergoing immunotherapy. METHODS: We used univariate and multivariate Cox risk proportional regression models to evaluate the relationship between non-synonymous mutations with a mutation frequency greater than 10%. We made a prognosis of an immunotherapy HCC cohort using mutation and prognosis data. An additional three HCC queues from the cbioportal webtool were used for further verification. The CIBERSORT, IPS, quanTIseq, and MCPcounter algorithms were used to evaluate the immune cells. PCA and z-score algorithm were used to calculate immune-related signature with published gene sets. Gene set enrichment analysis (GSEA) was used to compare the differences in the pathway-based enrichment scores of candidate genes between mutant and wild types. RESULTS: Univariate and multivariate Cox results showed that only CTNNB1-Mutant(CTNNB1-MUT) was associated with progression-free survival (PFS) of HCC patients in the immunotherapy cohort. After excluding the potential bias introduced by other clinical features, it was found that CTNNB1-MUT served as an independent predictor of the prognosis of HCC patients after immunotherapy (P < 0.05; HR > 1). The results of the tumor immune microenvironment (TIME) analysis showed that patients with CTNNB1-MUT had significantly reduced activated immune cells [such as T cells, B cells, M1-type macrophages, and dendritic cells (DCs)], significantly increased M2-type macrophages, a significantly decreased expression of immunostimulating molecules, low activity of the immune activation pathways (cytokine pathway, immune cell activation and recruitment) and highly active immune depletion pathways (fatty acid metabolism, cholesterol metabolism, and Wnt pathway). CONCLUSIONS: In this study, we found CTNNB1-MUT to be a potential biomarker for HCC immunotherapy patients, because it identified those patients are less likely to benefit from ICIs.

97. GPR Expression in Intestinal Biopsies From SCT Patients Is Upregulated in GvHD and Is Suppressed by Broad-Spectrum Antibiotics.

Front Immunol

2021 Oct 28

Ghimire S, Weber D, Hippe K

98. Plasma Gradient of Soluble Urokinase-Type Plasminogen Activator Receptor Is Linked to Pathogenic Plasma Proteome and Immune Transcriptome and Stratifies Outcomes in Severe COVID-19.

Front Immunol

2021 Oct 28

Sarif J, Raychaudhuri D, D'Rozario R

99. Unraveling the Effects of a Talimogene Laherparepvec (T-VEC)-Induced Tumor Oncolysate on Myeloid Dendritic Cells.

Front Immunol

2021 Oct 28

Tijtgat J, De Munck J, Dufait I

100. Immune Regulatory Cell Bias Following Alemtuzumab Treatment in Relapsing-Remitting Multiple Sclerosis.

Front Immunol

2021 Oct 28

Kashani N, Kelland EE, Vajdi B

Alemtuzumab is a highly effective treatment for relapsing-remitting multiple sclerosis. It selectively targets the CD52 antigen to induce profound lymphocyte depletion, followed by recovery of T and B cells with regulatory phenotypes. We previously showed that regulatory T cell function is restored with cellular repletion, but little is known about the functional capacity of regulatory B-cells and peripheral blood monocytes during the repletion phase. In this study (ClinicalTrials.gov ID# NCT03647722) we simultaneously analyzed the change in composition and function of both regulatory lymphocyte populations and distinct monocyte subsets in cross-sectional cohorts of MS patients prior to or 6, 12, 18, 24 or 36 months after their first course of alemtuzumab treatment. We found that the absolute number and percentage of cells with a regulatory B cell phenotype were significantly higher after treatment and were positivity correlated with regulatory T cells. In addition, B cells from treated patients secreted higher levels of IL-10 and BDNF, and inhibited the proliferation of autologous CD4+CD25- T cell targets. Though there was little change in monocytes populations overall, following the second annual course of treatment, CD14+ monocytes had a significantly increased anti-inflammatory bias in cytokine secretion patterns. These results confirmed that the immune system in alemtuzumab-treated patients is altered in favor of a regulatory milieu that involves expansion and increased functionality of multiple regulatory populations including B cells, T cells and monocytes. Here, we showed for the first time that functionally competent regulatory B cells re-appear with similar kinetics to that of regulatory T-cells, whereas the change in anti-inflammatory bias of monocytes does not occur until after the second treatment course. These findings justify future studies of all regulatory cell types following alemtuzumab treatment to reveal further insights into mechanisms of drug action, and to identify key immunological predictors of durable clinical efficacy in alemtuzumab-treated patients.

101. UnAIDed Class Switching in Activated B-Cells Reveals Intrinsic Features of a Self-Cleaving IgH Locus.

Front Immunol

2021 Oct 28

Dalloul I, Laffleur B, Dalloul Z

102. Chemical Stimulants and Stressors Impact the Outcome of Virus Infection and Immune Gene Expression in Honey Bees (Apis mellifera).

Front Immunol

2021 Oct 28

Parekh F, Daughenbaugh KF, Flenniken ML.

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

Front Immunol

2021 Oct 28

Ma M, Sun Q, Li X

104. Dysregulated Inflammation During Obesity: Driving Disease Severity in Influenza Virus and SARS-CoV-2 Infections.

Front Immunol

2021 Oct 28

Hulme KD, Noye EC, Short KR

105. Optimizing the Clinical Impact of CAR-T Cell Therapy in B-Cell Acute Lymphoblastic Leukemia: Looking Back While Moving Forward.

Front Immunol

2021 Oct 28

Safarzadeh Kozani P, Safarzadeh Kozani P, Rahbarizadeh F.

106. Complex Involvement of Interleukin-26 in Bacterial Lung Infection.

Front Immunol

2021 Oct 28

Che KF, Paulsson M, Piersiala K

107. The Use of Induced Pluripotent Stem Cells to Study the Effects of Adenosine Deaminase Deficiency on Human Neutrophil Development.

Front Immunol

2021 Oct 28

Tsui M, Min W, Ng S

Inherited defects that abrogate the function of the adenosine deaminase (ADA) enzyme and consequently lead to the accumulation of toxic purine metabolites cause profound lymphopenia and severe combined immune deficiency. Additionally, neutropenia and impaired neutrophil function have been reported among ADA-deficient patients. However, due to the rarity of the disorder, the neutrophil developmental abnormalities and the mechanisms contributing to them have not been characterized. Induced pluripotent stem cells (iPSC) generated from two unrelated ADA-deficient patients and from healthy controls were differentiated through embryoid bodies into neutrophils. ADA deficiency led to a significant reduction in the number of all early multipotent hematopoietic progenitors. At later stages of differentiation, ADA deficiency impeded the formation of granulocyte colonies in methylcellulose cultures, leading to a significant decrease in the number of neutrophils generated from ADA-deficient iPSCs. The viability and apoptosis of ADA-deficient neutrophils isolated from methylcellulose cultures were unaffected, suggesting that the abnormal purine homeostasis in this condition interferes with differentiation or proliferation. Additionally, there was a significant increase in the percentage of hyperlobular ADA-deficient neutrophils, and these neutrophils demonstrated significantly reduced ability to phagocytize fluorescent microspheres. Supplementing iPSCs and methylcellulose cultures with exogenous ADA, which can correct adenosine metabolism, reversed all abnormalities, cementing the critical role of ADA in neutrophil development. Moreover, chemical inhibition of the ribonucleotide reductase (RNR) enzyme, using hydroxyurea or a combination of nicotinamide and trichostatin A in iPSCs from healthy controls, led to abnormal neutrophil differentiation similar to that observed in ADA deficiency, implicating RNR inhibition as a potential mechanism for the neutrophil abnormalities. In conclusion, the findings presented here demonstrate the important role of ADA in the development and function of neutrophils while clarifying the mechanisms responsible for the neutrophil abnormalities in ADA-deficient patients.

108. Type I Interferons Are Involved in the Intracellular Growth Control of Mycobacterium abscessus by Mediating NOD2-Induced Production of Nitric Oxide in Macrophages.

Front Immunol

2021 Oct 28

Ahn JH, Park JY, Kim DY

109. Maternal, Decidual, and Neonatal Lymphocyte Composition Is Affected in Pregnant Kidney Transplant Recipients.

Front Immunol

2021 Oct 28

Feyaerts D, Gillard J, van Cranenbroek B

110. PMEPA1 Is a Prognostic Biomarker That Correlates With Cell Malignancy and the Tumor Microenvironment in Bladder Cancer.

Front Immunol

2021 Oct 28

Qiu D, Hu J, Hu J

111. Immune Microenvironment and Response in Prostate Cancer Using Large Population Cohorts.

Front Immunol

2021 Oct 28

Ren X, Chen X, Zhang X

112. Editorial: The State-of-Art in Immuno-Oncology, What to Do With Glioblastoma?

Front Immunol

2021 Oct 27

Cui X, Wang Q, Kang C.

113. Single Dose of a VSV-Based Vaccine Rapidly Protects Macaques From Marburg Virus Disease.

Front Immunol

2021 Oct 27

Marzi A, Jankeel A, Menicucci AR

114. Making a Killer: Selecting the Optimal Natural Killer Cells for Improved Immunotherapies.

Front Immunol

2021 Oct 27

Barnes SA, Trew I, de Jong E

115. The Role of HDAC6 in Autophagy and NLRP3 Inflammasome.

Front Immunol

2021 Oct 27

Chang P, Li H, Hu H

116. Genome-Wide Profiling Reveals Alternative Polyadenylation of Innate Immune-Related mRNA in Patients With COVID-19.

Front Immunol

2021 Oct 27

An S, Li Y, Lin Y

117. Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts.

Front Immunol

2021 Oct 27

Sánchez-Maldonado JM, Cáliz R, López-Nevot MÁ

We aimed to validate the association of 28 GWAS-identified genetic variants for response to TNF inhibitors (TNFi) in a discovery cohort of 1361 rheumatoid arthritis (RA) patients monitored in routine care and ascertained through the REPAIR consortium and DANBIO registry. We genotyped selected markers and evaluated their association with response to TNFi after 6 months of treatment according to the change in disease activity score 28 (ΔDAS28). Next, we confirmed the most interesting results through meta-analysis of our data with those from the DREAM cohort that included 706 RA patients treated with TNFi. The meta-analysis of the discovery cohort and DREAM registry including 2067 RA patients revealed an overall association of the LINC02549rs7767069 SNP with a lower improvement in DAS28 that remained significant after correction for multiple testing (per-allele ORMeta=0.83, PMeta=0.000077; PHet=0.61). In addition, we found that each copy of the LRRC55rs717117G allele was significantly associated with lower improvement in DAS28 in rheumatoid factor (RF)-positive patients (per-allele ORMeta=0.67, P=0.00058; PHet=0.06) whereas an opposite but not significant effect was detected in RF-negative subjects (per-allele ORMeta=1.38, P=0.10; PHet=0.45; PInteraction=0.00028). Interestingly, although the identified associations did not survive multiple testing correction, the meta-analysis also showed overall and RF-specific associations for the MAFBrs6071980 and CNTN5rs1813443 SNPs with decreased changes in DAS28 (per-allele ORMeta_rs6071980 = 0.85, P=0.0059; PHet=0.63 and ORMeta_rs1813443_RF+=0.81, P=0.0059; PHet=0.69 and ORMeta_rs1813443_RF-=1.00, P=0.99; PHet=0.12; PInteraction=0.032). Mechanistically, we found that subjects carrying the LINC02549rs7767069T allele had significantly increased numbers of CD45RO+CD45RA+ T cells (P=0.000025) whereas carriers of the LINC02549rs7767069T/T genotype showed significantly increased levels of soluble scavengers CD5 and CD6 in serum (P=0.00037 and P=0.00041). In addition, carriers of the LRRC55rs717117G allele showed decreased production of IL6 after stimulation of PBMCs with B burgdorferi and E coli bacteria (P=0.00046 and P=0.00044), which suggested a reduced IL6-mediated anti-inflammatory effect of this marker to worsen the response to TNFi. In conclusion, this study confirmed the influence of the LINC02549 and LRRC55 loci to determine the response to TNFi in RA patients and suggested a weak effect of the MAFB and CNTN5 loci that need to be further investigated.

118. Identification of Two Subsets of Murine DC1 Dendritic Cells That Differ by Surface Phenotype, Gene Expression, and Function.

Front Immunol

2021 Oct 26

Hongo D, Zheng P, Dutt S

119. Mesenchymal Stromal Cells for the Treatment of Graft Versus Host Disease.

Front Immunol

2021 Oct 26

Kelly K, Rasko JEJ.

120. Isolation and Characterization of Mouse Monoclonal Antibodies That Neutralize SARS-CoV-2 and Its Variants of Concern Alpha, Beta, Gamma and Delta by Binding Conformational Epitopes of Glycosylated RBD With High Potency.

Front Immunol

2021 Oct 26

Mariotti S, Capocefalo A, Chiantore MV

Antibodies targeting Receptor Binding Domain (RBD) of SARS-CoV-2 have been suggested to account for the majority of neutralizing activity in COVID-19 convalescent sera and several neutralizing antibodies (nAbs) have been isolated, characterized and proposed as emergency therapeutics in the form of monoclonal antibodies (mAbs). However, SARS-CoV-2 variants are rapidly spreading worldwide from the sites of initial identification. The variants of concern (VOC) B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.167.2 (Delta) showed mutations in the SARS-CoV-2 spike protein potentially able to cause escape from nAb responses with a consequent reduction of efficacy of vaccines and mAbs-based therapy. We produced the recombinant RBD (rRBD) of SARS-CoV-2 spike glycoprotein from the Wuhan-Hu 1 reference sequence in a mammalian system, for mice immunization to isolate new mAbs with neutralizing activity. Here we describe four mAbs that were able to bind the rRBD in Enzyme-Linked Immunosorbent Assay and the transmembrane full-length spike protein expressed in HEK293T cells by flow cytometry assay. Moreover, the mAbs recognized the RBD in supernatants of SARS-CoV-2 infected VERO E6 cells by Western Blot under non-reducing condition or in supernatants of cells infected with lentivirus pseudotyped for spike protein, by immunoprecipitation assay. Three out of four mAbs lost their binding efficiency to completely N-deglycosylated rRBD and none was able to bind the same recombinant protein expressed in Escherichia coli, suggesting that the epitopes recognized by three mAbs are generated by the conformational structure of the glycosylated native protein. Of particular relevance, three mAbs were able to inhibit Wuhan SARS-CoV-2 infection of VERO E6 cells in a plaque-reduction neutralization test and the Wuhan SARS-CoV-2 as well as the Alpha, Beta, Gamma and Delta VOC in a pseudoviruses-based neutralization test. These mAbs represent important additional tools for diagnosis and therapy of COVID-19 and may contribute to the understanding of the functional structure of SARS-CoV-2 RBD.

Front Immunol

2021 Oct 26

Deng ZM, Hu W, Dai FF

122. Axitinib Reverses Resistance to Anti-Programmed Cell Death-1 Therapy in a Patient With Renal Cell Carcinoma.

Front Immunol

2021 Oct 26

Yang Y, Huang H, Li T

123. Pharmacological Activation Of Aldehyde Dehydrogenase 2 Protects Against Heatstroke-Induced Acute Lung Injury by Modulating Oxidative Stress and Endothelial Dysfunction.

Front Immunol

2021 Oct 26

Tsai HY, Hsu YJ, Lu CY

Heatstroke (HS) can cause acute lung injury (ALI). Heat stress induces inflammation and apoptosis via reactive oxygen species (ROS) and endogenous reactive aldehydes. Endothelial dysfunction also plays a crucial role in HS-induced ALI. Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that detoxifies aldehydes such as 4-hydroxy-2-nonenal (4-HNE) protein adducts. A single point mutation in ALDH2 at E487K (ALDH2*2) intrinsically lowers the activity of ALDH2. Alda-1, an ALDH2 activator, attenuates the formation of 4-HNE protein adducts and ROS in several disease models. We hypothesized that ALDH2 can protect against heat stress-induced vascular inflammation and the accumulation of ROS and toxic aldehydes. Homozygous ALDH2*2 knock-in (KI) mice on a C57BL/6J background and C57BL/6J mice were used for the animal experiments. Human umbilical vein endothelial cells (HUVECs) were used for the in vitro experiment. The mice were directly subjected to whole-body heating (WBH, 42°C) for 1 h at 80% relative humidity. Alda-1 (16 mg/kg) was administered intraperitoneally prior to WBH. The severity of ALI was assessed by analyzing the protein levels and cell counts in the bronchoalveolar lavage fluid, the wet/dry ratio and histology. ALDH2*2 KI mice were susceptible to HS-induced ALI in vivo. Silencing ALDH2 induced 4-HNE and ROS accumulation in HUVECs subjected to heat stress. Alda-1 attenuated the heat stress-induced activation of inflammatory pathways, senescence and apoptosis in HUVECs. The lung homogenates of mice pretreated with Alda-1 exhibited significantly elevated ALDH2 activity and decreased ROS accumulation after WBH. Alda-1 significantly decreased the WBH-induced accumulation of 4-HNE and p65 and p38 activation. Here, we demonstrated the crucial roles of ALDH2 in protecting against heat stress-induced ROS production and vascular inflammation and preserving the viability of ECs. The activation of ALDH2 by Alda-1 attenuates WBH-induced ALI in vivo.

124. Human Complement C4B Allotypes and Deficiencies in Selected Cases With Autoimmune Diseases.

Front Immunol

2021 Oct 26

Zhou D, Rudnicki M, Chua GT

Human complement C4 is one of the most diverse but heritable effectors for humoral immunity. To help understand the roles of C4 in the defense and pathogenesis of autoimmune and inflammatory diseases, we determined the bases of polymorphisms including the frequent genetic deficiency of C4A and/or C4B isotypes. We demonstrated the diversities of C4A and C4B proteins and their gene copy number variations (CNVs) in healthy subjects and patients with autoimmune disease, such as type 1 diabetes, systemic lupus erythematosus (SLE) and encephalitis. We identified subjects with (a) the fastest migrating C4B allotype, B7, or (b) a deficiency of C4B protein caused by genetic mutation in addition to gene copy-number variation. Those variants and mutants were characterized, sequenced and specific techniques for detection developed. Novel findings were made in four case series. First, the amino acid sequence determinant for C4B7 was likely the R729Q variation at the anaphylatoxin-like region. Second, in healthy White subject MS630, a C-nucleotide deletion at codon-755 led to frameshift mutations in his single C4B gene, which was a private mutation. Third, in European family E94 with multiplex lupus-related mortality and low serum C4 levels, the culprit was a recurrent haplotype with HLA-A30, B18 and DR7 that segregated with two defective C4B genes and identical mutations at the donor splice site of intron-28. Fourth, in East-Asian subject E133P with anti-NMDA receptor encephalitis, the C4B gene had a mutation that changed tryptophan-660 to a stop-codon (W660x), which was present in a haplotype with HLA-DRB1*04:06 and B*15:27. The W660x mutation is recurrent among East-Asians with a frequency of 1.5% but not detectable among patients with SLE. A meticulous annotation of C4 sequences revealed clusters of variations proximal to sites for protein processing, activation and inactivation, and binding of interacting molecules.

125. Following the Clues: Usefulness of Biomarkers of Neuroinflammation and Neurodegeneration in the Investigation of HTLV-1-Associated Myelopathy Progression.

Front Immunol

2021 Oct 26

Souza FDS, Freitas NL, Gomes YCP

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease due to axonal damage of the corticospinal secondary to an inflammatory response against infected T-cells. In the present work, we aimed to evaluate biomarkers of neurodegeneration and neuroinflammation in the definition of HAM/TSP prognosis. Neurofilament light (NfL) and phosphorylated heavy (pNfH) chains, total Tau protein, cellular prion protein (PrPc), inflammatory chemokines, and neopterin were quantified in paired cerebrospinal fluid (CSF) and serum samples from HAM/TSP patients (n=21), HTLV-1 asymptomatic carriers (AC) (n=13), and HTLV-1 seronegative individuals with non-inflammatory non-degenerative neurological disease (normal-pressure hydrocephalus) (n=9) as a control group. HTLV-1 proviral load in peripheral blood mononuclear cells and the expression of chemokine receptors CCR4, CCR5, and CXCR3 in infected CD4+ T-cells (HTLV-1 Tax+ cells) were also assessed. CSF levels of Tau, NfL, and pNfH were similar between groups, but PrPc and neopterin were elevated in HAM/TSP patients. Most individuals in the control group and all HTLV-1 AC had CSF/serum neopterin ratio < 1.0, and two-thirds of HAM/TSP patients had ratio values > 1.0, which positively correlated with the speed of disease progression and pNfH levels, indicating active neuroinflammation. HAM/TSP patients showed high serum levels of CXCR3-binding chemokines (CXCL9, CXCL10, and CXCL11) and elevated CSF levels of CCL2, CCL3, CCL4, CCL17, CXCL5, CXCL10, and CXCL11. Indeed, CXCL10 concentration in CSF of HAM/TSP patients was 5.8-fold and 8.7-fold higher in than in HTLV-1 AC and controls, respectively, and correlated with CSF cell counts. HAM/TSP patients with typical/rapid disease progression had CSF/serum CXCL10 ratio > 1.0 and a higher frequency of CXCR3+Tax+CD4+ T-cells in blood, which indicated a positive gradient for the migration of infected cells and infiltration into the central nervous system. In conclusion, the slow progression of HAM/TSP abrogates the usefulness of biomarkers of neuronal injury for the disease prognosis. Thus, markers of inflammation provide stronger evidence for HAM/TSP progression, particularly the CSF/serum neopterin ratio, which may contribute to overcome differences between laboratory assays.

126. Case Report: The Carotid Body in COVID-19: Histopathological and Virological Analyses of an Autopsy Case Series.

Front Immunol

2021 Oct 26

Porzionato A, Emmi A, Contran M

127. Disruption of Glucocorticoid Action on CD11c(+) Dendritic Cells Favors the Generation of CD4(+) Regulatory T Cells and Improves Fetal Development in Mice.

Front Immunol

2021 Oct 26

Diao L, Hierweger AM, Wieczorek A

128. Single-Cell Sequencing Reveals the Novel Role of Ezh2 in NK Cell Maturation and Function.

Front Immunol

2021 Oct 26

Yu M, Su Z, Huang X

129. Tissue-Specific Molecular Markers and Heterogeneity in Type 2 Innate Lymphoid Cells.

Front Immunol

2021 Oct 25

Olguín-Martínez E, Ruiz-Medina BE, Licona-Limón P.

130. Retinoic Acid Signaling Modulates Recipient Gut Barrier Integrity and Microbiota After Allogeneic Hematopoietic Stem Cell Transplantation in Mice.

Front Immunol

2021 Oct 25

Pan P, Atkinson SN, Taylor B

131. Depletion of Human Papilloma Virus E6- and E7-Oncoprotein-Specific T-Cell Responses in Women Living With HIV.

Front Immunol

2021 Oct 25

Mbuya W, Held K, Mcharo RD

BACKGROUND: Cervical cancer - caused by persistent High Risk Human Papilloma Virus (HR HPV) infections - is the second most common cancer affecting women globally. HIV infection increases the risk for HPV persistence, associated disease progression and malignant cell transformation. We therefore hypothesized that this risk increase is directly linked to HIV infection associated dysfunction or depletion of HPV-oncoprotein-specific T-cell responses. METHODS: The 2H study specifically included HIV+ and HIV- women with and without cervical lesions and cancer to analyze HPV oncogene-specific T cell responses in relation to HPV infection, cervical lesion status and HIV status. Oncoprotein E6 and E7 specific T-cell responses were quantified for the most relevant types HPV16, 18 and 45 and control antigens (CMV-pp65) and M.tb-PPD in 373 women, using fresh peripheral blood mononuclear cells in an IFN-γ release ELISpot assay. RESULTS: Overall, systemic E6- and E7-oncoprotein-specific T-cell responses were infrequent and of low magnitude, when compared to CMV-pp65 and M.tb-PPD (p < 0.001 for all HR HPV types). Within HIV negative women infected with either HPV16, 18 or 45, HPV16 infected women had lowest frequency of autologous-type-E6/E7-specific T-cell responses (33%, 16/49), as compared to HPV18 (46% (6/13), p = 0.516) and HPV45 (69% (9/13), p = 0.026) infected women. Prevalent HPV18 and 45, but not HPV16 infections were linked to detectable oncoprotein-specific T-cell responses, and for these infections, HIV infection significantly diminished T-cell responses targeting the autologous infecting genotype. Within women living with HIV, low CD4 T-cell counts, detectable HIV viremia as well as cancerous and precancerous lesions were significantly associated with depletion of HPV oncoprotein-specific T-cell responses. DISCUSSION: Depletion of HPV-oncoprotein-specific T-cell responses likely contributes to the increased risk for HR HPV persistence and associated cancerogenesis in women living with HIV. The low inherent immunogenicity of HPV16 oncoproteins may contribute to the exceptional potential for cancerogenesis associated with HPV16 infections.

132. Milking the Cow: Cattle-Derived Chimeric Ultralong CDR-H3 Antibodies and Their Engineered CDR-H3-Only Knobbody Counterparts Targeting Epidermal Growth Factor Receptor Elicit Potent NK Cell-Mediated Cytotoxicity.

Front Immunol

2021 Oct 25

Pekar L, Klewinghaus D, Arras P

133. Interleukin-22 Deficiency Contributes to Dextran Sulfate Sodium-Induced Inflammation in Japanese Medaka, Oryzias latipes.

Front Immunol

2021 Oct 25

Takahashi Y, Okamura Y, Harada N

Mucosal tissue forms the first line of defense against pathogenic microorganisms. Cellular damage in the mucosal epithelium may induce the interleukin (IL)-22-related activation of many immune cells, which are essential for maintaining the mucosal epithelial barrier. A previous study on mucosal immunity elucidated that mammalian IL-22 contributes to mucus and antimicrobial peptides (AMPs) production and anti-apoptotic function. IL-22 has been identified in several teleost species and is also induced in response to bacterial infections. However, the roles of IL-22 in teleost immunity and mucus homeostasis are poorly understood. In this study, Japanese medaka (Oryzias latipes) was used as a model fish. The medaka il22, il22 receptor A1 (il22ra1), and il22 binding protein (il22bp) were cloned and characterized. The expression of medaka il22, il22ra1, and il22bp in various tissues was measured using qPCR. These genes were expressed at high levels in the mucosal tissues of the intestines, gills, and skin. The localization of il22 and il22bp mRNA in the gills and intestines was confirmed by in situ hybridizations. Herein, we established IL-22-knockout (KO) medaka using the CRISPR/Cas9 system. In the IL-22-KO medaka, a 4-bp deletion caused a frameshift in il22. To investigate the genes subject to IL-22-dependent regulation, we compared the transcripts of larval medaka between wild-type (WT) and IL-22-KO medaka using RNA-seq and qPCR analyses. The comparison was performed not only in the naïve state but also in the dextran sulfate sodium (DSS)-exposed state. At the transcriptional level, 368 genes, including immune genes, such as those encoding AMPs and cytokines, were significantly downregulated in IL-22-KO medaka compared that in WT medaka in naïve states. Gene ontology analysis revealed that upon DSS stimulation, genes associated with cell death, acute inflammatory response, cell proliferation, and others were upregulated in WT medaka. Furthermore, in DSS-stimulated IL-22-KO medaka, wound healing was delayed, the number of apoptotic cells increased, and the number of goblet cells in the intestinal epithelium decreased. These results suggested that in medaka, IL-22 is important for maintaining intestinal homeostasis, and the disruption of the IL-22 pathway is associated with the exacerbation of inflammatory pathology, as observed for mammalian IL-22.

134. Vedolizumab for the Management of Refractory Behçet's Disease: From a Case Report to New Pieces of Mosaic in a Complex Disease.

Front Immunol

2021 Oct 25

Arbrile M, Radin M, Rossi D

135. Clinical Immunogenicity Evaluation of Eptinezumab, a Therapeutic Humanized Monoclonal Antibody Targeting Calcitonin Gene-Related Peptide (CGRP) for the Preventive Treatment of Migraine.

Front Immunol

2021 Oct 25

Pederson S, Biondi DM, Allan B

BACKGROUND: Eptinezumab is a humanized monoclonal antibody that selectively binds calcitonin gene-related peptide and is indicated for the preventive treatment of migraine in adults. This analysis characterizes the immunogenic profile of eptinezumab using data from clinical trials of eptinezumab for migraine prevention. METHODS: Immunogenicity data were collected from five studies that included 2076 patients with episodic or chronic migraine treated with eptinezumab at dose levels ranging from 10 to 1000 mg, administered intravenously for up to 4 doses at 12-week intervals. Anti-drug antibody (ADA) results were available from 2074 of these patients. Four studies were randomized, double-blind, placebo-controlled trials with ADA monitoring for up to 56 weeks; one was a 2-year, open-label, phase 3 safety study with ADA monitoring for 104 weeks. Patients who had a confirmed ADA-positive result at the end-of-study visit were monitored for up to 6 additional months. Development of ADA and neutralizing antibodies (NAbs) were evaluated to explore three key areas of potential impact: pharmacokinetic exposure profile (eptinezumab trough plasma concentrations), efficacy (change in monthly migraine days), and safety (rates of treatment-emergent adverse events). These studies included methods designed to capture the dynamics of a potential humoral immune response to eptinezumab treatment, and descriptive analyses were applied to interpret the relationship of ADA signals to drug exposure, efficacy, and safety. RESULTS: Pooled across the five clinical trials, treatment-emergent ADAs and NAbs occurred in 15.8 and 6.2% of eptinezumab-treated patients, respectively. Highly consistent profiles were observed across all studies, with initial onset of detectable ADA observed at the week 8 measurement and maximal ADA frequency and titer observed at week 24, regardless of eptinezumab dose level or number of doses. After 24 weeks, the ADA and NAb titers steadily declined despite additional doses of eptinezumab. INTERPRETATION: Collectively, these integrated analyses did not demonstrate any clinically meaningful impact from ADA occurring after treatment with eptinezumab. The ADA profiles were low titer and transient, with the incidence and magnitude of ADA or NAb responses declining after week 24. Development of ADAs and NAbs did not impact the efficacy and safety profiles of eptinezumab.

136. Single-Cell Transcriptome Profiling Identifies Phagocytosis-Related Dual-Feature Cells in A Model of Acute Otitis Media in Rats.

Front Immunol

2021 Oct 25

Rao Y, Zhong D, Qiu K

BACKGROUND: The molecular mechanisms of acute otitis media (AOM) development, and the intercellular crosstalk within the multicellular ecosystem of AOM, are not clear. METHODS: We established a model of AOM in rats (with normal rats as controls) and undertook single-cell RNA sequencing (scRNA-seq) for the middle-ear mucosa (MEM). Cell clustering and trajectory analyses were undertaken using Seurat and Monocle 2 packages in R software. Pathway analyses were done by gene set enrichment analysis (GSEA). Cell-cell interactions were inferred by CellChat. Cell scores were calculated to identify cells with dual-feature. RESULTS: A total of 7023 cells from three samples of inflamed MEM and 5258 cells from three samples of healthy MEM underwent scRNA-seq, which identified 20 cell clusters belonging to eight major cell types. After exposure to lipopolysaccharide, the MEM underwent significant conversion of cell types characterized by rapid infiltration of macrophages and neutrophils. M2 macrophages seemed to play a key part in inflammatory intercellular crosstalk, which facilitated the maintenance and proliferation of macrophages, cell chemotaxis, and regulation of the proinflammatory activities of cytokines. Three rare cell clusters with phagocytosis-related dual-feature were also identified. They coexisted with professional phagocytes in the MEM, and displayed distinct immunoregulatory functions by maintaining a normal immune microenvironment or influencing inflammation progression. CONCLUSIONS: Macrophages might be the "master" initiators and regulators of the inflammatory response of the MEM to external stimuli. And their functions are fulfilled by a specific polarization status (M2) and sophisticated intercellular crosstalk via certain signaling pathways. Besides, the coexistence of professional phagocytes and non-professional phagocytes as well as their interplay in the MEM provides new clues for deciphering the underlying pathogenic mechanisms of AOM.

137. Advancing Adjuvants for Mycobacterium tuberculosis Therapeutics.

Front Immunol

2021 Oct 25

Enriquez AB, Izzo A, Miller SM

138. Secondary Immunodeficiency in Hematological Malignancies: Focus on Multiple Myeloma and Chronic Lymphocytic Leukemia.

Front Immunol

2021 Oct 25

Allegra A, Tonacci A, Musolino C

139. Nociceptive Sensory Fibers Drive Interleukin-23 Production in a Murine Model of Psoriasis via Calcitonin Gene-Related Peptide.

Front Immunol

2021 Oct 22

Zhang X, Cao J, Zhao S

140. DAMPs and Innate Immune Training.

Front Immunol

2021 Oct 22

Jentho E, Weis S.

141. Dynamic Microbial Shifts and Signatures of Long-Term Remission in Allergic Rhinitis After an Herbal Formula Treatment.

Front Immunol

2021 Oct 22

Zhu L, Wu Y, Lin C

142. Diagnostic Value of sIL-2R, TNF-α and PCT for Sepsis Infection in Patients With Closed Abdominal Injury Complicated With Severe Multiple Abdominal Injuries.

Front Immunol

2021 Oct 22

Zhai GH, Zhang W, Xiang Z

OBJECTIVE: We aimed to evaluate the diagnostic value of soluble interleukin-2 receptor (sIL-2R), tumor necrosis factor-α (TNF-α), procalcitonin (PCT), and combined detection for sepsis infection in patients with closed abdominal injury complicated with severe multiple abdominal injuries. PATIENTS AND METHODS: One hundred forty patients with closed abdominal injury complicated with severe multiple abdominal injuries who were diagnosed and treated from 2015 to 2020 were divided into a sepsis group (n = 70) and an infection group (n = 70). RESULTS: The levels of sIL-2R, TNF-α, and PCT in the sepsis group were higher than those in the infection group (p < 0.05). The receiver operating characteristic (ROC) curve showed that the areas under the ROC curve (AUCs) of sIL-2R, TNF-α, PCT and sIL-2R+TNF-a+PCT were 0.827, 0.781, 0.821, and 0.846, respectively, which were higher than those of white blood cells (WBC, 0.712), C-reactive protein (CRP, 0.766), serum amyloid A (SAA, 0.666), and IL-6 (0.735). The AUC of the three combined tests was higher than that of TNF-α, and the difference was statistically significant (p < 0.05). There was no significant difference in the AUCs of sIL-2R and TNF-α, sIL-2R and PCT, TNF-α and PCT, the three combined tests and sIL-2R, and the three combined tests and PCT (p > 0.05). When the median was used as the cut point, the corrected sIL-2R, TNF-α, and PCT of the high-level group were not better than those of the low-level group (p > 0.05). When the four groups were classified by using quantile as the cut point, the OR risk values of high levels of TNF-α and PCT (Q4) and the low level of PCT (Q1) after correction were 7.991 and 21.76, respectively, with statistical significance (p < 0.05). CONCLUSIONS: The detection of sIL-2R, TNF-α, and PCT has good value in the diagnosis of sepsis infection in patients with closed abdominal injury complicated with severe multiple abdominal injuries. The high concentrations of PCT and TNF-α can be used as predictors of the risk of septic infection.

143. International Prognostic Index-Based Immune Prognostic Model for Diffuse Large B-Cell Lymphoma.

Front Immunol

2021 Oct 22

Mu S, Shi D, Ai L

144. Anti-Phosphatidylserine/Prothrombin Antibodies at Two Points: Correlation With Lupus Anticoagulant and Thrombotic Risk.

Front Immunol

2021 Oct 21

Egri N, Bentow C, Rubio L

145. Crosstalk Between Trophoblast and Macrophage at the Maternal-Fetal Interface: Current Status and Future Perspectives.

Front Immunol

2021 Oct 21

Ding J, Zhang Y, Cai X

146. Downregulation of Renal Hsa-miR-127-3p Contributes to the Overactivation of Type I Interferon Signaling Pathway in the Kidney of Lupus Nephritis.

Front Immunol

2021 Oct 21

Wu L, Han X, Jiang X

147. A Dynamic Transcriptome Map of Different Tissue Microenvironment Cells Identified During Gastric Cancer Development Using Single-Cell RNA Sequencing.

Front Immunol

2021 Oct 21

Yin H, Guo R, Zhang H

148. Premature Senescence and Telomere Shortening Induced by Oxidative Stress From Oxalate, Calcium Oxalate Monohydrate, and Urine From Patients With Calcium Oxalate Nephrolithiasis.

Front Immunol

2021 Oct 21

Chuenwisad K, More-Krong P, Tubsaeng P

Oxidative stress, a well-known cause of stress-induced premature senescence (SIPS), is increased in patients with calcium oxalate (CaOx) kidney stones (KS). Oxalate and calcium oxalate monohydrate (COM) induce oxidative stress in renal tubular cells, but to our knowledge, their effect on SIPS has not yet been examined. Here, we examined whether oxalate, COM, or urine from patients with CaOx KS could induce SIPS and telomere shortening in human kidney (HK)-2 cells, a proximal tubular renal cell line. Urine from age- and sex-matched individuals without stones was used as a control. In sublethal amounts, H2O2, oxalate, COM, and urine from those with KS evoked oxidative stress in HK-2 cells, indicated by increased protein carbonyl content and decreased total antioxidant capacity, but urine from those without stones did not. The proportion of senescent HK-2 cells, as indicated by SA-βgal staining, increased after treatment with H2O2, oxalate, COM, and urine from those with KS. Expression of p16 was higher in HK-2 cells treated with H2O2, oxalate, COM, and urine from those with KS than it was in cells treated with urine from those without stones and untreated controls. p16 was upregulated in the SA-βgal positive cells. Relative telomere length was shorter in HK-2 cells treated with H2O2, oxalate, COM, and urine from those with KS than that in cells treated with urine from those without stones and untreated controls. Transcript expression of shelterin components (TRF1, TRF2 and POT1) was decreased in HK-2 cells treated with H2O2, oxalate, COM, and urine from those with KS, in which case the expression was highest. Urine from those without KS did not significantly alter TRF1, TRF2, and POT1 mRNA expression in HK-2 cells relative to untreated controls. In conclusion, oxalate, COM, and urine from patients with CaOx KS induced SIPS and telomere shortening in renal tubular cells. SIPS induced by a lithogenic milieu may result from upregulation of p16 and downregulation of shelterin components, specifically POT1, and might contribute, at least in part, to the development of CaOx KS.

149. The Feasibility of Using Coxiella burnetii Avirulent Nine Mile Phase II Viable Bacteria as a Live Attenuated Vaccine Against Q fever.

Front Immunol

2021 Oct 21

Kumaresan V, Alam S, Zhang Y

150. Comparative Histological Subtyping of Immune Cell Infiltrates in MPO-ANCA and PR3-ANCA Glomerulonephritis.

Front Immunol

2021 Oct 21

Hakroush S, Tampe D, Ströbel P

BACKGROUND: Acute kidney injury (AKI) is a common and severe complication of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), potentially leading to chronic kidney disease (CKD), end-stage renal disease (ESRD), or death. Pathogenic ANCAs, in particular proteinase 3 (PR3) and myeloperoxidase (MPO), trigger a deleterious immune response with intrarenal immune cell infiltration resulting in a pauci-immune necrotizing and crescentic glomerulonephritis (GN). However, a systematic analysis of intrarenal immune cell subtypes concerning neutrophils, eosinophils, plasma cells, and mononuclear cell infiltrates (macrophages, lymphocytes) in ANCA GN remains elusive. Therefore, we aimed to compare distinct immune cell infiltrates in association with clinicopathological findings in ANCA GN. METHODS: A total of 53 kidney biopsies with ANCA GN at the University Medical Center Göttingen were retrospectively analyzed. Histological infiltrates of neutrophils, eosinophils, plasma cells, and mononucleated cells (macrophages, lymphocytes) were quantified as a fraction of the total area of inflammation. RESULTS: Neutrophilic infiltrates were associated with glomerular necrosis and severe kidney injury in ANCA GN. Among tubulointerstitial lesions, intrarenal neutrophils correlated with interstitial inflammation, tubulitis, and inflammation in areas of interstitial fibrosis/tubular atrophy (IFTA), representing active inflammatory lesions. Concerning eosinophils, infiltrates were associated with severe kidney injury, interstitial inflammation, and cellular casts independent of glomerular lesions, implicating a distinct role in inflammation and damage in ANCA GN. Plasma cell infiltrates correlated with tubulitis and interstitial fibrosis and were associated with renal replacement therapy during the short-term disease course. Finally, mononuclear cell infiltrates correlated with severe kidney injury and active histopathological lesions (glomerular crescents, interstitial inflammation, tubulitis, inflammation, and tubulitis in areas of IFTA) besides chronic lesions (interstitial fibrosis and tubular atrophy) in ANCA GN. Interestingly, intrarenal subtypes of immune cell infiltrates differed in MPO-ANCA versus PR3-ANCA GN and were associated with distinct glomerular and tubulointerstitial lesions, implicating different pathogenic mechanisms of kidney injury in ANCA subtypes. CONCLUSION: Our observations imply distinct pathomechanisms contributing to inflammation and renal injury in MPO vs. PR3-associated ANCA GN and potentially contribute to new therapeutic targets in specific ANCA subtypes.

151. Dysregulated Immune Responses in COVID-19 Patients Correlating With Disease Severity and Invasive Oxygen Requirements.

Front Immunol

2021 Oct 21

García-González P, Tempio F, Fuentes C

152. Growth Factors and Their Roles in Multiple Sclerosis Risk.

Front Immunol

2021 Oct 21

Lu H, Wu PF, Ma DL

153. Semi-Automated Live Tracking of Microglial Activation in CX3CR1(GFP) Mice During Experimental Autoimmune Encephalomyelitis by Confocal Scanning Laser Ophthalmoscopy.

Front Immunol

2021 Oct 21

Frenger MJ, Hecker C, Sindi M

154. Understanding Viral and Immune Interplay During Vertical Transmission of HIV: Implications for Cure.

Front Immunol

2021 Oct 21

Amin O, Powers J, Bricker KM

155. Sequential Analysis of the N/O-Glycosylation of Heavily Glycosylated HIV-1 gp120 Using EThcD-sceHCD-MS/MS.

Front Immunol

2021 Oct 21

Zhang Y, Zheng S, Zhao W

156. The ASC Speck and NLRP3 Inflammasome Function Are Spatially and Temporally Distinct.

Front Immunol

2021 Oct 21

Nagar A, Rahman T, Harton JA.

157. Hide and Seek: The Interplay Between Zika Virus and the Host Immune Response.

Front Immunol

2021 Oct 21

Lee LJ, Komarasamy TV, Adnan NAA

Zika virus (ZIKV) received worldwide attention over the past decade when outbreaks of the disease were found to be associated with severe neurological syndromes and congenital abnormalities. Unlike most other flaviviruses, ZIKV can spread through sexual and transplacental transmission, adding to the complexity of Zika pathogenesis and clinical outcomes. In addition, the spread of ZIKV in flavivirus-endemic regions, and the high degree of structural and sequence homology between Zika and its close cousin Dengue have raised questions on the interplay between ZIKV and the pre-existing immunity to other flaviviruses and the potential immunopathogenesis. The Zika epidemic peaked in 2016 and has affected over 80 countries worldwide. The re-emergence of large-scale outbreaks in the future is certainly a possibility. To date, there has been no approved antiviral or vaccine against the ZIKV. Therefore, continuing Zika research and developing an effective antiviral and vaccine is essential to prepare the world for a future Zika epidemic. For this purpose, an in-depth understanding of ZIKV interaction with many different pathways in the human host and how it exploits the host immune response is required. For successful infection, the virus has developed elaborate mechanisms to escape the host response, including blocking host interferon response and shutdown of certain host cell translation. This review provides a summary on the key host factors that facilitate ZIKV entry and replication and the mechanisms by which ZIKV antagonizes antiviral innate immune response and involvement of adaptive immune response leading to immunopathology. We also discuss how ZIKV modulates the host immune response during sexual transmission and pregnancy to induce infection, how the cross-reactive immunity from other flaviviruses impacts ZIKV infection, and provide an update on the current status of ZIKV vaccine development.

158. Comprehensive Analyses Identify APOBEC3A as a Genomic Instability-Associated Immune Prognostic Biomarker in Ovarian Cancer.

Front Immunol

2021 Oct 21

Xu F, Liu T, Zhou Z

Ovarian cancer (OC) is one of the most malignant tumors whose mortality rate ranks first in gynecological tumors. Although immunotherapy sheds new light on clinical treatments, the low response still restricts its clinical use because of the unique characteristics of OC such as immunosuppressive microenvironment and unstable genomes. Further exploration on determining an efficient biomarker to predict the immunotherapy response of OC patients is of vital importance. In this study, integrative analyses were performed systematically using transcriptome profiles and somatic mutation data from The Cancer Genome Atlas (TCGA) based on the immune microenvironment and genomic instability of OC patients. Firstly, intersection analysis was conducted to identify immune-related differentially expressed genes (DEGs) and genomic instability-related DEGs. Secondly, Apolipoprotein B MRNA Editing Enzyme Catalytic Subunit 3A (APOBEC3A) was recognized as a protective factor for OC, which was also verified through basic experiments such as quantitative reverse transcription PCR (RT-qPCR), immunohistochemistry (IHC), Cell Counting Kit-8 (CCK-8), and transwell assays. Thirdly, the correlation analyses of APOBEC3A expression with tumor-infiltrating immune cells (TICs), inhibitory checkpoint molecules (ICPs), Immunophenoscores (IPS), and response to anti-PD-L1 immunotherapy were further applied along with single-sample GSEA (ssGSEA), demonstrating APOBEC3A as a promising biomarker to forecast the immunotherapy response of OC patients. Last, the relationship between APOBEC3A expression with tumor mutation burden (TMB), DNA damage response (DDR) genes, and m6A-related regulators was also analyzed along with the experimental verification of immunofluorescence (IF) and RT-qPCR, comprehensively confirming the intimate association of APOBEC3A with genomic instability in OC. In conclusion, APOBEC3A was identified as a protective signature and a promising prognostic biomarker for forecasting the survival and immunotherapy effect of OC patients, which might accelerate the clinical application and improve immunotherapy effect.

159. Specific Protein Antigen Delivery to Human Langerhans Cells in Intact Skin.

Front Immunol

2021 Oct 21

Rentzsch M, Wawrzinek R, Zelle-Rieser C

160. Kynurenic Acid and Its Analogue SZR-72 Ameliorate the Severity of Experimental Acute Necrotizing Pancreatitis.

Front Immunol

2021 Oct 21

Balla Z, Kormányos ES, Kui B

The pathophysiology of acute pancreatitis (AP) is not well understood, and the disease does not have specific therapy. Tryptophan metabolite L-kynurenic acid (KYNA) and its synthetic analogue SZR-72 are antagonists of the N-methyl-D-aspartate receptor (NMDAR) and have immune modulatory roles in several inflammatory diseases. Our aims were to investigate the effects of KYNA and SZR-72 on experimental AP and to reveal their possible mode of action. AP was induced by intraperitoneal (i.p.) injection of L-ornithine-HCl (LO) in SPRD rats. Animals were pretreated with 75-300 mg/kg KYNA or SZR-72. Control animals were injected with physiological saline instead of LO, KYNA and/or SZR-72. Laboratory and histological parameters, as well as pancreatic and systemic circulation were measured to evaluate AP severity. Pancreatic heat shock protein-72 and IL-1β were measured by western blot and ELISA, respectively. Pancreatic expression of NMDAR1 was investigated by RT-PCR and immunohistochemistry. Viability of isolated pancreatic acinar cells in response to LO, KYNA, SZR-72 and/or NMDA administration was assessed by propidium-iodide assay. The effects of LO and/or SZR-72 on neutrophil granulocyte function was also studied. Almost all investigated laboratory and histological parameters of AP were significantly reduced by administration of 300 mg/kg KYNA or SZR-72, whereas the 150 mg/kg or 75 mg/kg doses were less or not effective, respectively. The decreased pancreatic microcirculation was also improved in the AP groups treated with 300 mg/kg KYNA or SZR-72. Interestingly, pancreatic heat shock protein-72 expression was significantly increased by administration of SZR-72, KYNA and/or LO. mRNA and protein expression of NMDAR1 was detected in pancreatic tissue. LO treatment caused acinar cell toxicity which was reversed by 250 µM KYNA or SZR-72. Treatment of acini with NMDA (25, 250, 2000 µM) did not influence the effects of KYNA or SZR-72. Moreover, SZR-72 reduced LO-induced H2O2 production of neutrophil granulocytes. KYNA and SZR-72 have dose-dependent protective effects on LO-induced AP or acinar toxicity which seem to be independent of pancreatic NMDA receptors. Furthermore, SZR-72 treatment suppressed AP-induced activation of neutrophil granulocytes. This study suggests that administration of KYNA and its derivative could be beneficial in AP.

161. NOD1 Is Associated With the Susceptibility of Pekin Duck Flock to Duck Hepatitis A Virus Genotype 3.

Front Immunol

2021 Oct 20

Liang S, Wang MS, Zhang B

162. Immune Modulation of Metastatic Niche Formation in the Bone.

Front Immunol

2021 Oct 20

Cheng X, Wang Z.

163. Single-Cell Analysis Revealed the Role of CD8(+) Effector T Cells in Preventing Cardioprotective Macrophage Differentiation in the Early Phase of Heart Failure.

Front Immunol

2021 Oct 20

Komai K, Ito M, Nomura S

164. Identification of a DNA Methylation-Driven Genes-Based Prognostic Model and Drug Targets in Breast Cancer: In silico Screening of Therapeutic Compounds and in vitro Characterization.

Front Immunol

2021 Oct 20

Tian S, Fu L, Zhang J

DNA methylation is a vital epigenetic change that regulates gene transcription and helps to keep the genome stable. The deregulation hallmark of human cancer is often defined by aberrant DNA methylation which is critical for tumor formation and controls the expression of several tumor-associated genes. In various cancers, methylation changes such as tumor suppressor gene hypermethylation and oncogene hypomethylation are critical in tumor occurrences, especially in breast cancer. Detecting DNA methylation-driven genes and understanding the molecular features of such genes could thus help to enhance our understanding of pathogenesis and molecular mechanisms of breast cancer, facilitating the development of precision medicine and drug discovery. In the present study, we retrospectively analyzed over one thousand breast cancer patients and established a robust prognostic signature based on DNA methylation-driven genes. Then, we calculated immune cells abundance in each patient and lower immune activity existed in high-risk patients. The expression of leukocyte antigen (HLA) family genes and immune checkpoints genes were consistent with the above results. In addition, more mutated genes were observed in the high-risk group. Furthermore, a in silico screening of druggable targets and compounds from CTRP and PRISM databases was performed, resulting in the identification of five target genes (HMMR, CCNB1, CDC25C, AURKA, and CENPE) and five agents (oligomycin A, panobinostat, (+)-JQ1, voxtalisib, and arcyriaflavin A), which might have therapeutic potential in treating high-risk breast cancer patients. Further in vitro evaluation confirmed that (+)-JQ1 had the best cancer cell selectivity and exerted its anti-breast cancer activity through CENPE. In conclusion, our study provided new insights into personalized prognostication and may inspire the integration of risk stratification and precision therapy.

165. Construction of an Immune Cell Infiltration Score to Evaluate the Prognosis and Therapeutic Efficacy of Ovarian Cancer Patients.

Front Immunol

2021 Oct 20

Liu J, Wang Y, Yuan S

166. Mycobacterium tuberculosis Exploits Focal Adhesion Kinase to Induce Necrotic Cell Death and Inhibit Reactive Oxygen Species Production.

Front Immunol

2021 Oct 20

Afriyie-Asante A, Dabla A, Dagenais A

Tuberculosis is a deadly, contagious respiratory disease that is caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb). Mtb is adept at manipulating and evading host immunity by hijacking alveolar macrophages, the first line of defense against inhaled pathogens, by regulating the mode and timing of host cell death. It is established that Mtb infection actively blocks apoptosis and instead induces necrotic-like modes of cell death to promote disease progression. This survival strategy shields the bacteria from destruction by the immune system and antibiotics while allowing for the spread of bacteria at opportunistic times. As such, it is critical to understand how Mtb interacts with host macrophages to manipulate the mode of cell death. Herein, we demonstrate that Mtb infection triggers a time-dependent reduction in the expression of focal adhesion kinase (FAK) in human macrophages. Using pharmacological perturbations, we show that inhibition of FAK (FAKi) triggers an increase in a necrotic form of cell death during Mtb infection. In contrast, genetic overexpression of FAK (FAK+) completely blocked macrophage cell death during Mtb infection. Using specific inhibitors of necrotic cell death, we show that FAK-mediated cell death during Mtb infection occurs in a RIPK1-depedent, and to a lesser extent, RIPK3-MLKL-dependent mechanism. Consistent with these findings, FAKi results in uncontrolled replication of Mtb, whereas FAK+ reduces the intracellular survival of Mtb in macrophages. In addition, we demonstrate that enhanced control of intracellular Mtb replication by FAK+ macrophages is a result of increased production of antibacterial reactive oxygen species (ROS) as inhibitors of ROS production restored Mtb burden in FAK+ macrophages to same levels as in wild-type cells. Collectively, our data establishes FAK as an important host protective response during Mtb infection to block necrotic cell death and induce ROS production, which are required to restrict the survival of Mtb.

167. Transcriptomic Analysis Identifies A Tolerogenic Dendritic Cell Signature.

Front Immunol

2021 Oct 20

Robertson H, Li J, Kim HJ

168. Non-Randomized Trial of Dornase Alfa for Acute Respiratory Distress Syndrome Secondary to Covid-19.

Front Immunol

2021 Oct 20

Holliday ZM, Earhart AP, Alnijoumi MM

169. Mitochondrial Fission Factor Is a Novel Interacting Protein of the Critical B Cell Survival Regulator TRAF3 in B Lymphocytes.

Front Immunol

2021 Oct 20

Liu Y, Gokhale S, Jung J

Proteins controlling mitochondrial fission have been recognized as essential regulators of mitochondrial functions, mitochondrial quality control and cell apoptosis. In the present study, we identified the critical B cell survival regulator TRAF3 as a novel binding partner of the key mitochondrial fission factor, MFF, in B lymphocytes. Elicited by our unexpected finding that the majority of cytoplasmic TRAF3 proteins were localized at the mitochondria in resting splenic B cells after ex vivo culture for 2 days, we found that TRAF3 specifically interacted with MFF as demonstrated by co-immunoprecipitation and GST pull-down assays. We further found that in the absence of stimulation, increased protein levels of mitochondrial TRAF3 were associated with altered mitochondrial morphology, decreased mitochondrial respiration, increased mitochondrial ROS production and membrane permeabilization, which eventually culminated in mitochondria-dependent apoptosis in resting B cells. Loss of TRAF3 had the opposite effects on the morphology and function of mitochondria as well as mitochondria-dependent apoptosis in resting B cells. Interestingly, co-expression of TRAF3 and MFF resulted in decreased phosphorylation and ubiquitination of MFF as well as decreased ubiquitination of TRAF3. Moreover, lentivirus-mediated overexpression of MFF restored mitochondria-dependent apoptosis in TRAF3-deficient malignant B cells. Taken together, our findings provide novel insights into the apoptosis-inducing mechanisms of TRAF3 in B cells: as a result of survival factor deprivation or under other types of stress, TRAF3 is mobilized to the mitochondria through its interaction with MFF, where it triggers mitochondria-dependent apoptosis. This new role of TRAF3 in controlling mitochondrial homeostasis might have key implications in TRAF3-mediated regulation of B cell transformation in different cellular contexts. Our findings also suggest that mitochondrial fission is an actionable therapeutic target in human B cell malignancies, including those with TRAF3 deletion or relevant mutations.

170. Dermatomyositis With Anti-MDA5 Antibodies: Bioclinical Features, Pathogenesis and Emerging Therapies.

Front Immunol

2021 Oct 20

Nombel A, Fabien N, Coutant F.

171. Dynamics of Vascular Protective and Immune Supportive Sphingosine-1-Phosphate During Cardiac Surgery.

Front Immunol

2021 Oct 20

Greiwe G, Moritz E, Amschler K

INTRODUCTION: Sphingosine-1-phosphate (S1P) is a signaling lipid and crucial in vascular protection and immune response. S1P mediated processes involve regulation of the endothelial barrier, blood pressure and S1P is the only known inducer of lymphocyte migration. Low levels of circulatory S1P correlate with severe systemic inflammatory syndromes such as sepsis and shock states, which are associated with endothelial barrier breakdown and immunosuppression. We investigated whether S1P levels are affected by sterile inflammation induced by cardiac surgery. MATERIALS AND METHODS: In this prospective observational study we included 46 cardiac surgery patients, with cardiopulmonary bypass (CPB, n=31) and without CPB (off-pump, n=15). Serum-S1P, S1P-sources and carriers, von-Willebrand factor (vWF), C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6) were measured at baseline, post-surgery and at day 1 (POD 1) and day 4 (POD 4) after surgical stimulus. RESULTS: Median S1P levels at baseline were 0.77 nmol/mL (IQR 0.61-0.99) and dropped significantly post-surgery. S1P was lowest post-surgery with median levels of 0.37 nmol/mL (IQR 0.31-0.47) after CPB and 0.46 nmol/mL (IQR 0.36-0.51) after off-pump procedures (P<0.001). The decrease of S1P was independent of surgical technique and observed in all individuals. In patients, in which S1P levels did not recover to preoperative baseline ICU stay was longer and postoperative inflammation was more severe. S1P levels are associated with its sources and carriers and vWF, as a more specific endothelial injury marker, in different phases of the postoperative course. Determination of S1P levels during surgery suggested that also the anticoagulative effect of heparin might influence systemic S1P. DISCUSSION: In summary, serum-S1P levels are disrupted by major cardiac surgery. Low S1P levels post-surgery may play a role as a new marker for severity of cardiac surgery induced inflammation. Due to well-known protective effects of S1P, low S1P levels may further contribute to the observed prolonged ICU stay and worse clinical status. Moreover, we cannot exclude a potential inhibitory effect on circulating S1P levels by heparin anticoagulation during surgery, which would be a new pro-inflammatory pleiotropic effect of high dose heparin in patients undergoing cardiac surgery.

172. CD4+ T Cells Are Dispensable for Induction of Broad Heterologous HIV Neutralizing Antibodies in Rhesus Macaques.

Front Immunol

2021 Oct 20

Sarkar S, Spencer DA, Barnette P

173. Ductal Macrophages Predominate in the Immune Landscape of the Lactating Mammary Gland.

Front Immunol

2021 Oct 20

Hassel C, Gausserès B, Guzylack-Piriou L

174. Targeting Molecular Inflammatory Pathways in Granuloma as Host-Directed Therapies for Tuberculosis.

Front Immunol

2021 Oct 20

Guler R, Ozturk M, Sabeel S

175. Resistance Against Leishmania major Infection Depends on Microbiota-Guided Macrophage Activation.

Front Immunol

2021 Oct 20

Lopes ME, Dos Santos LM, Sacks D

176. Complex Pathophysiological Mechanisms and the Propose of the Three-Dimensional Schedule For Future COVID-19 Treatment.

Front Immunol

2021 Oct 20

Zhou Y, Xu X, Wei H.

177. Roles of RAGE/ROCK1 Pathway in HMGB1-Induced Early Changes in Barrier Permeability of Human Pulmonary Microvascular Endothelial Cell.

Front Immunol

2021 Oct 20

Zhao MJ, Jiang HR, Sun JW

BACKGROUND: High mobility group box 1 (HMGB1) causes microvascular endothelial cell barrier dysfunction during acute lung injury (ALI) in sepsis, but the mechanisms have not been well understood. We studied the roles of RAGE and Rho kinase 1 (ROCK1) in HMGB1-induced human pulmonary endothelial barrier disruption. METHODS: In the present study, the recombinant human high mobility group box 1 (rhHMGB1) was used to stimulate human pulmonary microvascular endothelial cells (HPMECs). The endothelial cell (EC) barrier permeability was examined by detecting FITC-dextran flux. CCK-8 assay was used to detect cell viability under rhHMGB1 treatments. The expression of related molecules involved in RhoA/ROCK1 pathway, phosphorylation of myosin light chain (MLC), F-actin, VE-cadherin and ZO-1 of different treated groups were measured by pull-down assay, western blot and immunofluorescence. Furthermore, we studied the effects of Rho kinase inhibitor (Y-27632), ROCK1/2 siRNA, RAGE-specific blocker (FPS-ZM1) and RAGE siRNA on endothelial barrier properties to elucidate the related mechanisms. RESULTS: In the present study, we demonstrated that rhHMGB1 induced EC barrier hyperpermeability in a dose-dependent and time-dependent manner by measuring FITC-dextran flux, a reflection of the loss of EC barrier integrity. Moreover, rhHMGB1 induced a dose-dependent and time-dependent increases in paracellular gap formation accompanied by the development of stress fiber rearrangement and disruption of VE-cadherin and ZO-1, a phenotypic change related to increased endothelial contractility and endothelial barrier permeability. Using inhibitors and siRNAs directed against RAGE and ROCK1/2, we systematically determined that RAGE mediated the rhHMGB1-induced stress fiber reorganization via RhoA/ROCK1 signaling activation and the subsequent MLC phosphorylation in ECs. CONCLUSION: HMGB1 is capable of disrupting the endothelial barrier integrity. This study demonstrates that HMGB1 activates RhoA/ROCK1 pathway via RAGE, which phosphorylates MLC inducing stress fiber formation at short time, and HMGB1/RAGE reduces AJ/TJ expression at long term independently of RhoA/ROCK1 signaling pathway.

178. Microbiota Signals Suppress B Lymphopoiesis With Aging in Mice.

Front Immunol

2021 Oct 19

Krambs JR, Monlish DA, Gao F

179. Pyroptosis in the Retinal Neurovascular Unit: New Insights Into Diabetic Retinopathy.

Front Immunol

2021 Oct 19

Meng C, Gu C, He S

180. The Role of Plasmacytoid Dendritic Cells in Cancers.

Front Immunol

2021 Oct 19

Zhou B, Lawrence T, Liang Y.

181. Easy or Not-The Advances of EZH2 in Regulating T Cell Development, Differentiation, and Activation in Antitumor Immunity.

Front Immunol

2021 Oct 19

Huang J, Zhang J, Guo Z

182. Antibody- Based Immunotherapy Combined With Antimycotic Drug TMP- SMX to Treat Infection With Paracoccidioides brasiliensis.

Front Immunol

2021 Oct 19

Boniche-Alfaro C, Kischkel B, Thomaz L

183. Applicability of Small-Molecule Inhibitors in the Study of Peptidyl Arginine Deiminase 2 (PAD2) and PAD4.

Front Immunol

2021 Oct 19

Martín Monreal MT, Rebak AS, Massarenti L

184. Non-Coding RNAs in the Etiology and Control of Major and Neglected Human Tropical Diseases.

Front Immunol

2021 Oct 19

Tamgue O, Mezajou CF, Ngongang NN

Non-coding RNAs (ncRNAs) including microRNAs (miRs) and long non-coding RNAs (lncRNAs) have emerged as key regulators of gene expression in immune cells development and function. Their expression is altered in different physiological and disease conditions, hence making them attractive targets for the understanding of disease etiology and the development of adjunctive control strategies, especially within the current context of mitigated success of control measures deployed to eradicate these diseases. In this review, we summarize our current understanding of the role of ncRNAs in the etiology and control of major human tropical diseases including tuberculosis, HIV/AIDS and malaria, as well as neglected tropical diseases including leishmaniasis, African trypanosomiasis and leprosy. We highlight that several ncRNAs are involved at different stages of development of these diseases, for example miR-26-5p, miR-132-3p, miR-155-5p, miR-29-3p, miR-21-5p, miR-27b-3p, miR-99b-5p, miR-125-5p, miR-146a-5p, miR-223-3p, miR-20b-5p, miR-142-3p, miR-27a-5p, miR-144-5p, miR-889-5p and miR-582-5p in tuberculosis; miR-873, MALAT1, HEAL, LINC01426, LINC00173, NEAT1, NRON, GAS5 and lincRNA-p21 in HIV/AIDS; miR-451a, miR-let-7b and miR-106b in malaria; miR-210, miR-30A-5P, miR-294, miR-721 and lncRNA 7SL RNA in leishmaniasis; and miR-21, miR-181a, miR-146a in leprosy. We further report that several ncRNAs were investigated as diseases biomarkers and a number of them showed good potential for disease diagnosis, including miR-769-5p, miR-320a, miR-22-3p, miR-423-5p, miR-17-5p, miR-20b-5p and lncRNA LOC152742 in tuberculosis; miR-146b-5p, miR-223, miR-150, miR-16, miR-191 and lncRNA NEAT1 in HIV/AIDS; miR-451 and miR-16 in malaria; miR-361-3p, miR-193b, miR-671, lncRNA 7SL in leishmaniasis; miR-101, miR-196b, miR-27b and miR-29c in leprosy. Furthermore, some ncRNAs have emerged as potential therapeutic targets, some of which include lncRNAs NEAT1, NEAT2 and lnr6RNA, 152742 in tuberculosis; MALAT1, HEAL, SAF, lincRNA-p21, NEAT1, GAS5, NRON, LINC00173 in HIV/AIDS; miRNA-146a in malaria. Finally, miR-135 and miR-126 were proposed as potential targets for the development of therapeutic vaccine against leishmaniasis. We also identify and discuss knowledge gaps that warrant for increased research work. These include investigation of the role of ncRNAs in the etiology of African trypanosomiasis and the assessment of the diagnostic potential of ncRNAs for malaria, and African trypanosomiasis. The potential targeting of ncRNAs for adjunctive therapy against tuberculosis, leishmaniasis, African trypanosomiasis and leprosy, as well as their targeting in vaccine development against tuberculosis, HIV/AIDS, malaria, African trypanosomiasis and leprosy are also new avenues to explore.

185. Tumor-Infiltrating Immune-Related Long Non-Coding RNAs Indicate Prognoses and Response to PD-1 Blockade in Head and Neck Squamous Cell Carcinoma.

Front Immunol

2021 Oct 19

Ma B, Jiang H, Luo Y

186. Neutrophil-Dependent Immunity During Pulmonary Infections and Inflammations.

Front Immunol

2021 Oct 19

Effah CY, Drokow EK, Agboyibor C

187. Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease and Varicella Zoster Virus Infection - Frequency of an Association.

Front Immunol

2021 Oct 19

Di Pauli F, Morschewsky P, Berek K

188. Inclusion of the Inducible Caspase 9 Suicide Gene in CAR Construct Increases Safety of CAR.CD19 T Cell Therapy in B-Cell Malignancies.

Front Immunol

2021 Oct 19

Guercio M, Manni S, Boffa I

189. N(6)-Methyladenosine Methylomic Landscape of Lung Tissues in Murine Acute Allergic Asthma.

Front Immunol

2021 Oct 19

Teng F, Tang W, Wuniqiemu T

190. Multisystem Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Role of Oxidative Stress.

Front Immunol

2021 Oct 19

Graciano-Machuca O, Villegas-Rivera G, López-Pérez I

191. The Genomic Organization of the LILR Region Remained Largely Conserved Throughout Primate Evolution: Implications for Health And Disease.

Front Immunol

2021 Oct 19

Storm L, Bruijnesteijn J, de Groot NG

192. Myeloperoxidase and Other Markers of Neutrophil Activation Associate With Malaria and Malaria/HIV Coinfection in the Human Placenta.

Front Immunol

2021 Oct 19

Sarr D, Oliveira LJ, Russ BN

INTRODUCTION: Placental malaria (PM) is characterized by accumulation of inflammatory leukocytes in the placenta, leading to poor pregnancy outcomes. Understanding of the underlying mechanisms remains incomplete. Neutrophils respond to malaria parasites by phagocytosis, generation of oxidants, and externalization of Neutrophil Extracellular Traps (NETs). NETs drive inflammation in malaria but evidence of NETosis in PM has not been reported. Neutrophil activity in the placenta has not been directly investigated in the context of PM and PM/HIV-co-infection. METHODS: Using peripheral and placental plasma samples and placental tissue collected from Kenyan women at risk for malaria and HIV infections, we assessed granulocyte levels across all gravidities and markers of neutrophil activation, including NET formation, in primi- and secundigravid women, by ELISA, western blot, immunohistochemistry and immunofluorescence. RESULTS: Reduced peripheral blood granulocyte numbers are observed with PM and PM/HIV co-infection in association with increasing parasite density and placental leukocyte hemozoin accumulation. In contrast, placental granulocyte levels are unchanged across infection groups, resulting in enhanced placental: peripheral count ratios with PM. Within individuals, PM- women have reduced granulocyte counts in placental relative to peripheral blood; in contrast, PM stabilizes these relative counts, with HIV coinfection tending to elevate placental counts relative to the periphery. In placental blood, indicators of neutrophil activation, myeloperoxidase (MPO) and proteinase 3 (PRTN3), are significantly elevated with PM and, more profoundly, with PM/HIV co-infection, in association with placental parasite density and hemozoin-bearing leukocyte accumulation. Another neutrophil marker, matrix metalloproteinase (MMP9), together with MPO and PRTN3, is elevated with self-reported fever. None of these factors, including the neutrophil chemoattractant, CXCL8, differs in relation to infant birth weight or gestational age. CXCL8 and MPO levels in the peripheral blood do not differ with infection status nor associate with birth outcomes. Indicators of NETosis in the placental plasma do not vary with infection, and while structures consistent with NETs are observed in placental tissue, the results do not support an association with PM. CONCLUSIONS: Granulocyte levels are differentially regulated in the peripheral and placental blood in the presence and absence of PM. PM, both with and without pre-existing HIV infection, enhances neutrophil activation in the placenta. The impact of local neutrophil activation on placental function and maternal and fetal health remains unclear. Additional investigations exploring how neutrophil activation and NETosis participate in the pathogenesis of malaria in pregnant women are needed.

193. DNA Vaccines Targeting Novel Cancer-Associated Antigens Frequently Expressed in Head and Neck Cancer Enhance the Efficacy of Checkpoint Inhibitor.

Front Immunol

2021 Oct 18

Wang C, Zainal NS, Chai SJ

194. β2-Adrenergic Receptor Enhances the Alternatively Activated Macrophages and Promotes Biliary Injuries Caused by Helminth Infection.

Front Immunol

2021 Oct 18

Koda S, Zhang B, Zhou QY

195. Decreased IgG Antibody Response to Viral Protein Mimotopes of Oncogenic Merkel Cell Polyomavirus in Sera From Healthy Elderly Subjects.

Front Immunol

2021 Oct 18

Mazziotta C, Lanzillotti C, Govoni M

Merkel cell polyomavirus (MCPyV) is the main causative agent of Merkel cell carcinoma (MCC), a rare but aggressive skin tumor with a typical presentation age >60 years. MCPyV is ubiquitous in humans. After an early-age primary infection, MCPyV establishes a clinically asymptomatic lifelong infection. In immunocompromised patients/individuals, including elders, MCC can arise following an increase in MCPyV replication events. Elders are prone to develop immunesenescence and therefore represent an important group to investigate. In addition, detailed information on MCPyV serology in elders has been debated. These findings cumulatively indicate the need for new research verifying the impact of MCPyV infection in elderly subjects (ES). Herein, sera from 226 ES, aged 66-100 years, were analyzed for anti-MCPyV IgGs with an indirect ELISA using peptides mimicking epitopes from the MCPyV capsid proteins VP1-2. Immunological data from sera belonging to a cohort of healthy subjects (HS) (n = 548) aged 18-65 years, reported in our previous study, were also included for comparisons. Age-/gender-specific seroprevalence and serological profiles were investigated. MCPyV seroprevalence in ES was 63.7% (144/226). Age-specific MCPyV seroprevalence resulted as 62.5% (25/40), 71.7% (33/46), 64.9% (37/57), 63.8% (30/47), and 52.8% (19/36) in ES aged 66-70, 71-75, 76-80, 81-85, and 86-100 years, respectively (p > 0.05). MCPyV seroprevalence was 67% (71/106) and 61% (73/120) in ES males and females, respectively (p > 0.05). Lack of age-/gender-related variations in terms of MCPyV serological profiles was found in ES (p > 0.05). Notably, serological profile analyses indicated lower optical densities (ODs) in ES compared with HS (p < 0.05), while lower ODs were also determined in ES males compared with HS males (p < 0.05). Our data cumulatively suggest that oncogenic MCPyV circulates in elders asymptomatically at a relatively high prevalence, while immunesenescence might be responsible for a decreased IgG antibody response to MCPyV, thereby potentially leading to an increase in MCPyV replication levels. In the worse scenario, alongside other factors, MCPyV might drive MCC carcinogenesis, as described in elders with over 60 years of age.

196. Radiogenomics Map Reveals the Landscape of m6A Methylation Modification Pattern in Bladder Cancer.

Front Immunol

2021 Oct 18

Ye F, Hu Y, Gao J

197. Cytomegalovirus in Haematological Tumours.

Front Immunol

2021 Oct 18

Alonso-Álvarez S, Colado E, Moro-García MA

198. Overexpressing Kallistatin Aggravates Experimental Autoimmune Uveitis Through Promoting Th17 Differentiation.

Front Immunol

2021 Oct 18

Chen N, Chen S, Zhang Z

199. Kickstarting Immunity in Cold Tumours: Localised Tumour Therapy Combinations With Immune Checkpoint Blockade.

Front Immunol

2021 Oct 18

Appleton E, Hassan J, Chan Wah Hak C

200. Immunoglobulin Glycosylation - An Unexploited Potential for Immunomodulatory Strategies in Farm Animals.

Front Immunol

2021 Oct 18

Zlatina K, Galuska SP.

201. Mannan Oligosaccharides Application: Multipath Restriction From Aeromonas hydrophila Infection in the Skin Barrier of Grass Carp (Ctenopharyngodon idella).

Front Immunol

2021 Oct 18

Lu Z, Feng L, Jiang WD

202. Identification and Mapping of HBsAg Loss-Related B-Cell Linear Epitopes in Chronic HBV Patients by Peptide Array.

Front Immunol

2021 Oct 15

Gu S, Liu Z, Lin L

Identification of immunogenic targets against hepatitis B virus (HBV)-encoded proteins will provide crucial advances in developing potential antibody therapies. In this study, 63 treatment-naïve patients with chronic HBV infection and 46 patients who achieved hepatitis B surface antigen loss (sAg loss) following antiviral treatment were recruited. Moreover, six patients who transitioned from the hepatitis B e antigen-positive chronic infection phase (eAg+CInf) to the hepatitis phase (eAg+CHep) were enrolled from real-life clinical practice. Additionally, telbivudine-treated eAg+CHep patients and relapsers or responders from an off-treatment cohort were longitudinally studied. The frequencies and function of B cells were assessed by flow cytometry. We devised a peptide array composed of 15-mer overlapping peptides of HBV-encoded surface (S), core (C), and polymerase (P) proteins and performed a screening on B-cell linear epitopes with sera. Naïve B cells and plasmablasts were increased, whereas total memory, activated memory (AM), and atypical memory (AtM) B cells were reduced in sAg- patients compared with sAg+ patients. Importantly, longitudinal observations found that AtM B cells were associated with successful treatment withdrawal. Interestingly, we identified six S-specific dominant epitopes (S33, S34, S45, S76, S78, and S89) and one C-specific dominant epitope (C37) that reacted with the majority of sera from sAg- patients. Of note, more B-cell linear epitopes were detected in CHep patients with alanine aminotransferase (ALT) flares than in nonflare CInf patients, and five B-cell linear epitopes (S4, S5, S10, S11, and S68) were overwhelmingly recognized by ALT flare patients. The recognition rates of epitopes on C and P proteins were significantly increased in CHep patients relative to CInf patients. Strikingly, a statistically significant elevation in the number of positive epitopes was observed when ALT nonflare patients shifted into the flare phase. Moreover, S76 identified at baseline was confirmed to be associated with a complete response after 48 weeks of telbivudine therapy. Taken together, we identified several functional cure-related B-cell linear epitopes of chronic HBV infection, and these epitopes may serve as vaccine candidates to elicit neutralizing antibodies to treat HBV infection.

203. Integrating Serum Metabolome and Gut Microbiome to Evaluate the Benefits of Lauric Acid on Lipopolysaccharide- Challenged Broilers.

Front Immunol

2021 Oct 15

Wu Y, Li Q, Liu J

Lauric acid (LA) is a crucial medium-chain fatty acid (MCFA) that has many beneficial effects on humans and animals. This study aimed to investigate the effects of LA on the intestinal barrier, immune functions, serum metabolism, and gut microbiota of broilers under lipopolysaccharide (LPS) challenge. A total of 384 one-day-old broilers were randomly divided into four groups, and fed with a basal diet, or a basal diet supplemented with 75 mg/kg antibiotic (ANT), or a basal diet supplemented with 1000 mg/kg LA. After 42 days of feeding, three groups were intraperitoneally injected with 0.5 mg/kg Escherichia coli- derived LPS (LPS, ANT+LPS and LA+LPS groups) for three consecutive days, and the control (CON) group was injected with the same volume of saline. Then, the birds were sacrificed. Results showed that LA pretreatment significantly alleviated the weight loss and intestinal mucosal injuries caused by LPS challenge. LA enhanced immune functions and inhibited inflammatory responses by upregulating the concentrations of immunoglobulins (IgA, IgM, and IgY), decreasing IL-6 and increasing IL-4 and IL-10. Metabolomics analysis revealed a significant difference of serum metabolites by LA pretreatment. Twenty-seven serum metabolic biomarkers were identified and mostly belong to lipids. LA also markedly modulated the pathway for sphingolipid metabolism, suggesting its ability to regulate lipid metabolism. Moreover,16S rRNA analysis showed that LA inhibited LPS-induced gut dysbiosis by altering cecal microbial composition (reducing Escherichia-Shigella, Barnesiella and Alistipes, and increasing Lactobacillus and Bacteroides), and modulating the production of volatile fatty acids (VFAs). Pearson's correlation assays showed that alterations in serum metabolism and gut microbiota were strongly correlated to the immune factors; there were also strong correlations between serum metabolites and microbiota composition. The results highlight the potential of LA as a dietary supplement to combat bacterial LPS challenge in animal production and to promote food safety.

204. RNA-Containing Immune Complexes Formed by Anti-Melanoma Differentiation Associated Gene 5 Autoantibody Are Potent Inducers of IFN-α.

Front Immunol

2021 Oct 15

Wang K, Zhao J, Wu W

205. Extracellular Vesicles and DAMPs in Cancer: A Mini-Review.

Front Immunol

2021 Oct 15

Abu N, Rus Bakarurraini NAA, Nasir SN.

206. Repertoire of Naturally Acquired Maternal Antibodies Transferred to Infants for Protection Against Shigellosis.

Front Immunol

2021 Oct 15

Ndungo E, Andronescu LR, Buchwald AG

Shigella is the second leading cause of diarrheal diseases, accounting for >200,000 infections and >50,000 deaths in children under 5 years of age annually worldwide. The incidence of Shigella-induced diarrhea is relatively low during the first year of life and increases substantially, reaching its peak between 11 to 24 months of age. This epidemiological trend hints at an early protective immunity of maternal origin and an increase in disease incidence when maternally acquired immunity wanes. The magnitude, type, antigenic diversity, and antimicrobial activity of maternal antibodies transferred via placenta that can prevent shigellosis during early infancy are not known. To address this knowledge gap, Shigella-specific antibodies directed against the lipopolysaccharide (LPS) and virulence factors (IpaB, IpaC, IpaD, IpaH, and VirG), and antibody-mediated serum bactericidal (SBA) and opsonophagocytic killing antibody (OPKA) activity were measured in maternal and cord blood sera from a longitudinal cohort of mother-infant pairs living in rural Malawi. Protein-specific (very high levels) and Shigella LPS IgG were detected in maternal and cord blood sera; efficiency of placental transfer was 100% and 60%, respectively, and had preferential IgG subclass distribution (protein-specific IgG1 > LPS-specific IgG2). In contrast, SBA and OPKA activity in cord blood was substantially lower as compared to maternal serum and varied among Shigella serotypes. LPS was identified as the primary target of SBA and OPKA activity. Maternal sera had remarkably elevated Shigella flexneri 2a LPS IgM, indicative of recent exposure. Our study revealed a broad repertoire of maternally acquired antibodies in infants living in a Shigella-endemic region and highlights the abundance of protein-specific antibodies and their likely contribution to disease prevention during the first months of life. These results contribute new knowledge on maternal infant immunity and target antigens that can inform the development of vaccines or therapeutics that can extend protection after maternally transferred immunity wanes.

207. Elevated Peripheral T Helper Cells Are Associated With Atrial Fibrillation in Patients With Rheumatoid Arthritis.

Front Immunol

2021 Oct 15

Wang X, Fan H, Wang Y

208. Leukemic Stem Cells: From Leukemic Niche Biology to Treatment Opportunities.

Front Immunol

2021 Oct 15

Marchand T, Pinho S.

209. Editorial: Frontiers' Research Topic "Cancer Vaccines: Time to Think Differently!".

Front Immunol

2021 Oct 15

McArdle SEB, Pawelec G, Pockley AG

210. HIV-1-Specific CD11c(+) CD8(+) T Cells Display Low PD-1 Expression and Strong Anti-HIV-1 Activity.

Front Immunol

2021 Oct 15

Guo AL, Zhao JF, Gao L

211. Prime-Boost Vaccination With Covaxin/BBV152 Induces Heightened Systemic Cytokine and Chemokine Responses.

Front Immunol

2021 Oct 15

Kumar NP, Banurekha VV, C P GK

212. The HHV-6A Proteins U20 and U21 Target NKG2D Ligands to Escape Immune Recognition.

Front Immunol

2021 Oct 15

Chaouat AE, Seliger B, Mandelboim O

213. Abnormalities in Gut Microbiota and Metabolism in Patients With Chronic Spontaneous Urticaria.

Front Immunol

2021 Oct 15

Wang X, Yi W, He L

214. Role of Gut Microbiome in COVID-19: An Insight Into Pathogenesis and Therapeutic Potential.

Front Immunol

2021 Oct 14

Hussain I, Cher GLY, Abid MA

215. Graft-Versus-Host Disease Prevention by In Vitro-Generated Myeloid-Derived Suppressor Cells Is Exclusively Mediated by the CD11b+CD11c+ MDSC Subpopulation.

Front Immunol

2021 Oct 14

Scheurer J, Kitt K, Huber HJ

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid progenitor cells that dampen overwhelming adaptive immune responses through multiple mechanisms and are recognized as an attractive novel immune intervention therapy for counteracting the destructive effects of graft- versus -host disease (GVHD) developing after allogeneic bone marrow transplantation (BMT). MDSCs can be produced in great numbers for cellular therapy, but they present a mixture of subsets whose functions in GVHD prevention are undefined. Here, we generated MDSCs in vitro from murine BM cells in the presence of GM-CSF and defined the integrin CD11c as a marker to subdivide MDSCs into two functional subgroups: CD11b+CD11c+ and CD11b+CD11c- MDSCs. Isolated CD11b+CD11c+ and CD11b+CD11c- MDSCs both inhibited alloantigen-stimulated T-cell proliferation in vitro, although CD11b+CD11c+ MDSCs were more efficient and expressed higher levels of different immunosuppressive molecules. Likewise, expression of surface markers such as MHC class II, CD80, CD86, or PD-L1 further delineated both subsets. Most importantly, only the adoptive transfer of CD11b+CD11c+ MDSCs into a single MHC class I-disparate allogeneic BMT model prevented GVHD development and strongly decreased disease-induced mortality, while CD11b+CD11c- MDSCs were totally ineffective. Surprisingly, allogeneic T-cell homing and expansion in lymphatic and GVHD target organs were not affected by cotransplanted CD11b+CD11c+ MDSCs indicating a clear contradiction between in vitro and in vivo functions of MDSCs. However, CD11b+CD11c+ MDSCs shifted immune responses towards type 2 immunity reflected by increased Th2-specific cytokine expression of allogeneic T cells. Induction of type 2 immunity was mandatory for GVHD prevention, since CD11b+CD11c+ MDSCs were ineffective if recipients were reconstituted with STAT6-deficient T cells unable to differentiate into Th2 cells. Most importantly, the beneficial graft- versus -tumor (GVT) effect was maintained in the presence of CD11b+CD11c+ MDSCs since syngeneic tumor cells were efficiently eradicated. Strong differences in the transcriptomic landscape of both subpopulations underlined their functional differences. Defining CD11b+CD11c+ MDSCs as the subset of in vitro-generated MDSCs able to inhibit GVHD development might help to increase efficiency of MDSC therapy and to further delineate relevant target molecules and signaling pathways responsible for GVHD prevention.

216. Case Report: Combined Liver-Kidney Transplantation to Correct a Mutation in Complement Factor B in an Atypical Hemolytic Uremic Syndrome Patient.

Front Immunol

2021 Oct 14

López-Trascasa M, Alonso-Melgar Á, Melgosa-Hijosa M

217. Dysregulated Microbiota-Driven Gasdermin D Activation Promotes Colitis Development by Mediating IL-18 Release.

Front Immunol

2021 Oct 14

Gao H, Cao M, Yao Y

218. Advanced Genomics-Based Approaches for Defining Allograft Rejection With Single Cell Resolution.

Front Immunol

2021 Oct 14

Shi T, Roskin K, Baker BM

Solid organ transplant recipients require long-term immunosuppression for prevention of rejection. Calcineurin inhibitor (CNI)-based immunosuppressive regimens have remained the primary means for immunosuppression for four decades now, yet little is known about their effects on graft resident and infiltrating immune cell populations. Similarly, the understanding of rejection biology under specific types of immunosuppression remains to be defined. Furthermore, development of innovative, rationally designed targeted therapeutics for mitigating or preventing rejection requires a fundamental understanding of the immunobiology that underlies the rejection process. The established use of microarray technologies in transplantation has provided great insight into gene transcripts associated with allograft rejection but does not characterize rejection on a single cell level. Therefore, the development of novel genomics tools, such as single cell sequencing techniques, combined with powerful bioinformatics approaches, has enabled characterization of immune processes at the single cell level. This can provide profound insights into the rejection process, including identification of resident and infiltrating cell transcriptomes, cell-cell interactions, and T cell receptor α/β repertoires. In this review, we discuss genomic analysis techniques, including microarray, bulk RNAseq (bulkSeq), single-cell RNAseq (scRNAseq), and spatial transcriptomic (ST) techniques, including considerations of their benefits and limitations. Further, other techniques, such as chromatin analysis via assay for transposase-accessible chromatin sequencing (ATACseq), bioinformatic regulatory network analyses, and protein-based approaches are also examined. Application of these tools will play a crucial role in redefining transplant rejection with single cell resolution and likely aid in the development of future immunomodulatory therapies in solid organ transplantation.

219. MALT1-Dependent Cleavage of HOIL1 Modulates Canonical NF-κB Signaling and Inflammatory Responsiveness.

Front Immunol

2021 Oct 14

Fung SY, Lu HY, Sharma M

220. 21-Hydroxylase-Specific CD8+ T Cells in Autoimmune Addison's Disease Are Restricted by HLA-A2 and HLA-C7 Molecules.

Front Immunol

2021 Oct 14

Hellesen A, Aslaksen S, Breivik L

221. Efficacy and Safety of Dupilumab in Moderate-to-Severe Bullous Pemphigoid.

Front Immunol

2021 Oct 14

Zhang Y, Xu Q, Chen L

222. Low Frequency Ultrasound With Injection of NMO-IgG and Complement Produces Lesions Different From Experimental Autoimmune Encephalomyelitis Mice.

Front Immunol

2021 Oct 14

Xiang W, Xie C, Luo J

223. Commentary: PIRs Mediate Innate Myeloid Cell Memory to Nonself MHC Molecules.

Front Immunol

2021 Oct 14

Cai Z, Xing R, Liu J

224. Decreased miR-4512 Levels in Monocytes and Macrophages of Individuals With Systemic Lupus Erythematosus Contribute to Innate Immune Activation and Neutrsophil NETosis by Targeting TLR4 and CXCL2.

Front Immunol

2021 Oct 14

Yang B, Huang X, Xu S

OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease with complex etiology that is not yet entirely understood. We aimed to elucidate the mechanisms and therapeutic potential of microRNAs (miRNAs) in SLE in a Tibetan population. METHODS: Peripheral blood mononuclear cells from SLE patients (n = 5) and healthy controls (n = 5) were used for miRNA-mRNA co-sequencing to detect miRNAs related to immune abnormalities associated with SLE. Luciferase reporter assay was used to identify potential targets of candidate miRNA. The target genes were verified in miRNA-agomir/antagomir transfection assays with multiple cells lines and by expression analysis. The effects of candidate miRNA on monocyte and macrophage activation were evaluated by multiple cytokine profiling. Neutrophil extracellular traps (NETs) formation was analyzed in vitro by cell stimulation with supernatants of monocytes and macrophages transfected with candidate miRNA. The rodent MRL/lpr lupus model was used to evaluate the therapeutic effect of CXCL2Ab on SLE and the regulation effect of immune disorders. RESULTS: Integrated miRNA and mRNA expression profiling identified miRNA-4512 as a candidate miRNA involved in the regulation of neutrophil activation and chemokine-related pathways. MiR-4512 expression was significantly reduced in monocytes and macrophages from SLE patients. MiR-4512 suppressed the TLR4 pathway by targeting TLR4 and CXCL2. Decreased monocyte and macrophage miR-4512 levels led to the expression of multiple proinflammatory cytokines in vitro. Supernatants of miR-4512 antagomir-transfected monocytes and macrophages significantly promoted NETs formation (P < 0.05). Blocking of CXCL2 alleviated various pathogenic manifestations in MRL/lpr mice, including kidney damage and expression of immunological markers of SLE. CONCLUSIONS: We here demonstrated the role of miR-4512 in innate immunity regulation in SLE. The effect of miR-4512 involves the regulation of monocytes, macrophages, and NETs formation by direct targeting of TLR4 and CXCL2, indicating the miR-4512-TLR4-CXCL2 axis as a potential novel therapeutic target in SLE.

225. Repeated Influenza Vaccination Boosts and Maintains H1N1pdm09 Neuraminidase Antibody Titers.

Front Immunol

2021 Oct 14

Hansen L, Zhou F, Amdam H

Antibodies to influenza surface protein neuraminidase (NA) have been found to reduce disease severity and may be an independent correlate of protection. Despite this, current influenza vaccines have no regulatory requirements for the quality or quantity of the NA antigen and are not optimized for induction of NA-specific antibodies. Here we investigate the induction and durability of NA-specific antibody titers after pandemic AS03-adjuvanted monovalent H1N1 vaccination and subsequent annual vaccination in health care workers in a five-year longitudinal study. NA-specific antibodies were measured by endpoint ELISA and functional antibodies measured by enzyme-linked lectin assay (ELLA) and plaque reduction naturalisation assay. We found robust induction of NA inhibition (NAI) titers with a 53% seroconversion rate (>4-fold) after pandemic vaccination in 2009. Furthermore, the endpoint and NAI geometric mean titers persisted above pre-vaccination levels up to five years after vaccination in HCWs that only received the pandemic vaccine, which demonstrates considerable durability. Vaccination with non-adjuvanted trivalent influenza vaccines (TIV) in subsequent influenza seasons 2010/2011 - 2013/2014 further boosted NA-specific antibody responses. We found that each subsequent vaccination increased durable endpoint titers and contributed to maintaining the durability of functional antibody titers. Although the trivalent influenza vaccines boosted NA-specific antibodies, the magnitude of fold-increase at day 21 declined with repeated vaccination, particularly for functional antibody titers. High levels of pre-existing antibodies were associated with lower fold-induction in repeatedly vaccinated HCWs. In summary, our results show that durable NA-specific antibody responses can be induced by an adjuvanted influenza vaccine, which can be maintained and further boosted by TIVs. Although NA-specific antibody responses are boosted by annual influenza vaccines, high pre-existing titers may negatively affect the magnitude of fold-increase in repeatedly vaccinated individuals. Our results support continued development and standardization of the NA antigen to supplement current influenza vaccines and reduce the burden of morbidity and mortality.

226. Physical Fitness Attenuates the Impact of Higher Body Mass and Adiposity on Inflammation in Women With Systemic Lupus Erythematosus.

Front Immunol

2021 Oct 14

Sola-Rodríguez S, Vargas-Hitos JA, Gavilán-Carrera B

227. Expression Analysis of NF-κB-Related lncRNAs in Parkinson's Disease.

Front Immunol

2021 Oct 13

Ghafouri-Fard S, Gholipour M, Abak A

Parkinson's disease (PD) has been shown to affect approximately 1% of the persons aged more than 65 years. This multifactorial disorder has been associated with abnormal function of NF-κB signals. In this research, we have evaluated expressions of NF-κB-related long non-coding RNAs in the circulation of PD patients compared with healthy controls. Expression of PACER was lower in total PD patients compared with healthy persons (Ratio of mean expressions (RME)=0.32, P value<0.001). This pattern was also evident among males (RME=0.25, P value<0.001). Expression of DILC was higher in total PD patients (RME=4.07, P value<0.001), and in both sex-based subgroups (RME=3.77, P value=0.01 and RME=4.25, P value<0.001, for females and males, respectively). Similarly, CEBPA was significantly over-expressed in total PD patients (RME=14.76, P value<0.001), and in both sex-based subgroups (RME=12.42, P value<0.001 and RME=15.80, P value<0.001, for females and males, respectively). ATG5 had a similar expression pattern (RME=2.6, P value=1E-08, RME=1.73, P value=0.03 and RME=3.09, P value=1E-07, for total cases, females and males, respectively). H19 was up-regulated in total cases and male cases compared with corresponding controls (RME=2.19, P value<0.001, RME=2.68, P value=0.01, respectively). Finally, HNFA1-AS was down-regulated in all comparisons (RME=0.10, P value=2E-06, RME=0.08, P value<0.001 and RME=0.12, P value<0.001, for total cases, females and males, respectively). Among PD patients, expressions of NKILA and ADINR were robustly correlated with each other (r=0.75, P value=2.40E-10). In addition, expression levels of DICER1-AS were significantly correlated with those of ADINR, PACER and H19 in these patients (r=0.73, P value=1.76E-9; r=0.72, P value=5.15E-09 and r=0.72, P value=3.09E-09, respectively). Correlation analyses among healthy controls revealed robust correlations between CHAST and CEBPA (r=0.84, P value=3.09E-09), NKILA and ADINR (r=0.80, P value=4.24E-12) as well as between DILC and CHAST (r=0.76, P value=1.70E-10). CEBPA had the best parameters among all assessed genes (AUC=0.96, Sensitivity=0.90 and specificity=0.97). DILC and ATG5 were the most appropriate markers after CEBPA with AUC values of 0.82 and 0.80, respectively. Most notably, combination of all genes improved AUC, sensitivity and specificity parameters to 1, 0.97 and 0.99, respectively. Cumulatively, the current study provides evidence for participation of NF-κB-related lncRNAs in the pathoetiology of PD.

228. Rituximab Immunomonitoring Predicts Remission in Membranous Nephropathy.

Front Immunol

2021 Oct 13

Teisseyre M, Cremoni M, Boyer-Suavet S

Primary membranous nephropathy (pMN) is an autoimmune kidney disease and a common cause of nephrotic syndrome in adults. Rituximab is becoming a first line therapy for patients with persistent nephrotic syndrome with proven safety and efficacy, achieving remission in 60%-80% of cases. For the remaining 20%-40% of patients there is an urgent need to identify early biomarkers of resistance to rituximab to adapt therapeutic management. In nephrotic patients, rituximab is found in the blood more transiently than in other autoimmune diseases without proteinuria, due to rituximab wasting in the urine. However, rituximab immunomonitoring is not routinely performed. We evaluated the predictive value of serum rituximab levels in patients with pMN three months after rituximab injection (month-3) on clinical remission rates six months (month-6) and 12 months (month-12) after injection and investigated predictive factors for serum rituximab levels at month-3. Sixty-eight patients treated with rituximab between July 2015 and January 2020 from two French nephrology centers were included. We identified residual rituximab levels at month-3 as a novel early predictor of remission at month-6 (p <0.0001) and month-12 (p = 0.001). Reduced likelihood of remission in patients with undetectable rituximab at month-3 was associated with lower serum albumin and higher anti-PLA2R1 titers at baseline and with lower serum albumin, higher proteinuria, higher CD19+ counts and higher anti-PLA2R1 titers during follow-up. In multivariate analysis, high baseline proteinuria and undetectable rituximab levels at month-3 were independent risk factors for treatment failure at month-6 and high baseline weight and undetectable rituximab levels at month-3 were independent risk factors for treatment failure at month-12. We identified serum albumin at baseline as a predictive factor for serum rituximab levels at month-3. Patients with serum albumin below 22.5 g/L at baseline had an 8.66-fold higher risk of having undetectable rituximab levels at month-3. Therefore, rituximab immunomonitoring in pMN patients treated with rituximab would allow the detection of patients at risk of treatment failure as early as month-3. Studies are needed to assess whether patients with low residual rituximab levels at month-3 may benefit from an early additional course of rituximab.

229. Inflammatory Factors of Macular Atrophy in Eyes With Neovascular Age-Related Macular Degeneration Treated With Aflibercept.

Front Immunol

2021 Oct 13

Sato T, Enoki T, Karasawa Y

BACKGROUND: Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness in older people. Low-grade inflammation is well-known as one of the pathogenic mechanisms in nAMD. Anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment for nAMD, although macula atrophy (MA) developed under anti-VEGF therapy causes irreversible visual function impairment and is recognized as a serious disorder. Here, we show specific expression patterns of aqueous humor (AH) cytokines in nAMD eyes developing MA under intravitreal injection of aflibercept (IVA) as an anti-VEGF antibody and present predictive cytokines as biomarkers for the incidence of MA in nAMD eyes under IVA treatment. METHODS: Twenty-eight nAMD patients received three consecutive monthly IVA, followed by a pro re nata regimen for 2 years. AH specimens were collected before first IVA (pre-IVA) and before third IVA (post-IVA). AH cytokine levels, visual acuity (VA), and central retinal thickness (CRT) were measured. RESULTS: Two-year incidence of MA was 21.4%. In nAMD eyes developing MA [MA (+) group], pre-IVA levels of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1β, VEGF and post-IVA level of MCP-1 were higher than those in nAMD eyes without MA [MA (-) group]. In hierarchical cluster analysis, pre-IVA MCP-1 and VEGF were grouped into the same subcluster, as were post-IVA MCP-1 and CRT. In principal component analysis, principal component loading (PCL) of pre-IVA interferon-γ-inducible protein 10 (IP-10) was 0.61, but PCL of post-IVA IP-10 decreased to -0.09. In receiver operating characteristic analysis and Kaplan-Meier curves, pre-IVA MCP-1, MIP-1β, and VEGF and post-IVA interleukin-6, MCP-1, and MIP-1β were detected as predictive factors for MA incidence. In 2-year clinical course, changes of VA in groups with high levels of pre-IVA MIP-1β (over 39.9 pg/ml) and VEGF (over 150.4 pg/ml) were comparable to those in MA (+) group. CONCLUSION: Substantial loss of IP-10 effects and persistent inflammation contribute to incidence of MA, and screening of AH cytokine levels could be a useful method to predict MA incidence in nAMD eyes under anti-VEGF therapy.

230. Drug Repurposing for Atopic Dermatitis by Integration of Gene Networking and Genomic Information.

Front Immunol

2021 Oct 13

Adikusuma W, Irham LM, Chou WH

231. Defining the Role of Nuclear Factor (NF)-κB p105 Subunit in Human Macrophage by Transcriptomic Analysis of NFKB1 Knockout THP1 Cells.

Front Immunol

2021 Oct 13

Somma D, Kok FO, Kerrigan D

Since its discovery over 30 years ago the NF-ĸB family of transcription factors has gained the status of master regulator of the immune response. Much of what we understand of the role of NF-ĸB in immune development, homeostasis and inflammation comes from studies of mice null for specific NF-ĸB subunit encoding genes. The role of inflammation in diseases that affect a majority of individuals with health problems globally further establishes NF-ĸB as an important pathogenic factor. More recently, genomic sequencing has revealed loss of function mutations in the NFKB1 gene as the most common monogenic cause of common variable immunodeficiencies in Europeans. NFKB1 encodes the p105 subunit of NF-ĸB which is processed to generate the NF-ĸB p50 subunit. NFKB1 is the most highly expressed transcription factor in macrophages, key cellular drivers of inflammation and immunity. Although a key role for NFKB1 in the control of the immune system is apparent from Nfkb1-/- mouse studies, we know relatively little of the role of NFKB1 in regulating human macrophage responses. In this study we use the THP1 monocyte cell line and CRISPR/Cas9 gene editing to generate a model of NFKB1-/- human macrophages. Transcriptomic analysis reveals that activated NFKB1-/- macrophages are more pro-inflammatory than wild type controls and express elevated levels of TNF, IL6, and IL1B, but also have reduced expression of co-stimulatory factors important for the activation of T cells and adaptive immune responses such as CD70, CD83 and CD209. NFKB1-/- THP1 macrophages recapitulate key observations in individuals with NFKB1 haploinsufficiency including decreased IL10 expression. These data supporting their utility as an in vitro model for understanding the role of NFKB1 in human monocytes and macrophages and indicate that of loss of function NFKB1 mutations in these cells is an important component in the associated pathology.

232. Children and Adults in a Household Cohort Study Have Robust Longitudinal Immune Responses Following SARS-CoV-2 Infection or Exposure.

Front Immunol

2021 Oct 13

Neeland MR, Bannister S, Clifford V

233. Immune Response in Severe and Non-Severe Coronavirus Disease 2019 (COVID-19) Infection: A Mechanistic Landscape.

Front Immunol

2021 Oct 13

Mukund K, Nayak P, Ashokkumar C

234. Effectiveness of Sublingual Immunotherapy in the Treatment of HDM-Induced Nasobronchial Allergies: A 3-Year Randomized Case-Control Study From Kashmir.

Front Immunol

2021 Oct 13

Baba SM, Rasool R, Gull A

235. Biophysical Evaluation of Rhesus Macaque Fc Gamma Receptors Reveals Similar IgG Fc Glycoform Preferences to Human Receptors.

Front Immunol

2021 Oct 12

Crowley AR, Osei-Owusu NY, Dekkers G

236. Topological Dissection of Proteomic Changes Linked to the Limbic Stage of Alzheimer's Disease.

Front Immunol

2021 Oct 12

Velásquez E, Szeitz B, Gil J

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia worldwide. In AD, neurodegeneration spreads throughout different areas of the central nervous system (CNS) in a gradual and predictable pattern, causing progressive memory decline and cognitive impairment. Deposition of neurofibrillary tangles (NFTs) in specific CNS regions correlates with the severity of AD and constitutes the basis for disease classification into different Braak stages (I-VI). Early clinical symptoms are typically associated with stages III-IV (i.e., limbic stages) when the involvement of the hippocampus begins. Histopathological changes in AD have been linked to brain proteome alterations, including aberrant posttranslational modifications (PTMs) such as the hyperphosphorylation of Tau. Most proteomic studies to date have focused on AD progression across different stages of the disease, by targeting one specific brain area at a time. However, in AD vulnerable regions, stage-specific proteomic alterations, including changes in PTM status occur in parallel and remain poorly characterized. Here, we conducted proteomic, phosphoproteomic, and acetylomic analyses of human postmortem tissue samples from AD (Braak stage III-IV, n=11) and control brains (n=12), covering all anatomical areas affected during the limbic stage of the disease (total hippocampus, CA1, entorhinal and perirhinal cortices). Overall, ~6000 proteins, ~9000 unique phosphopeptides and 221 acetylated peptides were accurately quantified across all tissues. Our results reveal significant proteome changes in AD brains compared to controls. Among others, we have observed the dysregulation of pathways related to the adaptive and innate immune responses, including several altered antimicrobial peptides (AMPs). Notably, some of these changes were restricted to specific anatomical areas, while others altered according to disease progression across the regions studied. Our data highlights the molecular heterogeneity of AD and the relevance of neuroinflammation as a major player in AD pathology. Data are available via ProteomeXchange with identifier PXD027173.

237. TNFSF13 Is a Novel Onco-Inflammatory Marker and Correlates With Immune Infiltration in Gliomas.

Front Immunol

2021 Oct 12

Chen R, Wang X, Dai Z

238. Influenza Vaccination Is Associated With Lower Incidental Asthma Risk in Patients With Atopic Dermatitis: A Nationwide Cohort Study.

Front Immunol

2021 Oct 12

Li KH, Leong PY, Tseng CF

239. Recent Metabolic Advances for Preventing and Treating Acute and Chronic Graft Versus Host Disease.

Front Immunol

2021 Oct 12

Mohamed FA, Thangavelu G, Rhee SY

The therapeutic efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by the development of graft-versus-host disease (GVHD). In GVHD, rigorous pre-conditioning regimen resets the immune landscape and inflammatory milieu causing immune dysregulation, characterized by an expansion of alloreactive cells and a reduction in immune regulatory cells. In acute GVHD (aGVHD), the release of damage- and pathogen- associated molecular patterns from damaged tissue caused by the conditioning regimen sets the stage for T cell priming, activation and expansion further exacerbating tissue injury and organ damage, particularly in the gastrointestinal tract. Studies have shown that donor T cells utilize multiple energetic and biosynthetic pathways to mediate GVHD that can be distinct from the pathways used by regulatory T cells for their suppressive function. In chronic GVHD (cGVHD), donor T cells may differentiate into IL-21 producing T follicular helper cells or tissue resident T helper cells that cooperate with germinal center B cells or memory B cells, respectively, to produce allo- and auto-reactive antibodies with subsequent tissue fibrosis. Alternatively, donor T cells can become IFN- γ/IL-17 cytokine expressing T cells that mediate sclerodermatous skin injury. Patients refractory to the first line standard regimens for GVHD treatment have a poor prognosis indicating an urgent need for new therapies to restore the balance between effector and regulatory immune cells while preserving the beneficial graft-versus-tumor effect. Emerging data points toward a role for metabolism in regulating these allo- and auto-immune responses. Here, we will discuss the preclinical and clinical data available on the distinct metabolic demands of acute and chronic GVHD and recent efforts in identifying therapeutic targets using metabolomics. Another dimension of this review will examine the changing microbiome after allo-HSCT and the role of microbial metabolites such as short chain fatty acids and long chain fatty acids on regulating immune responses. Lastly, we will examine the metabolic implications of coinhibitory pathway blockade and cellular therapies in allo-HSCT. In conclusion, greater understanding of metabolic pathways involved in immune cell dysregulation during allo-HSCT may pave the way to provide novel therapies to prevent and treat GVHD.

240. NLRC5 Deficiency Deregulates Hepatic Inflammatory Response but Does Not Aggravate Carbon Tetrachloride-Induced Liver Fibrosis.

Front Immunol

2021 Oct 12

Quenum AJI, Shukla A, Rexhepi F

The nucleotide-binding leucine-rich repeat-containing receptor (NLR) family protein-5 (NLRC5) controls NF-κB activation and production of inflammatory cytokines in certain cell types. NLRC5 is considered a potential regulator of hepatic fibrogenic response due to its ability to inhibit hepatic stellate activation in vitro. To test whether NLRC5 is critical to control liver fibrosis, we treated wildtype and NLRC5-deficient mice with carbon tetrachloride (CCl4) and assessed pathological changes in the liver. Serum alanine transaminase levels and histopathology examination of liver sections revealed that NLRC5 deficiency did not exacerbate CCl4-induced liver damage or inflammatory cell infiltration. Sirius red staining of collagen fibers and hydroxyproline content showed comparable levels of liver fibrosis in CCl4-treated NLRC5-deficient and control mice. Myofibroblast differentiation and induction of collagen genes were similarly increased in both groups. Strikingly, the fibrotic livers of NLRC5-deficient mice showed reduced expression of matrix metalloproteinase-3 (Mmp3) and tissue inhibitor of MMPs-1 (Timp1) but not Mmp2 or Timp2. Fibrotic livers of NLRC5-deficient mice had increased expression of TNF but similar induction of TGFβ compared to wildtype mice. CCl4-treated control and NLRC5-deficient mice displayed similar upregulation of Cx3cr1, a monocyte chemoattractant receptor gene, and the Cd68 macrophage marker. However, the fibrotic livers of NLRC5-deficient mice showed increased expression of F4/80 (Adgre1), a marker of tissue-resident macrophages. NLRC5-deficient livers showed increased phosphorylation of the NF-κB subunit p65 that remained elevated following fibrosis induction. Taken together, NLRC5 deficiency deregulates hepatic inflammatory response following chemical injury but does not significantly aggravate the fibrogenic response, showing that NLRC5 is not a critical regulator of liver fibrosis pathogenesis.

241. Linking Microstructural Integrity and Motor Cortex Excitability in Multiple Sclerosis.

Front Immunol

2021 Oct 12

Radetz A, Mladenova K, Ciolac D

Motor skills are frequently impaired in multiple sclerosis (MS) patients following grey and white matter damage with cortical excitability abnormalities. We applied advanced diffusion imaging with 3T magnetic resonance tomography for neurite orientation dispersion and density imaging (NODDI), as well as diffusion tensor imaging (DTI) in 50 MS patients and 49 age-matched healthy controls to quantify microstructural integrity of the motor system. To assess excitability, we determined resting motor thresholds using non-invasive transcranial magnetic stimulation. As measures of cognitive-motor performance, we conducted neuropsychological assessments including the Nine-Hole Peg Test, Trail Making Test part A and B (TMT-A and TMT-B) and the Symbol Digit Modalities Test (SDMT). Patients were evaluated clinically including assessments with the Expanded Disability Status Scale. A hierarchical regression model revealed that lower neurite density index (NDI) in primary motor cortex, suggestive for axonal loss in the grey matter, predicted higher motor thresholds, i.e. reduced excitability in MS patients (p = .009, adjusted r² = 0.117). Furthermore, lower NDI was indicative of decreased cognitive-motor performance (p = .007, adjusted r² = .142 for TMT-A; p = .009, adjusted r² = .129 for TMT-B; p = .006, adjusted r² = .142 for SDMT). Motor WM tracts of patients were characterized by overlapping clusters of lowered NDI (p <.05, Cohen's d = 0.367) and DTI-based fractional anisotropy (FA) (p <.05, Cohen's d = 0.300), with NDI exclusively detecting a higher amount of abnormally appearing voxels. Further, orientation dispersion index of motor tracts was increased in patients compared to controls, suggesting a decreased fiber coherence (p <.05, Cohen's d = 0.232). This study establishes a link between microstructural characteristics and excitability of neural tissue, as well as cognitive-motor performance in multiple sclerosis. We further demonstrate that the NODDI parameters neurite density index and orientation dispersion index detect a larger amount of abnormally appearing voxels in patients compared to healthy controls, as opposed to the classical DTI parameter FA. Our work outlines the potential for microstructure imaging using advanced biophysical models to forecast excitability alterations in neuroinflammation.

242. Effect of Immune Checkpoint Blockade on Myeloid-Derived Suppressor Cell Populations in Patients With Melanoma.

Front Immunol

2021 Oct 12

Sun SH, Benner B, Savardekar H

243. Low Dose Radiation Therapy Induces Long-Lasting Reduction of Pain and Immune Modulations in the Peripheral Blood - Interim Analysis of the IMMO-LDRT01 Trial.

Front Immunol

2021 Oct 12

Donaubauer AJ, Becker I, Weissmann T

244. Transport Stress Induces Skin Innate Immunity Response in Hybrid Yellow Catfish (Tachysurus fulvidraco♀ × P. vachellii♂) Through TLR/NLR Signaling Pathways and Regulation of Mucus Secretion.

Front Immunol

2021 Oct 12

Zheng T, Song Z, Qiang J

The transport of live fish is a necessary step for commercial production. The skin of teleost fish is the first non-specific immune barrier against exogenous stimuli, and it plays an important protective role under transport stress. Thus, the aim of this study was to explore the skin responses to transport stress in hybrid yellow catfish (Tachysurus fulvidraco♀ × Pseudobagrus vachellii♂) through transcriptome and biochemical analyses. Water samples were collected during a simulated transport treatment. Biochemical indexes and/or gene expression in blood, skin, and mucus in fish in control groups and transport-stress groups (0 h, 2 h, 4 h, 8 h, 16 h) were assayed. The levels of total ammonia-nitrogen and nitrite-nitrogen in the water increased with increasing transport time. Comparison of skin transcriptomes between the control group and the group subjected to 16 h of transport revealed 1547 differentially expressed genes (868 up-regulated and 679 down-regulated). The results of the transcriptome analysis were validated by analyses of the expression levels of selected genes by qRT-PCR. The results indicated that the toll-like receptors and nod-like receptors signaling pathways mediate the skin's immune response to transport stress: tlr9, mfn2, and ikbke were significantly up-regulated and nfkbia and map3k7cl were significantly down-regulated under transport stress. With increasing transport time, lysozyme activity and the immunoglobulin M content in skin mucus first increased and then decreased. The number of mucous cells peaked at 8 h of transport stress, and then decreased. The mucus cells changed from types II and IV to types I, II, III, and IV. The amounts of red and white blood cells and the levels of hemoglobin and hematocrit first increased and then decreased during 16 h of transport stress. Together, the results showed that the skin responds to transport stress by activating the immune signaling pathway and regulating mucus secretion. These findings have important biological significance for selecting strains that tolerate transport, as well as economic significance for optimizing the transport conditions for scaleless fish.

245. Erratum: uhrf1 and dnmt1 Loss Induces an Immune Response in Zebrafish Livers Due to Viral Mimicry by Transposable Elements.

Front Immunol

2021 Oct 11

Frontiers Production Office.

246. Development of a Scrub Typhus Diagnostic Platform Incorporating Cell-Surface Display Technology.

Front Immunol

2021 Oct 11

Liao CC, Tsai CH, Lo HR

247. New Insights on CD8(+) T Cells in Inflammatory Bowel Disease and Therapeutic Approaches.

Front Immunol

2021 Oct 11

Casalegno Garduño R, Däbritz J.

248. Alternative Complement Pathway Inhibition Abrogates Pneumococcal Opsonophagocytosis in Vaccine-Naïve, but Not in Vaccinated Individuals.

Front Immunol

2021 Oct 11

Muri L, Ispasanie E, Schubart A

249. Effects of Neutrophil Extracellular Traps in Patients With Septic Coagulopathy and Their Interaction With Autophagy.

Front Immunol

2021 Oct 11

Mao JY, Zhang JH, Cheng W

250. Mycoplasma genitalium and M. pneumoniae Regulate a Distinct Set of Protein-Coding Genes in Epithelial Cells.

Front Immunol

2021 Oct 11

Ramos EI, Das K, Harrison AL

251. NLRP3 Inflammasome: Checkpoint Connecting Innate and Adaptive Immunity in Autoimmune Diseases.

Front Immunol

2021 Oct 11

Zhang Y, Yang W, Li W

252. Efficacy, Immunogenicity and Safety of COVID-19 Vaccines: A Systematic Review and Meta-Analysis.

Front Immunol

2021 Oct 11

Sharif N, Alzahrani KJ, Ahmed SN

There is a significant research gap in meta-analysis on the efficacy and safety of coronavirus disease 2019 (COVID-19) vaccines. This study analyzed the efficacy of COVID-19 vaccines. Published phase I, phase II, and phase III trials analyzing safety and immunogenicity and phase III randomized clinical trials evaluating the efficacy of COVID-19 vaccines were included. We searched MEDLINE, Scopus, and The Lancet for published articles evaluating the relative reduction in COVID-19 risk after vaccination. Selected literatures were published between December 15, 2019 and May 15, 2021 on the safety, efficacy, and immunogenicity of COVID-19 vaccines. This meta-analysis included studies that confirmed cases of COVID-19 using reverse transcriptase polymerase chain reaction. This study detected 8,926 eligible research articles published on COVID-19 vaccines. Of these, 25 studies fulfilled the inclusion criteria. Among the selected articles, 19 randomized clinical trials, 2 non-randomized clinical trials, and 3 observational studies were analyzed. Seven (28%) studies were included in the meta-analysis. The efficacy of the adenovirus vector vaccine was 73% (95% CI = 69-77) and that of the messenger RNA (mRNA) vaccine was 85% (95% CI = 82-88) in participants aged ≥18 years. There are no reports of clinical trials in participants aged under 16 years. The production of neutralizing antibodies against receptor-binding domains (RBDs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in >90% of the vaccinated samples was reported within 0-30 days of the first or the second dose of the vaccine. Pain at the injection site was the most common local symptom in people receiving mRNA vaccines (29%-85% of participants). Fever (0.2%-95%) was the most prevalent in people receiving adenovirus vector vaccines, and fatigue (8.4%-55%) was the most common side effect in people receiving the mRNA vaccines. Studies suggest that mRNA vaccines and adenovirus vector vaccines can provide moderate to high protection against COVID-19 infection in people over 18 years. Evidence of the long-term protection of the vaccines in people aged under 16 years against the multiple variants of COVID-19 are limited. This study will provide an integrated evaluation on the efficacy, safety, and immunogenicity of the COVID-19 vaccines.

253. Pro-Inflammatory and B Cell Regulating Capacities of TWEAK in Rainbow Trout (Oncorhynchus mykiss).

Front Immunol

2021 Oct 1

Abós B, Pérez-Fernández E, Morel E

254. Current Status of Cell-Based Therapies for COVID-19: Evidence From Mesenchymal Stromal Cells in Sepsis and ARDS.

Front Immunol

2021 Oct 1

Xu Z, Huang Y, Zhou J

255. Semen-Derived Exosomes Mediate Immune Escape and Transmission of Reticuloendotheliosis Virus.

Front Immunol

2021 Oct 1

Su Q, Zhang Y, Cui Z

256. B Cells Control Mucosal-Associated Invariant T Cell Responses to Salmonella enterica Serovar Typhi Infection Through the CD85j HLA-G Receptor.

Front Immunol

2021 Oct 1

Salerno-Gonçalves R, Rezwan T, Luo D

257. Beyond Vaccines: Clinical Status of Prospective COVID-19 Therapeutics.

Front Immunol

2021 Oct 1

Kumar S, Çalışkan DM, Janowski J

Since November 2019 the SARS-CoV-2 pandemic has caused nearly 200 million infection and more than 4 million deaths globally (Updated information from the World Health Organization, as on 2nd Aug 2021). Within only one year into the pandemic, several vaccines were designed and reached approval for the immunization of the world population. The remarkable protective effects of the manufactured vaccines are demonstrated in countries with high vaccination rates, such as Israel and UK. However, limited production capacities, poor distribution infrastructures and political hesitations still hamper the availability of vaccines in many countries. In addition, due to the emergency of SARS-CoV-2 variants with immune escape properties towards the vaccines the global numbers of new infections as well as patients developing severe COVID-19, remains high. New studies reported that about 8% of infected individuals develop long term symptoms with strong personal restrictions on private as well as professional level, which contributes to the long socioeconomic problems caused by this pandemic. Until today, emergency use-approved treatment options for COVID-19 are limited to the antiviral Remdesivir, a nucleoside analogue targeting the viral polymerase, the glucocorticosteroide Dexamethasone as well as neutralizing antibodies. The therapeutic benefits of these treatments are under ongoing debate and clinical studies assessing the efficiency of these treatments are still underway. To identify new therapeutic treatments for COVID-19, now and by the post-pandemic era, diverse experimental approaches are under scientific evaluation in companies and scientific research teams all over the world. To accelerate clinical translation of promising candidates, repurposing approaches of known approved drugs are specifically fostered but also novel technologies are being developed and are under investigation. This review summarizes the recent developments from the lab bench as well as the clinical status of emerging therapeutic candidates and discusses possible therapeutic entry points for the treatment strategies with regard to the biology of SARS-CoV-2 and the clinical course of COVID-19.

258. Insights From Single Cell RNA Sequencing Into the Immunology of Type 1 Diabetes- Cell Phenotypes and Antigen Specificity.

Front Immunol

2021 Oct 1

Hanna SJ, Tatovic D, Thayer TC

259. Environmental Determinants of Type 1 Diabetes: From Association to Proving Causality.

Front Immunol

2021 Oct 1

Quinn LM, Wong FS, Narendran P.

260. Characterization of Exosome-Related Gene Risk Model to Evaluate the Tumor Immune Microenvironment and Predict Prognosis in Triple-Negative Breast Cancer.

Front Immunol

2021 Oct 1

Qiu P, Guo Q, Yao Q

BACKGROUND: As a kind of small membrane vesicles, exosomes are secreted by most cell types from multivesicular endosomes, including tumor cells. The relationship between exosomes and immune response plays a vital role in the occurrence and development of tumors. Nevertheless, the interaction between exosomes and the microenvironment of tumors remains unclear. Therefore, we set out to study the influence of exosomes on the triple-negative breast cancer (TNBC) microenvironment. METHOD: One hundred twenty-one exosome-related genes were downloaded from ExoBCD database, and IVL, CXCL13, and AP2S1 were final selected because of the association with TNBC prognosis. Based on the sum of the expression levels of these three genes, provided by The Cancer Genome Atlas (TCGA), and the regression coefficients, an exosome risk score model was established. With the median risk score value, the patients in the two databases were divided into high- and low-risk groups. R clusterProfiler package was employed to compare the different enrichment ways between the two groups. The ESTIMATE and CIBERSORT methods were employed to analyze ESTIMATE Score and immune cell infiltration. Finally, the correlation between the immune checkpoint-related gene expression levels and exosome-related risk was analyzed. The relationship between selected gene expression and drug sensitivity was also detected. RESULTS: Different risk groups exhibited distinct result of TNBC prognosis, with a higher survival rate in the low-risk group than in the high-risk group. The two groups were enriched by immune response and biological process pathways. A better overall survival (OS) was demonstrated in patients with high scores of immune and ESTIMATE rather than ones with low scores. Subsequently, we found that CD4+-activated memory T cells and M1 macrophages were both upregulated in the low-risk group, whereas M2 macrophages and activated mast cell were downregulated in the low-risk group in patients from the TCGA and GEO databases, respectively. Eventually, four genes previously proposed to be targets of immune checkpoint inhibitors were evaluated, resulting in the expression levels of CD274, CTLA4, LAG3, and TIM3 being higher in the low-risk group than high-risk group. CONCLUSION: The results of our study suggest that exosome-related risk model was related to the prognosis and ratio of immune cell infiltration in patients with TNBC. This discovery may make contributions to improve immunotherapy for TNBC.

261. Monocyte Chemotactic Protein-Induced Protein 1 (MCPIP-1): A Key Player of Host Defense and Immune Regulation.

Front Immunol

2021 Oct 1

Jin Z, Zheng E, Sareli C

Inflammatory response is a host-protective mechanism against tissue injury or infections, but also has the potential to cause extensive immunopathology and tissue damage, as seen in many diseases, such as cardiovascular diseases, neurodegenerative diseases, metabolic syndrome and many other infectious diseases with public health concerns, such as Coronavirus Disease 2019 (COVID-19), if failure to resolve in a timely manner. Recent studies have uncovered a superfamily of endogenous chemical molecules that tend to resolve inflammatory responses and re-establish homeostasis without causing excessive damage to healthy cells and tissues. Among these, the monocyte chemoattractant protein-induced protein (MCPIP) family consisting of four members (MCPIP-1, -2, -3, and -4) has emerged as a group of evolutionarily conserved molecules participating in the resolution of inflammation. The focus of this review highlights the biological functions of MCPIP-1 (also known as Regnase-1), the best-studied member of this family, in the resolution of inflammatory response. As outlined in this review, MCPIP-1 acts on specific signaling pathways, in particular NFκB, to blunt production of inflammatory mediators, while also acts as an endonuclease controlling the stability of mRNA and microRNA (miRNA), leading to the resolution of inflammation, clearance of virus and dead cells, and promotion of tissue regeneration via its pleiotropic effects. Evidence from transgenic and knock-out mouse models revealed an involvement of MCPIP-1 expression in immune functions and in the physiology of the cardiovascular system, indicating that MCPIP-1 is a key endogenous molecule that governs normal resolution of acute inflammation and infection. In this review, we also discuss the current evidence underlying the roles of other members of the MCPIP family in the regulation of inflammatory processes. Further understanding of the proteins from this family will provide new insights into the identification of novel targets for both host effectors and microbial factors and will lead to new therapeutic treatments for infections and other inflammatory diseases.

Newmer生物

Newmer生物