scholarly journals MicroRNA-146a-deficient mice develop immune complex glomerulonephritis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Lucile Amrouche ◽  
Sylvaine You ◽  
Virginia Sauvaget ◽  
Victoria Manda ◽  
Baptiste Lamarthée ◽  
...  
Keyword(s):  
B Cell ◽  
Immune Complex ◽  
Inflammatory Responses ◽  
Transmembrane Protein ◽  
Regulatory B Cell ◽  
Immune Complex Glomerulonephritis ◽  
Cell Responses ◽  
Double Stranded Dna ◽  
Immune Mediated ◽  
Circulating Antibodies

Abstract MicroRNAs (miRNAs) play an important role in the kidneys under physiological and pathological conditions, but their role in immune glomerulonephritis is unclear. miR-146a has been identified as a key player in innate immunity and inflammatory responses, and in the kidney, this miRNA is involved in the response of injured tubular cells. We studied the renal and immune phenotypes of miR-146a+/+ and miR-146a−/− mice at 12 months of age, and the results showed that miR-146a−/− mice developed autoimmunity during aging, as demonstrated by circulating antibodies targeting double-stranded DNA and an immune complex-mediated glomerulonephritis associated with a mild renal immune infiltrate. In addition, miR-146a−/− mice showed reduced expression of the transmembrane protein Kim1/Tim1, a key regulator of regulatory B cell (Breg) homeostasis, in the kidney and the immune cells. The numbers of memory B cells and plasmablasts were increased in miR-146a−/− mice compared with the numbers in wild-type mice, whereas Bregs were decreased in number and displayed an altered capacity to produce IL-10. Finally, we showed that miR-146a−/− mice develop an autoimmune syndrome with increasing age, and this syndrome includes immune complex glomerulonephritis, which might be due to altered B cell responses associated with Kim1/Tim1 deficiency. This study unravels a link between miR-146a and Kim1 and identifies miR-146a as a significant player in immune-mediated glomerulonephritis pathogenesis.

scholarly journals The microbiota regulates murine inflammatory responses to toxin-induced CNS demyelination but has minimal impact on remyelination

2019 ◽  
Vol 116 (50) ◽  
pp. 25311-25321 ◽  
Author(s):  
Christopher E. McMurran ◽  
Alerie Guzman de la Fuente ◽  
Rosana Penalva ◽  
Ofra Ben Menachem-Zidon ◽  
Yvonne Dombrowski ◽  
...  
Keyword(s):  
Immune Response ◽  
Progenitor Cell ◽  
Inflammatory Responses ◽  
Oligodendrocyte Progenitor Cell ◽  
Oligodendrocyte Progenitor ◽  
Minimal Impact ◽  
Cell Responses ◽  
Immune Mediated ◽  
Probiotic Treatment ◽  
The Central Nervous System

The microbiota is now recognized as a key influence on the host immune response in the central nervous system (CNS). As such, there has been some progress toward therapies that modulate the microbiota with the aim of limiting immune-mediated demyelination, as occurs in multiple sclerosis. However, remyelination—the regeneration of myelin sheaths—also depends upon an immune response, and the effects that such interventions might have on remyelination have not yet been explored. Here, we show that the inflammatory response during CNS remyelination in mice is modulated by antibiotic or probiotic treatment, as well as in germ-free mice. We also explore the effect of these changes on oligodendrocyte progenitor cell differentiation, which is inhibited by antibiotics but unaffected by our other interventions. These results reveal that high combined doses of oral antibiotics impair oligodendrocyte progenitor cell responses during remyelination and further our understanding of how mammalian regeneration relates to the microbiota.

scholarly journals CD20+ T cells are associated with inflammatory responses in experimental arthritis

2021 ◽  
Author(s):  
Miguel Pineda ◽  
Piaopiao Pan ◽  
Yilin Wang ◽  
Aneesah Khan ◽  
Mukanthu H. Nyirenda
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Inflammatory Responses ◽  
Clinical Symptoms ◽  
Cell Subset ◽  
Lymphoid Tissues ◽  
Cell Responses ◽  
Helper Cells ◽  
B Cell Responses

AbstractCD20+ T cells comprise a small but highly inflammatory subset that has been implicated in autoimmunity, including rheumatoid arthritis (RA). We sought to characterise the CD20+ T cell subset at the site of inflammation in murine collagen-induced arthritis (CIA) model of RA and investigate the phenotype and functional relevance of CD3+CD20+ T cells in the lymph nodes and arthritic joints using flow cytometry and immunohistochemistry. We demonstrate that CD3+CD4+CD20+ and CD3+CD8+CD20+ T cells are expanded in the draining lymph nodes of CIA mice. In addition, compared to naïve mice and those that did not develop clinical symptoms, CD20 expressing T cells of arthritic mice produced increased levels of pro-inflammatory cytokines (GM-CSF, TNF-a, IL-17, and INF-g). Notably, CD3+CD4+CD20+ and CD3+CD8+CD20+ T cells of disease mice were enriched with CXCR5+PD-1+ T follicular helper cells and CXCR5-PD-1+ peripheral T helper cells, subsets of T cells that have been implicated in promoting B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues in RA. Importantly, CD3+CD20+ T cells were detected in the inflamed regions in the lymph nodes and paws of arthritic mice. Our findings suggest that CD20+ T cells are associated with inflammatory responses in the arthritic joint and may exacerbate pathology by promoting inflammatory B cell responses.

scholarly journals Efficacy and safety of SARS-CoV-2 revaccination in non-responders with immune-mediated inflammatory disease

2021 ◽  
pp. annrheumdis-2021-221554
Author(s):  
David Simon ◽  
Koray Tascilar ◽  
Filippo Fagni ◽  
Katja Schmidt ◽  
Gerhard Krönke ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Inflammatory Disease ◽  
Protective Immunity ◽  
Vaccine Dose ◽  
T Cell Responses ◽  
Antibody Activity ◽  
Efficacy And Safety ◽  
Cell Responses ◽  
Immune Mediated

ObjectivesTo test whether patients with immune-mediated inflammatory disease (IMIDs), who did not respond to two doses of the SARS-CoV-2 vaccine, develop protective immunity, if a third vaccine dose is administered.MethodsPatients with IMID who failed to seroconvert after two doses of SARS-CoV-2 vaccine were subjected to a third vaccination with either mRNA or vector-based vaccines. Anti-SARS-CoV-2 IgG, neutralising activity and T cell responses were assessed at baseline and 3 weeks after revaccination and also evaluated seprarately in rituximab (RTX) and non-RTX exposed patients.Results66 non-responders were recruited, 33 treated with RTX, and 33 non-exposed to RTX. Overall, 49.2% patients seroconverted and 50.0% developed neutralising antibody activity. Seroconversion (78.8% vs 18.2%) and neutralising activity (80.0% vs 21.9%) was higher in non-RTX than RTX-treated patients with IMID, respectively. Humoral vaccination responses were not different among patients showing positive (59.3%) or negative (49.7%) T cell responses at baseline. Patients remaining on mRNA-based vaccines showed similar vaccination responses compared with those switching to vector-based vaccines.ConclusionsOverall, these data strongly argue in favor of a third vaccination in patients with IMID lacking response to standard vaccination irrespective of their B cell status.

scholarly journals A Regulatory B Cell Subset with a Unique CD1dhiCD5+ Phenotype Controls T Cell-Dependent Inflammatory Responses

Immunity ◽  
2008 ◽  
Vol 28 (5) ◽  
pp. 639-650 ◽  
Author(s):  
Koichi Yanaba ◽  
Jean-David Bouaziz ◽  
Karen M. Haas ◽  
Jonathan C. Poe ◽  
Manabu Fujimoto ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Inflammatory Responses ◽  
Cell Subset ◽  
Regulatory B Cell

scholarly journals CNS Autoimmune Responses in BCMA-Deficient Mice Provide Insight for the Failure of Atacicept in MS

2021 ◽  
Vol 8 (3) ◽  
pp. e973
Author(s):  
Gaurav Kumar ◽  
Zahra Maria ◽  
Uday Kohli ◽  
Agnieshka Agasing ◽  
James L. Quinn ◽  
...  
Keyword(s):  
Cell Culture ◽  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Inflammatory Responses ◽  
Cell Responses ◽  
Cd20 Antibody ◽  
B Cell Responses ◽  
Anti Cd20 ◽  
Deficient Mice

ObjectiveB cells have emerged as a therapeutic target for MS. Anti-CD20 antibodies, which deplete B cells, are effective therapies for MS. However, atacicept (TACI-Fc), which blocks BAFF and APRIL and reduces B cells, unexpectedly exacerbates MS. We tested the hypothesis that B cell maturation antigen (BCMA), a receptor for BAFF and APRIL, plays a role in the paradoxical effects of anti-CD20 antibody and TACI-Fc using experimental autoimmune encephalomyelitis (EAE).MethodsEAE was induced in wild-type (BCMA+/+) and BCMA-deficient (BCMA−/−) mice with an immunization of rodent myelin oligodendrocyte glycoprotein (MOG)35–55 peptide. Treatment with anti-CD20 antibody, TACI-Fc, and isotype controls was administered by intraperitoneal injections. CNS infiltration was evaluated by histology; immune cell phenotypes were evaluated by flow cytometry; MOG-specific antibodies were determined by ELISA. Mixed bone marrow chimeras and cell culture assays were used to identify the specific subsets of immune cells affected by BCMA deficiency.ResultsFirst, we found that BCMA−/− mice had more severe EAE compared with BCMA+/+ mice and the increased disease was associated with elevated anti-MOG B-cell responses. Second, we found that anti-CD20 therapy attenuated EAE in BCMA−/− mice but not in BCMA+/+ mice. Third, TACI-Fc attenuated EAE in BCMA+/+ mice but not in BCMA−/− mice. Mixed bone marrow chimeric and cell culture experiments demonstrated that BCMA deficiency elevates inflammatory B-cell responses but inhibits inflammatory responses in macrophages.ConclusionsBCMA has multifaceted roles during inflammation that affects therapeutic efficacies of anti-CD20 and TACI-Fc in EAE. Our results from BCMA-deficient mice provide insights into the failure of atacicept in MS.

scholarly journals Human IL-23R Cytokine-Binding Homology Region-Fc Fusion Protein Ameliorates Psoriasis via the Decrease of Systemic Th17 and ILC3 Cell Responses

2019 ◽  
Vol 20 (17) ◽  
pp. 4170 ◽  
Author(s):  
Yue Gao ◽  
Zhengying Bian ◽  
Wenyao Xue ◽  
Qianwen Li ◽  
Yu Zeng ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Inflammatory Responses ◽  
Inflammatory Cells ◽  
Inflammatory Factors ◽  
Cell Responses ◽  
Adaptive Immune ◽  
Immune Mediated ◽  
Fc Fusion Protein ◽  
Shed Light

Interleukin (IL)-23 is considered an effective therapeutic target for the treatment of psoriasis because of the crucial role of the IL-23/IL-17 axis in the pathogenesis of psoriasis, and it has recently been reported to be involved in ILC3 cell differentiation. In this study, we report that eukaryotically expressed rhIL23R-CHR/Fc, as an endogenous extracellular receptor analogue, could be a natural antagonist in an imiquimod (IMQ)-induced psoriasis-like mouse model, including the antagonizing effect of suppressed inflammation in the skin lesion, decreased production of pro-inflammatory cells, and reduced the expression of pro-inflammatory factors. The rhIL23R-CHR/Fc fusion protein inhibits both innate immune and adaptive immune-mediated inflammatory responses. These findings shed light on rhIL23R-CHR/Fc as a promising candidate therapy for the treatment of psoriasis.

scholarly journals IL-33 Protects Mice against DSS-Induced Chronic Colitis by Increasing Both Regulatory B Cell and Regulatory T Cell Responses as Well as Decreasing Th17 Cell Response

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Jun-feng Zhu ◽  
Ying Xu ◽  
Jian Zhao ◽  
Xue Li ◽  
Xinrui Meng ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Response ◽  
Th17 Cell ◽  
Clinical Symptoms ◽  
Protective Role ◽  
Chronic Colitis ◽  
Mesenteric Lymph Nodes ◽  
Regulatory B Cell ◽  
Cell Responses ◽  
B Cell Subsets

Background. Previously, we have reported that IL-33 functioned as a protective modulator in dextran sulfate sodium- (DSS-) induced chronic colitis by suppressing Th17 cell response in colon lamina propria and IL-33 induced both regulatory B cells (Bregs) and regulatory T cells (Tregs) in mesenteric lymph nodes (MLNs) of mice with DSS-induced acute colitis. Moreover, we speculated that IL-33 would promote the Treg or Breg responses leading to the attenuation of DSS-induced chronic colitis. So, we investigated the role of IL-33 on Bregs and Tregs in the MLN of DSS-induced chronic colitis mice. Methods. IL-33 was administered by intraperitoneal injection to mice with DSS-induced chronic colitis. Clinical symptoms, colon length, and histological changes were determined. The production of cytokines was measured by ELISA. The T and B cell subsets were measured by flow cytometry. The expression of mRNA of transcription factors was measured by quantitative real-time PCR. Results. We show that IL-33 treatment increases both Breg and Treg responses in the MLN of mice with DSS-induced chronic colitis. Moreover, IL-33 treatment also decreases Th17 cell response in the MLN of mice with DSS-induced chronic colitis. Conclusion. Our data provide clear evidence that IL-33 plays a protective role in DSS-induced chronic colitis, which is closely related to increasing Breg and Treg responses in the MLN of mice as well as suppressing Th17 cell responses.

scholarly journals Pathogenesis of B-Cell Superantigen-Induced Immune Complex-Mediated Inflammation

2006 ◽  
Vol 74 (2) ◽  
pp. 1196-1203 ◽  
Author(s):  
Amy L. Anderson ◽  
Romeo Sporici ◽  
John Lambris ◽  
David LaRosa ◽  
Arnold I. Levinson
Keyword(s):  
B Cell ◽  
Immune Complex ◽  
Inflammatory Reaction ◽  
Inflammatory Responses ◽  
Protein A ◽  
Reaction Model ◽  
Staphylococcal Protein A ◽  
Complement Components ◽  
Necrosis Factor Alpha

ABSTRACT Staphylococcal protein A (SpA) is representative of a new class of antigens, the B-cell superantigens (SAgs). These antigens bind to the Fab regions of immunoglobulin molecules outside their complementarity-determining regions. SpA, the best-studied B-cell SAg, reacts with the Fabs of most VH3+ immunoglobulins, which are expressed on 30 to 60% of human peripheral B cells. Therefore, B-cell SAgs like SpA have great potential to elicit inflammatory responses in vivo. We previously reported that the interaction of SpA with VH3+ immunoglobulin molecules leads to activation of the complement cascade and produces a histologic pattern of inflammation in the skin of a rabbit indicative of immune complex injury. To elucidate the cellular and molecular events contributing to this type of unconventional immune complex-mediated inflammation, we established a mouse peritoneal Arthus reaction model. Mice treated intravenously with human polyclonal immunoglobulin G (IgG), followed by intraperitoneal injection of SpA, showed neutrophil influx into the peritoneal cavity with peak numbers appearing at 8 h. This inflammatory reaction was dependent on the interaction of SpA with VH3+ IgG. Mast cells, FcγRIII, complement components, and tumor necrosis factor alpha play obligatory roles, and the reaction is associated with the local release of the CXC chemokines macrophage inflammatory protein 2 and KC. The data provide further compelling evidence for the induction of immune complex-mediated injury by a B-cell SAg and highlight important factors contributing to the pathogenesis of this novel type of inflammatory reaction.

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