Germinal Center B Cells Are Essential for Collagen‐Induced Arthritis

Dahdah, Albert; Habir, Katrin; Nandakumar, Kutty Selva; Saxena, Amit; Xu, Bingze; Holmdahl, Rikard; Malin, Stephen

doi:10.1002/art.40354

Cited by 29 publications

(31 citation statements)

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“…Given the effect of WEHI‐112 in reducing CII‐specific IgG1 titers in CIA (Figure J), the importance of GCs for development of CIA , and the requirement for TBK‐1 in mediating ICOS signaling during Tfh cell maturation , we examined the GC response following WEHI‐112 treatment in the CIA model. Immunohistochemistry revealed an overall reduction in GC size as determined by GC area relative to total LN size (Figures A and B), although GC numbers were not affected by WEHI‐112 (Figure C).…”

Section: Resultsmentioning

confidence: 99%

Therapeutic Effects of a TANK‐Binding Kinase 1 Inhibitor in Germinal Center–Driven Collagen‐Induced Arthritis

Louis

Ngo

D'Silva

et al. 2018

Arthritis & Rheumatology

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We report that TBK-1 inhibition using WEHI-112 abrogated antibody-dependent CIA. As WEHI-112 failed to inhibit non-antibody-driven joint inflammation, we conclude that the major effect of this compound was most likely the targeting of TBK-1-mediated mechanisms in the GC reaction. This approach may have therapeutic potential in RA and in other GC-associated autoantibody-driven inflammatory diseases.

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Section: Resultsmentioning

confidence: 99%

Therapeutic Effects of a TANK‐Binding Kinase 1 Inhibitor in Germinal Center–Driven Collagen‐Induced Arthritis

Louis

Ngo

D'Silva

et al. 2018

Arthritis & Rheumatology

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“…This is likely due to differences in cytokine skewing induced by these ligands. Finally, to investigate if the combination of IL-18 + αGalCer could support autoimmunity, we injected IL-18 alone or in combination with αGalCer in the collagen-induced arthritis (CIA) model of RA (30). We selected a protocol that has been shown to induce mild autoimmune arthritis (31) and found that the combination of IL-18 + αGalCer clearly enhanced the development of arthritis (Fig.…”

Section: Significancementioning

confidence: 99%

Combined proinflammatory cytokine and cognate activation of invariant natural killer T cells enhances anti-DNA antibody responses

Sedimbi

Hägglöf

Garimella

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Invariant natural killer T (iNKT) cells serve as early rapid responders in the innate immune response to self-derived autoantigens and pathogen-derived danger signals and antigens. iNKT cells can serve both as helpers for effector B cells and negatively regulate autoreactive B cells. Specifically, iNKT cells drive B cell proliferation, class switch, and antibody production to induce primary antigen-specific immune responses. On the other hand, inflammasome-mediated activation drives accumulation of neutrophils, which license iNKT cells to negatively regulate autoreactive B cells via Fas ligand (FasL). This positions iNKT cells at an apex to support or inhibit B cell responses in inflammation. However, it is unknown which effector mechanism dominates in the face of cognate glycolipid activation during chronic inflammation, as might result from glycolipid vaccination or infection during chronic autoimmune disease. We stimulated iNKT cells by cognate glycolipid antigen α-galactosylceramide (αGalCer) and measured B cell activation during interleukin 18 (IL-18)-induced chronic inflammation. Moreover, glycolipid-activated iNKT cells increased the serum concentration of autoantibodies, frequency of germinal center (GC) B cells, and antigen-specific plasma cells induced during chronic IL-18–mediated inflammation, as compared with IL-18 alone. Further, activation of iNKT cells via cognate glycolipid during IL-18–mediated inflammation overrides the licensing function of neutrophils, instead inducing iNKT follicular helper (iNKTfh) cells that in turn promote autoimmunity. Thus, our data demonstrate that glycolipids which engage iNKT cells support antigen-specific B cell help during inflammasome-mediated inflammation.

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“…However, although CD4+ T cells are of essential significance for the induction and maintenance of inflammation in CIA and RA, the activation of self-antigen-specific B cells is thought to be extremely important for the target tissue damage 16 . The role of B cells in the pathogenesis of CIA, as in RA, is likely to be complex 17 .…”

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confidence: 99%

“…To corroborate the importance of antibodies in the pathogenesis of CIA are data indicating that the absence of B cells in genetically modified mice 19 and lowered number of B cells in mice treated with anti-CD20 antibodies 20 , inducing lack of CII-specific autoantibodies, protected mice against CIA 19 . The pathogenic role of B cells in CIA is mainly attributed to the secretion of anti-collagen antibodies 17 . The CII-specific autoantibodies are crucial for both the initiation and perpetuation of the clinical disease 21 .…”

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confidence: 99%

“…Germinal centres (GCs) provide a proper microenvironment for activation, somatic diversification, and affinity maturation of (auto)reactive B lymphocytes which occurred before the production of (auto)antibodies 25 . Mice that were selectively deficient in GCs are almost fully protected against CIA, whereas they are fully susceptible to collagen antibody-induced arthritis 17 . Following the induction of CIA GCs develop in inflamed joint tissues and secondary lymphoid tissues, including the lymph nodes draining inflamed joints and adjacent tissues (dLNs), often referred to as reactive lymph nodes 26 .…”

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confidence: 99%

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Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis

Dimitrijević

Arsenović-Ranin

Kosec

et al. 2020

Sci Rep

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The study examined germinal centre (GC) reaction in lymph nodes draining inflamed joints and adjacent tissues (dLNs) in male and female Dark Agouti rat collagen type II (CII)-induced arthritis (CIA) model of rheumatoid arthritis. Female rats exhibiting the greater susceptibility to CIA mounted stronger serum CII-specific IgG response than their male counterparts. This correlated with the higher frequency of GC B cells in female compared with male dLNs. Consistently, the frequency of activated/proliferating Ki- 67+ cells among dLN B cells was higher in females than in males. This correlated with the shift in dLN T follicular regulatory (Tfr)/T follicular helper (Tfh) cell ratio towards Tfh cells in females, and greater densities of CD40L and CD40 on their dLN T and B cells, respectively. The higherTfh cell frequency in females was consistent with the greater dLN expression of mRNA for IL-21/27, the key cytokines involved in Tfh cell generation and their help to B cells. Additionally, in CII-stimulated female rat dLN cell cultures IFN-γ/IL-4 production ratio was shifted towards IFN-γ. Consistently, the serum IgG2a(b)/ IgG1 CII-specific antibody ratio was shifted towards an IgG2a(b) response in females. Thus, targeting T-/B-cell interactions should be considered in putative further sex-based translational pharmacology research.Rheumatoid arthritis (RA) is a chronic autoimmune systemic inflammatory disease characterized by synovial inflammation and the progressive destruction of joint cartilage and bones significantly reducing health-related quality of life 1 . The prevalence of RA is approximately threefold higher in women than in men, and the disease in women exhibits a more severe course 2 . Thus, research focused on sex as a determinant of disease severity could be important for further personalized management of patients with this autoimmune disease 3 .Collagen-induced arthritis (CIA) is a well-established experimental model mimicking many aspects of RA immunopathogenesis 4 . Differently from most of the mouse models of experimentally induced arthritis 5,6 , in several studies, female rats exhibited greater susceptibility to CIA compared with their male counterparts 7-10 . Thus, these rat CIA models seem to be suitable for research aimed to elucidate cellular and molecular mechanisms underlying sex differences in pathogenesis and clinical outcome of RA, as a base for designing efficient sex-specific therapies.Sex differences in susceptibility to autoimmune diseases have been related to sex-based differences in immunopathogenesis and susceptibility of the target tissue to damage caused by autoimmune or inflammatory burden 11,12 . These differences most likely arise from intricate interactions between circulating sex steroids, microbiota, genetic and environmental factors 11,13 .CIA is shown to be T helper (Th)1/Th17 mediated disease 14 . The main function of Th cells is to activate macrophages and fibroblasts and transform them into tissue-destructive cells 15 . Our previous studies in Dark Agouti (DA) rat CIA mo...

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Germinal Center B Cells Are Essential for Collagen‐Induced Arthritis

Cited by 29 publications

References 50 publications

Therapeutic Effects of a TANK‐Binding Kinase 1 Inhibitor in Germinal Center–Driven Collagen‐Induced Arthritis

Therapeutic Effects of a TANK‐Binding Kinase 1 Inhibitor in Germinal Center–Driven Collagen‐Induced Arthritis

Combined proinflammatory cytokine and cognate activation of invariant natural killer T cells enhances anti-DNA antibody responses

Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis

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