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Abstract
BackgroundFunctional variants of the B cell gene, B cell scaffold protein with ankyrin repeats 1 (BANK1) contribute to rheumatoid arthritis (RA) susceptibility, but their influences on B cell responses are unclear. Moreover, the function of induced T regulatory cells (iTregs) in the inflammatory milieu in a collagen-induced arthritis (CIA) model is unknown. This study was performed to investigate the roles of BANK1 in CIA and the interaction between B cells and iTregs.MethodsThe changes in BANK1 mRNA and protein levels and their correlation with disease severity in CIA were determined. Next, the antigen-presenting function and autoantibody production in B cells were evaluated by co-culture with effector T cells and iTregs, respectively, both in vitro and in vivo. Then, the mechanisms underlying these interactions were studied by adding neutralizing antibodies or transwell inserts and by adoptive transfer to B-cell-depleted CIA mice.ResultsThe BANK1 level decreased in the peripheral blood, spleen and lymph nodes of CIA mice, particularly during the acute stage of arthritis, and exhibited negative correlation with disease severity and autoantibody production. B cell responses were enhanced by this decrease. B cells from CIA mice (CIA-B cells) promoted iTreg differentiation, proliferation and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) expression. Meanwhile, BANK1 expression in CIA-B cells increased after co-culture with iTregs, limiting B cell responses. All these interactions depended on cell contact with CTLA-4-overexpressing iTregs but were independent of CTLA-4 cytokine.ConclusionDecreased BANK1 expression promotes B cell responses, resulting in an increased antigen presentation ability and autoantibody production that subsequently influences the communication between B cells and iTregs through a cell-contact-dependent and CTLA-4- cytokine-independent mechanism in CIA mice.
Highlights
Functional variants of the B cell gene, B cell scaffold protein with ankyrin repeats 1 (BANK1) contribute to rheumatoid arthritis (RA) susceptibility, but their influences on B cell responses are unclear
BANK1 expression in collagen-induced arthritis (CIA) The BANK1 mRNA levels, the percentage of BANK1 +CD19+ cells and the level of the BANK1 protein were evaluated with real-time PCR, flow cytometry, western blotting, and immunohistochemical analyses, respectively, to characterize BANK1 expression in CIA
BANK1 was expressed at significantly lower levels in B cells on the 14th day and the 35th day after immunization (Fig. 1b), and BANK1 protein levels in draining lymph node cells (Fig. 1c) showed the same trend
Summary
Functional variants of the B cell gene, B cell scaffold protein with ankyrin repeats 1 (BANK1) contribute to rheumatoid arthritis (RA) susceptibility, but their influences on B cell responses are unclear. Rheumatoid arthritis (RA) is an autoimmune disease characterized by progressive, destructive arthritis and causes joint dysfunction. Both T cells and B cells play an important role in RA pathogenesis [1,2,3,4]. Some scientists have noticed that higher BANK1 transcript levels help maintain stable immune tolerance in the absence of immunosuppression [17]. Based on these data, BANK1 may negatively affect immuneregulatory mechanisms in some diseases
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