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Abstract
Self-reactive B cells are tolerized at various stages of B-cell development and differentiation, including the immature B-cell stage (central tolerance) and the germinal center (GC) B-cell stage, and B-cell tolerance involves various mechanisms such as deletion, anergy, and receptor editing. Self-reactive B cells generated by random immunoglobulin variable gene rearrangements are tolerized by central tolerance and anergy in the periphery, and these processes involve apoptosis regulated by Bim, a pro-apoptotic member of the Bcl-2 family, and regulation of B-cell signaling by various phosphatases, including SHIP-1 and SHP-1. Self-reactive B cells generated by somatic mutations during GC reaction are also eliminated. Fas is not directly involved in this process but prevents persistence of GC reaction that allows generation of less stringently regulated B cells, including self-reactive B cells. Defects in self-tolerance preferentially cause lupus-like disease with production of anti-nuclear antibodies, probably due to the presence of a large potential B-cell repertoire reactive to nucleic acids and the presence of nucleic acid-induced activation mechanisms in various immune cells, including B cells and dendritic cells. A feed-forward loop composed of anti-nuclear antibodies produced by B cells and type 1 interferons secreted from nucleic acid-activated dendritic cells plays a crucial role in the development of systemic lupus erythematosus.
Highlights
Studies on autoantibody-transgenic mice and analyses of the repertoire of various B-cell subsets in humans and mice have demonstrated that self-reactive B cells are negatively regulated at various stages of B-cell development and maturation, including the immature B-cell stage in bone marrow, transitional B-cell stage, and germinal center (GC) B-cell stage[1,2]
nucleic acid (NA) sensors play a crucial role in the defense against microbes, especially viruses, through recognition of microbial DNA and RNA and are involved in the activation of B cells reactive to nuclear antigens containing NAs, leading to production of autoantibodies to nuclear antigens
Crucial roles of these mechanisms are supported by the findings that systemic lupus erythematosus (SLE)-associated genes in humans contain a number of genes involved in the regulation of B-cell signaling, NA degradation, or sensing of NAs, including the NA sensors TLR7 and TLR917,18
Summary
Studies on autoantibody-transgenic mice and analyses of the repertoire of various B-cell subsets in humans and mice have demonstrated that self-reactive B cells are negatively regulated at various stages of B-cell development and maturation, including the immature B-cell stage in bone marrow, transitional B-cell stage, and germinal center (GC) B-cell stage[1,2]. Sm/RNP may co-ligate Sm/RNP-reactive BCR and CD72, thereby inducing phosphorylation of the CD72 ITIM by Lyn associated with BCR, the event required for SHP-1 activation and signal suppression[54] This finding is consistent with the previous findings that CD72-deficient mice develop lupus-like disease much more severely than mice deficient in other inhibitory receptors such as CD22 and PIR-B68,69, CD72 does not regulate polyclonal BCR signaling induced by anti-IgM antibody[70]. B cell-specific deletion of Fas induces the development of lupus-like disease[78], suggesting that Fas-mediated apoptosis of self-reactive GC B cells is involved in self-tolerance for nuclear antigens. Involvement of GC reaction and defect in the GC checkpoint in autoantibody production in autoimmune diseases need to be further addressed in the future
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