Follicular exclusion of autoreactive B cells requires Fc RIIb

Abstract

In non-autoimmune mice, the 3H9 transgenic Ig heavy chain can pair with endogenous Iglambda1 light chains to generate B cells with specificity for DNA. These autoreactive cells are actively regulated in vivo, as indicated by the exclusion of lambda1 cells from the splenic B cell follicle and the absence of auto-antibody production. To study the role of Fcgamma receptor IIb (FcgammaRIIb) in peripheral B cell tolerance, FcgammaRIIb(-/-) mice were crossed with C57BL/6 mice bearing a site-directed knock-in of the 3H9 transgene. 3H9FcgammaRIIb(-/-) mice become autoreactive, lose the follicular exclusion of anti-DNA B cells and instead have lambda1 B cells located within splenic germinal centers. They have increased frequencies of splenic auto-antibody-producing cells and elevated titers of IgG anti-DNA auto-antibody. The data implicate an FcgammaRIIb-dependent checkpoint that can exclude autoreactive B cells from splenic follicles. By restricting their participation in germinal center reactions, this putative checkpoint helps attenuate the production of potentially pathogenic auto-antibodies. The data further suggest that this FcgammaRIIb-dependent regulation is B cell autonomous.

FcγRIIB Inhibits the Development of Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

“…These findings may reflect that autoantibodies against mildly modified LDL particles are more beneficial than those recognizing severely modified forms of LDL. The importance of the inhibitory FcgRIIB in modulating B cell activity and humoral tolerance is supported by studies in both mice and humans (42)(43)(44). In line with these studies, we observed increased amount of splenic B cells and higher levels of plasma autoantibodies recognizing oxidized LDL in the absence of FcgRIIB.…”

“…The Ab pattern, showing higher levels of predominantly oxidized LDL-specific IgG2a/c autoantibodies, as well as increased levels of total IgG2a/c, in our hypercholesterolemic mouse model transplanted with FcgRIIBdeficient BM cells, is well in agreement with the hypothesis that atherosclerosis is driven by Th1 immune responses. Furthermore, the elevated levels of autoantibodies reflect findings in previous studies reporting that FcgRIIB controls BM plasma cell persistence and that absence of the receptor results in autoantibody production and unsatisfactory follicular exclusion of autoreactive B cells (43,44).…”

The Role of Rearrangement at the Second Ig Heavy Chain Locus in Maintaining B Cell Tolerance to DNA

“…Because these B cells were skewed toward being CD21 Ϫ CD23 Ϫ (Table II), they may be composed of memory B cells and/or preplasmablasts. Expansions of similar populations of B cells have been noted in other autoimmune mouse models (28,29). Consistent with this, sorted B220 int I-A b-int B cells from Tg-homozygous mice tended to elaborate more ANAs in culture (Fig.…”

Marginal Zone Precursor B Cells as Cellular Agents for Type I IFN–Promoted Antigen Transport in Autoimmunity

“…Specifically, the B cell migration pattern into the follicular regions of the spleen can alter the tempo and frequency of T-B cell contact and thus has been proposed as one mechanism to regulate the development of autoreactive B cells (1, 2). Early studies by Cyster et al (3) showed that under conditions of clonal selection, anergic B cells failed to enter the follicular areas, instead arresting at the T-B cell boundary in a process known as follicular exclusion.…”