Reduced Competitiveness of Autoantigen-Engaged B Cells due to Increased Dependence on BAFF

Abstract

Peripheral autoantigen binding B cells are poorly competitive with naive B cells for survival and undergo rapid cell death. However, in monoclonal Ig-transgenic mice lacking competitor B cells, autoantigen binding B cells can survive for extended periods. The basis for competitive elimination of autoantigen binding B cells has been unknown. Here we demonstrate that autoantigen binding B cells have increased dependence on BAFF for survival. In monoclonal Ig-transgenic mice, each autoantigen binding B cell receives elevated amounts of BAFF, exhibiting increased levels of NFkappaB p52 and of the prosurvival kinase Pim2. When placed in a diverse B cell compartment, BAFF receptor engagement and signaling are reduced and the autoantigen binding cells are unable to protect themselves from Bim and possibly other death-promoting factors induced by chronic BCR signaling. These findings indicate that under conditions where BAFF levels are elevated, autoantigen-engaged cells will be rescued from rapid competitive elimination, predisposing to the development of autoimmune disease.

Cutting Edge: Bim Is Required for Superantigen-Mediated B Cell Death

“…We speculate that a B cell SAg more commonly delivers a very strong BCR signal that is associated with greater cellular requirements for cytokine or cognate help that are critical for survival and/or cell cycle progression, as well as because a SAg also enhances cellular competition among the great numbers of B cells affected by this BCRtargeted ligand (3). This model is consistent with our demonstration that supraphysiological levels of BAFF can inhibit both the BCR-mediated up-regulation of Bim and subsequent apoptotic death akin to other systems (11,12,14). This model is also supported by our recent findings that relatively larger SAg doses induce limited proliferation with more rapid and larger scale death, presumably due to the more rapid exhaustion of available prosurvival signals (7).…”

“…In fact, B cells from SpA-treated Bimdeficient mice displayed enhanced responses to stimulation with the B cell mitogens, LPS, or anti-IgM (i.e., IgG F(abЈ) 2 ), or CD40 ligand, compared to those from control-treated mice (data not shown). Hence, B cells surviving from SpA exposure are not commonly anergic (12) and, under the conditions evaluated, Bim-deficient B cells instead displayed enhanced responsiveness to restimulation, which is consistent with evidence from other systems that Bim may contribute to non-deletional negative selection mechanisms (i.e., anergy) (12,14).…”

Genetic Dissection of Systemic Lupus Erythematosus Pathogenesis: Partial Functional Complementation betweenSle1andSle3/5Demonstrates Requirement for Intracellular Coexpression for Full Phenotypic Expression of Lupus

“…Recently, it was shown that Sle3/5 impacts IgH CDR3 sequences, somatic mutations, and receptor editing, although it remains uncertain whether these effects are extrinsic and/or intrinsic (39). Cultured B6.Sle3/5 bone marrow-derived DCs have been found to display high gene expression of BAFF/BLyS (40), which has been shown to rescue autoreactive B cells from apoptosis (41,42). This cytokine might be one contributor to the extrinsic effect of Sle3/5 on autoreactive B cells.…”

B cells and aging: Balancing the homeostatic equation

“…This has been tested in experiments using the HEL/anti-HEL double transgenic model (Lesley, Xu et al 2004;Thien, Phan et al 2004), and in our recent collaborative studies using the 3H9 transgenic model of dsDNA autoreactivity (Hondowicz, et al, submitted). Together, these studies show that the likelihood of autoreactive clonotypes being eliminated at the transitional stage is determined by the availability of BLyS and the degree of competition from other, concomitantly emerging clonotypes.…”