Excess BAFF Rescues Self-Reactive B Cells from Peripheral Deletion and Allows Them to Enter Forbidden Follicular and Marginal Zone Niches

Abstract

The role of BAFF in B cell self tolerance was examined by tracking the fate of anti-HEL self-reactive B cells in BAFF transgenic mice using four different models of self-reactive B cell deletion. BAFF overexpression did not affect the development of self-reactive B cells normally deleted in the bone marrow or during the early stages of peripheral development. By contrast, self-reactive B cells normally deleted around the late T2 stage of peripheral development were rescued from deletion, matured, and colonized the splenic follicle. Furthermore, self-reactive B cells normally selectively deleted from the marginal zone repopulated this compartment when excess BAFF was present. Self-reactive B cells rescued by excess BAFF were not anergic. BAFF overexpression therefore rescued only self-reactive B cells normally deleted with relatively low stringency and facilitated their migration into otherwise forbidden microenvironments. This partial subversion of B cell self tolerance is likely to underlie the autoimmunity associated with BAFF overexpression.

Enhanced responsiveness to T‐cell help causes loss of B‐lymphocyte tolerance to a β‐cell neo‐self‐antigen in type 1 diabetes prone NOD mice

“…Under these conditions, self-reactive B lymphocytes would not only be exposed to higher concentrations of Ag, but also to an environment where they must compete with non-autoreactive B lymphocytes for survival factors (e.g. BAFF) and physiological niches [19][20][21].…”

“…Under these conditions, self-reactive B lymphocytes would not only be exposed to higher concentrations of Ag, but also to an environment where they must compete with non-autoreactive B lymphocytes for survival factors (e.g. BAFF) and physiological niches [19][20][21].To examine B-lymphocyte tolerance to b-cell Ag within an environment where self-reactive clones comprise only a minor fraction of the total repertoire, NOD.insHEL and B6.insHEL mice as well as their non-Tg littermates were lethally irradiated and reconstituted with a mixture of BM cells from IgHEL-Tg and non-Tg donors of the same genetic background. Chimeras reconstituted with IgHEL to non-Tg BM ratios of 7:3 and 1:1 for B6 and NOD background mice, respectively, had equivalent proportions of HEL-specific B lymphocytes (mostly ranging between 10 and 20%) in BM, spleen and PLN 6 wk post-reconstitution, irrespective of whether recipients expressed insHEL or were non-Tg ( Fig.…”

Tolerance checkpoints in B‐cell development: Johnny B good

“…Moreover, elevated BAFF serum levels have been found in patients with autoimmune diseases in which B cells play an important role [81,82]. Studies aimed at elucidating the mechanisms by which over expression of BAFF can result in loss of B-cell tolerance showed that BAFF over expression does not interfere with the central tolerance program in the bone marrow but rather prevents autoreactive B cells being anergized in the periphery [83]. Currently, the potential of neutralizing BAFF as a therapy for auto-immunity is being tested both in mouse and clinical settings.…”

The Abnormal High Expression of B Cell Activating Factor Belonging to TNF Superfamily (BAFF) and Its Potential Role in Kidney Transplant Recipients

“…BAFF-induced autoimmunity in BAFF Tg mice appears to be highly dependent on B cells and possibly the production of autoantibodies (11). High levels of BAFF have been found in the blood of patients with autoimmune diseases, particularly SLE and SS (10,(12)(13)(14)(15). And BAFF was also found on T lymphocytes infiltrating labial salivary glands from patients with SS (16).…”