The Fas/CD95 Receptor Regulates the Death of Autoreactive B Cells and the Selection of Antigen-Specific B Cells

Abstract

Cell death receptors have crucial roles in the regulation of immune responses. Here we review recent in vivo data confirming that the Fas death receptor (TNFSR6) on B cells is important for the regulation of autoimmunity since the impairment of only Fas function on B cells results in uncontrolled autoantibody production and autoimmunity. Fas plays a role in the elimination of the non-specific and autoreactive B cells in germinal center, while during the selection of antigen-specific B cells different escape signals ensure the resistance to Fas-mediated apoptosis. Antigen-specific survival such as BCR or MHCII signal or coreceptors (CD19) cooperating with BCR inhibits the formation of death inducing signaling complex. Antigen-specific survival can be reinforced by antigen-independent signals of IL-4 or CD40 overproducing the anti-apoptotic members of the Bcl-2 family proteins.

B cell resistance to Fas-mediated apoptosis contributes to their ineffective control by regulatory T cells in rheumatoid arthritis

“…B cell Fas expression increases upon stimulation, and activated B cells are sensitive to Fas-mediated apoptosis,18 which is in agreement with our analysis of healthy B cells. Conversely, activated RA B cells were less sensitive to Fas-mediated apoptosis.…”

“…Fas is induced in B cells upon activation 18. Following in vitro activation in the presence of responder T cells, Fas was strongly expressed in B cells from healthy donors (figure 4A,B).…”

“…As Fas-mediated apoptosis is critical for the elimination of autoreactive B cells,17 18 we investigated Fas expression on B cells. Fas is induced in B cells upon activation 18.…”

“…Not only was Fas upregulation following activation diminished for RA B cells compared with their healthy counterparts, but the Treg-driven reduction in Fas surface expression was also markedly less. In fact, the level of Fas expressed at the cell surface may influence the sensitivity/resistance to FasL 18 34 35. Sensitivity to Fas-mediated apoptosis has been linked to its level of expression in a murine model of SLE 36.…”

Understanding and measuring human B‐cell tolerance and its breakdown in autoimmune disease

“…28,29 Accordingly, GC-based checkpoints are of critical importance and, in mouse studies, are implemented through multiple mechanisms including the aforementioned mechanism enforced by follicular exclusion (this is not strictly GC-based but prevents GC entry), Fas-mediated apoptosis, 30 FcγRIIB-induced inhibition, 31 receptor revision, 32-34 follicular dendritic cells (FDCs), 35 T regulatory cells (Tregs), 36,37 and T follicular regulatory cells (Tfrs). Moreover, non-autoreactive B-cells can acquire de novo autoreactivity through GC-induced SHM.…”