B Cell–Intrinsic CD84 and Ly108 Maintain Germinal Center B Cell Tolerance

Abstract

Signaling lymphocyte activation molecules (SLAMs) play an integral role in immune regulation. Polymorphisms in the SLAM family receptors are implicated in human and mouse model of lupus disease. The lupus-associated, somatically mutated and class-switched pathogenic autoantibodies are generated in spontaneously developed germinal centers (Spt-GCs) in secondary lymphoid organs. The role and mechanism of B cell-intrinsic expression of polymorphic SLAM receptors that affect B cell tolerance at the GC checkpoint is not clear. Here, we generated several bacterial artificial chromosome (BAC) transgenic mice that overexpress B6 alleles of different SLAM family genes in autoimmune-prone B6.Sle1b mice. B6.Sle1b mice overexpressing B6-derived Ly108 and CD84 exhibit a significant reduction in the Spt-GC response and autoantibody production compared to B6.Sle1b mice. These data suggest a prominent role of Sle1b-derived Ly108 and CD84 in altering the GC checkpoint. We further confirm that expression of lupus-associated CD84 and Ly108 specifically on GC B cells in B6.Sle1b mice is sufficient to break B cell tolerance leading to an increase in autoantibody production. In addition, we observe that B6.Sle1b B cells have reduced BCR signaling, and a lower frequency of B cell-T cell conjugates, which are reversed in B6.Sle1b mice overexpressing B6 alleles of CD84 and Ly108. Finally, we find a significant decrease in apoptotic GC B cells in B6.Sle1b mice compared to B6 controls. Our study establishes the central role of GC B cell-specific CD84 and Ly108 expression in maintaining B cell tolerance in GCs and in preventing autoimmunity.

Distinct and synergistic roles of FcγRIIB deficiency and 129 strain-derived SLAM family proteins in the development of spontaneous germinal centers and autoimmunity

“…1A). This is consistent with our recent report showing that the NZW-derived polymorphic SLAM family genes CD84 and Ly108 in the Sle1b sub-locus alter GC B cell tolerance [45]. Other genes downstream of the SLAM locus, including Ifi202b and Ifi204 , have previously been shown not to affect B cell tolerance and autoAb production [56].…”

“…Increased B cell survival within the GCs can lead to an accumulation of GC B cells [45]. We used an ex vivo assay to evaluate the percentage of B cells undergoing apoptosis within the GCs.…”

IL-10 from marginal zone precursor B cells controls the differentiation of Th17, Tfh and Tfr cells in transplantation tolerance

“…Tfh cells in the GC maximize the antigen-specific help to B cells through CD40L. Deficiency or blocking the CD40-CD40L interaction inhibits the GC reaction and helps in the maintenance of tolerance [22,48]. Treatment with anti-CD40 antibody significantly reduces GC frequency and size in rhesus macaques and prevents antibody-mediated allograft rejection [22].…”

The BANK1 SLE-risk variants are associated with alterations in peripheral B cell signaling and development in humans

“…As B cells start to accumulate in at-risk subjects, other genetic and environmental factors could act as additional triggers resulting in a shift towards BCR hyper-responsiveness, due in part to loss of negative regulation of BCR signaling via decreased FCγRIIB and Lyn expression [49, 50]. While hyper-responsive BCR signaling can promote SLE by increasing the degree of positive selection in the GC [51], there are examples where genetic alterations that limit GC B cell signaling lead to increased autoreactive B cell differentiation [52]. Decreases in B cell signaling could promote autoreactive populations by limiting negative selection of self-reactive antigens in the periphery and it is possible that the BANK1 risk haplotype might impact this process through decreased BCR, CD40 and TLR signaling [19, 20], in addition to its role in memory B cell expansion.…”