Dichotomy in FcγRIIB deficiency and autoimmune-prone SLAM haplotype clarifies the roles of the Fc receptor in development of autoantibodies and glomerulonephritis

Abstract

BackgroundThe significance of a unique inhibitory Fc receptor for IgG, FcγRIIB (RIIB), in the prevention of spontaneous production of autoantibodies remains controversial, due mainly to the fact that the RIIB locus is adjacent to the autoimmune-related SLAM locus harboring the genes coding for signaling lymphocyte activation molecules, making it difficult to isolate the effect of RIIB deletion from that of SLAM in gene-targeted mice. Our objective was to determine the influence of RIIB deletion on the spontaneous development of autoimmune diseases and to compare it with that of potentially pathogenic SLAM.ResultsWe established two congenic C57BL/6 (B6) strains, one with the RIIB deletion and the other with SLAM, by backcrossing 129/SvJ-based RIIB-deficient mice into the B6 genetic background extensively. The RIIB deficiency indeed led to the production and/or accumulation of a small amount of anti-nuclear autoantibodies (ANAs) and to weak IgG immune-complex deposition in glomeruli without any obvious manifestation of lupus nephritis. In contrast, pathogenic SLAM in the B6 genetic background induced ANAs but no IgG immune-complex deposition in the kidneys. Naïve SLAM mice but not RIIB-deficient mice exhibited hyperplasia of splenic germinal centers.ConclusionThe present results clarify the roles of RIIB in preventing production and/or accumulation of a small amount of ANAs, and development of glomerulonephritis. The combined effects of RIIB deletion and pathogenic SLAM can lead to severe lupus nephritis in the B6 genetic background.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-014-0047-y) contains supplementary material, which is available to authorized users.

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

“…Consistent with previous reports [18, 19], and the recent report by Kanari et al, [57], we also observe that B6.129.RIIBKO mice develop pathogenic autoAbs and lupus nephritis. In line with the effects of 129-SLAMs and FcγRIIB deficiency on Spt-GC responses, we observe an independent effect of each of them on the accumulation of class-switched autoAbs, further suggesting the generation of autoreactive B cells through the GCs (Fig.…”

“…They have not, however, examined either induced or spontaneous GC B cell and Tfh responses in these mice. Consistent with our observations, a recent study by Takai and co-workers reported enhanced Spt-GC B cell formation in the presence of 129-SLAM genes alone [57]. However, this study did not examine the effect of 129-SLAMs on Tfh formation and functions.…”

“…8). Our observations are strengthened by the studies from Takai and group, where they report a modest but significant increase in the accumulation of class-switched ANAs in mice deficient in FcγRIIB or expressing 129-SLAMs [57]. Consistent with their findings [57] we observe a significant contribution of FcγRIIB and not 129-SLAMs in the regulation of IgG deposition in the kidneys (Fig.…”

Inhibitory B cell co-receptors and autoimmune diseases

“…Initially, FccRIIB -/mice were reported to develop lupus-like disease [32]. Later, development of the disease turned out to require the 129 mouse strain-derived autoimmune-prone SLAM haplotype, which is closely located to the FccRIIB locus on the chromatin, and FccRIIB -/mice on the C57BL/6 background do not develop autoimmune disease [33]. Thus, SHIP1 appears to be activated by a mechanism independent of inhibitory receptors to regulate autoimmune disease.…”

FcγRIIb on B Cells and Myeloid Cells Modulates B Cell Activation and Autoantibody Responses via Different but Synergistic Pathways in Lupus-Prone Yaa Mice

“…The addition of Yaa locus to B6.FcgRIIb 2/2 mice results in the development of lupus nephritis with 30% penetrance at the age of 10-12 mo (13). Thus, the deletion of FcgRIIb, the presence of SLAM haplotype 2, and the Yaa locus all contribute to the development of severe autoimmunity (14,15).…”