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

Abstract

The inhibitory IgG Fc receptor (FcγRIIB) deficiency and 129 strain-derived signaling lymphocyte activation molecules (129-SLAMs) are proposed to contribute to the lupus phenotype in FcγRIIB-deficient mice generated using 129 ES cells and backcrossed to C57BL/6 mice (B6.129.RIIBKO). In this study, we examine the individual contributions and the cellular mechanisms by which FcγRIIB deficiency and 129-derived SLAM family genes promote dysregulated spontaneous germinal center (Spt-GC) B cell and follicular helper T cell (Tfh) responses in B6.129.RIIBKO mice. We find that B6 mice congenic for the 129-derived SLAM locus (B6.129-SLAM) and B6 mice deficient in FcγRIIB (B6. RIIBKO) have increased Spt-GC B cell responses compared to B6 controls but significantly lower than B6.129.RIIBKO mice. These data indicate that both FcγRIIB deficiency and 129-SLAMs contribute to elevated Spt-GC B cell responses in B6.129.RIIBKO mice. However, only 129-SLAMs contribute significantly to augmented Tfh responses in B6.129.RIIBKO mice, and do so by a combination of T cell-dependent effects and enhanced B cell and DC-dependent antigen presentation to T cells. Elevated Spt-GC B cell responses in mice with FcγRIIB deficiency and polymorphic 129-SLAMs were associated with elevated metabolic activity, improved GC B cell survival and increased differentiation of naïve B cells into GC B cell phenotype. Our data suggest that the interplay between 129-SLAM expression on B cells, T cells and DCs is central to the alteration of the GC tolerance checkpoint, and that deficiency of FcγRIIB on B cells is necessary to augment Spt-GC responses, pathogenic autoantibodies, and lupus disease.

Altered B cell signalling in autoimmunity

“…Both knock-in strains exhibited enhanced BCR and TCR signalling, spontaneous GC formation and an age-related expansion of effector memory T cells. However, systemic autoimmunity was only observed in mice that had a mixed C57BL/6J×129/Sv background, which potentially reflects the influence of signalling lymphocyte activation molecule (SLAM) family polymorphisms derived from the 129 background on autoimmune GC responses 101,102 .…”

Spontaneous germinal centers and autoimmunity

“…Recently, with more sensitive techniques and methods for detecting GCs, several labs have discovered that GCs can spontaneously develop (named Spt-GCs) in the absence of overt immunization or detectable adventitious infection (18, 24-28). Spt-GCs are detected in both non-autoimmune and autoimmune strains of mice, but the size and frequency of Spt-GCs are augmented in autoimmune-prone mice, leading to the development of class-switched pathogenic antibodies that drive antibody-mediated autoimmune disease (18, 24, 25, 27, 28).…”

“…Spt-GCs are detected in both non-autoimmune and autoimmune strains of mice, but the size and frequency of Spt-GCs are augmented in autoimmune-prone mice, leading to the development of class-switched pathogenic antibodies that drive antibody-mediated autoimmune disease (18, 24, 25, 27, 28). Spt-GCs are reported in several autoimmune diseases in both humans and animal models.…”

“…Although several Fc receptors are found on the surface of immune cells in humans and mice, most of these receptors are found on the surface of myeloid cells and few are found on the surface of lymphocytes (213, 214). As these receptors can be both activating and inhibitory, several studies have linked human susceptibility to autoimmune disease with dysregulated activity of Fcg receptors (28, 213-217). Correspondingly, several FcγRs have been the focus of novel targeted therapeutics for the treatment of autoimmune diseases (214).…”

“…FcγRIIb is a low-affinity inhibitory Fc receptor that is found on the surface of B cells that negatively regulates signaling through the B cell receptor (28, 218). In humans, two different mutations in the transmembrane region of FcgRIIb are correlated with susceptibility to SLE (217, 219-224).…”