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

J Autoimmun. 2015 Sep;63:31-46. doi: 10.1016/j.jaut.2015.06.011. Epub 2015 Jul 7.

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.

Keywords: Autoimmunity; B cells; Germinal centers; Inhibitory IgG receptor FcγRIIB; Signaling lymphocyte activation molecules; Systemic lupus erythematosus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • Autoimmunity* / physiology
  • B-Lymphocytes / immunology
  • Germinal Center* / immunology
  • Germinal Center* / metabolism
  • Immune Tolerance
  • Mice
  • Mice, 129 Strain
  • Receptors, Cell Surface / metabolism*
  • Receptors, IgG / deficiency*
  • Receptors, IgG / genetics
  • Signaling Lymphocytic Activation Molecule Family Member 1
  • T-Lymphocytes, Helper-Inducer / immunology

Substances

  • Antigens, CD
  • Fcgr2b protein, mouse
  • Receptors, Cell Surface
  • Receptors, IgG
  • Signaling Lymphocytic Activation Molecule Family Member 1