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

• Published in: Journal of autoimmunity 2015-09, Vol.63, p.31-46
• Main Authors: Soni, Chetna, Domeier, Phillip P, Wong, Eric B, Shwetank, Khan, Tahsin N, Elias, Melinda J, Schell, Stephanie L, Lukacher, Aron E, Cooper, Timothy K, Rahman, Ziaur S.M
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Animals; Antigens, CD - metabolism; Autoimmunity; Autoimmunity - physiology; B cells; B-Lymphocytes - immunology; Germinal Center - immunology; Germinal Center - metabolism; Germinal centers; Immune Tolerance; Inhibitory IgG receptor FcγRIIB; Mice; Mice, 129 Strain; Receptors, Cell Surface - metabolism; Receptors, IgG - deficiency; Receptors, IgG - genetics; Signaling lymphocyte activation molecules; Signaling Lymphocytic Activation Molecule Family Member 1; Systemic lupus erythematosus; T-Lymphocytes, Helper-Inducer - immunology
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2015.06.011

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.