title: 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.
authors.affiliation: Microbiology and Immunology, Pennsylvania State University College of Medicine, USA.
authors.forename: Chetna
authors.initials: C
authors.lastname: Soni
authors.affiliation: Microbiology and Immunology, Pennsylvania State University College of Medicine, USA.
authors.forename: Phillip P
authors.initials: PP
authors.lastname: Domeier
authors.affiliation: Microbiology and Immunology, Pennsylvania State University College of Medicine, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Wong
authors.affiliation: Microbiology and Immunology, Pennsylvania State University College of Medicine, USA.
authors.lastname: Shwetank
authors.affiliation: Microbiology and Immunology, Pennsylvania State University College of Medicine, USA.
authors.forename: Tahsin N
authors.initials: TN
authors.lastname: Khan
authors.affiliation: Microbiology and Immunology, Pennsylvania State University College of Medicine, USA.
authors.forename: Melinda J
authors.initials: MJ
authors.lastname: Elias
authors.affiliation: Microbiology and Immunology, Pennsylvania State University College of Medicine, USA.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Schell
authors.affiliation: Microbiology and Immunology, Pennsylvania State University College of Medicine, USA.
authors.forename: Aron E
authors.initials: AE
authors.lastname: Lukacher
authors.affiliation: Departments of Comparative Medicine and Pathology, Pennsylvania State University College of Medicine, USA.
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Cooper
authors.affiliation: Microbiology and Immunology, Pennsylvania State University College of Medicine, USA. Electronic address: zrahman@hmc.psu.edu.
authors.forename: Ziaur S M
authors.initials: ZS
authors.lastname: Rahman
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015551:Autoimmunity / Q000502:physiology; D001402:B-Lymphocytes / Q000276:immunology; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance; D051379:Mice; D057507:Mice, 129 Strain; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017452:Receptors, IgG / Q000172:deficiency* / Q000235:genetics; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
chemical_list: D015703:Antigens, CD; C499172:Fcgr2b protein, mouse; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1
keywords: Autoimmunity; B cells; Germinal centers; Inhibitory IgG receptor FcγRIIB; Signaling lymphocyte activation molecules; Systemic lupus erythematosus