title: B cell-intrinsic CD84 and Ly108 maintain germinal center B cell tolerance.
abstract: Signaling lymphocyte activation molecules (SLAMs) play an integral role in immune regulation. Polymorphisms in the SLAM family receptors are implicated in human and mouse model of lupus disease. The lupus-associated, somatically mutated, and class-switched pathogenic autoantibodies are generated in spontaneously developed germinal centers (GCs) in secondary lymphoid organs. The role and mechanism of B cell-intrinsic expression of polymorphic SLAM receptors that affect B cell tolerance at the GC checkpoint are not clear. In this study, we generated several bacterial artificial chromosome-transgenic mice that overexpress C57BL/6 (B6) alleles of different SLAM family genes on an autoimmune-prone B6.Sle1b background. B6.Sle1b mice overexpressing B6-derived Ly108 and CD84 exhibit a significant reduction in the spontaneously developed GC response and autoantibody production compared with B6.Sle1b mice. These data suggest a prominent role for Sle1b-derived Ly108 and CD84 in altering the GC checkpoint. We further confirm that expression of lupus-associated CD84 and Ly108 specifically on GC B cells in B6.Sle1b mice is sufficient to break B cell tolerance, leading to an increase in autoantibody production. In addition, we observe that B6.Sle1b B cells have reduced BCR signaling and a lower frequency of B cell-T cell conjugates; the reverse is seen in B6.Sle1b mice overexpressing B6 alleles of CD84 and Ly108. Finally, we find a significant decrease in apoptotic GC B cells in B6.Sle1b mice compared with B6 controls. Our study establishes a central role for GC B cell-specific CD84 and Ly108 expression in maintaining B cell tolerance in GCs and in preventing autoimmunity.
authors: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033;
authors: Eric B
authors: EB
authors: Wong
authors: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033;
authors: Chetna
authors: C
authors: Soni
authors: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and.
authors: Alice Y
authors: AY
authors: Chan
authors: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033;
authors: Phillip P
authors: PP
authors: Domeier
authors: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033;
authors: Shwetank
authors: Department of Research Resources, Pennsylvania State University College of Medicine, Hershey, PA 17033.
authors: Thomas
authors: T
authors: Abraham
authors: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and.
authors: Nisha
authors: N
authors: Limaye
authors: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033;
authors: Tahsin N
authors: TN
authors: Khan
authors: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033;
authors: Melinda J
authors: MJ
authors: Elias
authors: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033;
authors: Sathi Babu
authors: SB
authors: Chodisetti
authors: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and.
authors: Edward K
authors: EK
authors: Wakeland
authors: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033; zrahman@hmc.psu.edu.
authors: Ziaur S M
authors: ZS
authors: Rahman
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D005260:Female; D018858:Germinal Center / Q000166:cytology / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D000071176:Signaling Lymphocytic Activation Molecule Family
chemical_list: D015703:Antigens, CD; D000950:Antigens, Ly; C498971:Cd84 protein, mouse; D000071176:Signaling Lymphocytic Activation Molecule Family