title: The lupus-prone NZM2410/NZW strain-derived Sle1b sublocus alters the germinal center checkpoint in female mice in a B cell-intrinsic manner.
abstract: C57BL/6 (B6) mice carrying the Sle1b sublocus (named B6.Sle1b), which harbors the lupus-associated NZM2410/NZW SLAM family genes, produce antinuclear Abs (ANAs). However, the role and mechanism(s) involved in the alteration of the germinal center (GC) tolerance checkpoint in the development of ANAs in these mice is not defined. In this study, we show significantly higher spontaneously formed GCs (Spt-GCs) in B6.Sle1b female mice compared with B6 controls. We also found a significant increase in CD4(+)CXCR5(hi)PD-1(hi) spontaneously activated follicular Th cells in B6.Sle1b female mice. Compared with B6 controls, B6.Sle1b female mice had increased numbers of proliferating B cells predominantly located in Spt-GCs. The elevated Spt-GCs in B6.Sle1b female mice were strongly associated with increased ANA-specific Ab-forming cells and ANA titers. The increased numbers of Spt-GCs and spontaneously activated follicular Th cells in B6.Sle1b mice were not the result of a generalized defect in B cells expressing Sle1b. Consistent with the elevated spontaneous response in B6.Sle1b mice, the attenuated GC response characteristic of DNA and p-azophenylarsonate reactive B cells from Ig V(H) knock-in mice (termed HKIR) were relieved in adoptively transferred recipients in the presence of Sle1b. Finally, by generating mixed bone marrow chimeras, we showed that the effect of Sle1b on Spt-GC, follicular Th cell, and autoantibody responses in B6.Sle1b mice was B cell autonomous. These data indicate that the NZM2410/NZW-derived Sle1b sublocus in conjunction with the female sex primarily affects B cells, leading to the alteration of the GC tolerance checkpoint and the generation of ANA-specific Ab-forming cells.
authors.affiliation: Department of Microbiology and Immunology, Jefferson Medical College, Philadelphia, PA 19107, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Wong
authors.forename: Tahsin N
authors.initials: TN
authors.lastname: Khan
authors.forename: Chandra
authors.initials: C
authors.lastname: Mohan
authors.forename: Ziaur S M
authors.initials: ZS
authors.lastname: Rahman
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D000918:Antibody Specificity / Q000235:genetics; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D055879:Gene Knock-In Techniques; D056426:Genetic Loci / Q000276:immunology; D020022:Genetic Predisposition to Disease; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D007108:Immune Tolerance / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D011828:Radiation Chimera / Q000276:immunology
chemical_list: D000974:Antibodies, Antinuclear