NDLI: The lupus-prone NZM2410/NZW strain-derived Sle1b sublocus alters the germinal center checkpoint in female mice in a B cell-intrinsic manner.

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The lupus-prone NZM2410/NZW strain-derived Sle1b sublocus alters the germinal center checkpoint in female mice in a B cell-intrinsic manner.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Mohan, Chandra Khan, Tahsin N. Wong, Eric B. Rahman, Ziaur S. M.
Description	Country affiliation: United States Author Affiliation: Wong EB ( Department of Microbiology and Immunology, Jefferson Medical College, Philadelphia, PA 19107, USA.)
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.
ISSN	00221767
e-ISSN	15506606
DOI	10.4049/jimmunol.1201661
Journal	The Journal of Immunology
Issue Number	12
Volume Number	189
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2012-12-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	B-lymphocyte Subsets Immunology Pathology Genetic Predisposition To Disease Germinal Center Lupus Erythematosus, Systemic Genetics Animals Antibodies, Antinuclear Biosynthesis Antibody Specificity Metabolism Gene Knock-in Techniques Genetic Loci Immune Tolerance Mice Mice, 129 Strain Mice, Inbred C57bl Mice, Inbred Nzb Mice, Knockout Radiation Chimera Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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