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The Lupus Susceptibility Locus Sle1 Breaches Peripheral B Cell Tolerance at the Antibody-Forming Cell and Germinal Center Checkpoints¹

Raja Vuyyuru, Chandra Mohan, Tim Manser, and Ziaur S. M. Rahman^2*

^*Department of Microbiology and Immunology, Jefferson Medical College, Jefferson Alumni Hall, Philadelphia, PA 19107; Department of Microbiology and Immunology, Jefferson Medical College, Bluemle Life Sciences Building, Philadelphia, PA 19107; and Division of Rheumatology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390

We have described a line of V_H knock-in mice termed HKIR in which the transgenic Igh locus partially encodes "dual-reactive" antichromatin and anti-p-azophenylarsonate (Ars) BCRs. HKIR B cells termed canonical, expressing a particular V L chain, evade central tolerance by down-regulating BCR levels. Canonical HKIR B cells can be recruited into the primary germinal center (GC) and Ab-forming cell (AFC) compartments via Ars immunization. However, their participation in the GC response rapidly wanes and they do not efficiently contribute to the memory compartment, indicating that they are regulated by a GC tolerance checkpoint. We analyzed the influence of the Sle1 genetic interval, shown to break tolerance of chromatin-reactive B cells, on the behavior of HKIR B cells during the anti-Ars response. Canonical B cells from congenic HKIR.Sle1 mice gave rise to elevated short and long-lived AFC responses, and the attenuated GC and memory responses characteristic of these B cells were relieved in adoptive, wild-type recipients. HKIR GC B cells containing Sle1 expressed increased levels of Bcl-2 and c-FLIP and decreased levels of Fas RNA compared with HKIR controls, suggesting direct alteration of the regulation of the GC response by Sle1. High titers of canonical and anti-dsDNA Abs spontaneously developed in many aged HKIR.Sle1 mice. Together, these data indicate that Sle1 perturbs the action of peripheral tolerance checkpoints operative on antinuclear Ag B cells in both the AFC and GC pathways in a cell autonomous fashion.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These studies were supported by grants from the National Institutes of Health to T.M. (AI038965) and Z.S.M.R. (AR055701) and to Z.S.M.R. from the Arthritis National Research Foundation.

² Address correspondence and reprint requests to Dr. Ziaur Rahman, Department of Microbiology and Immunology, Jefferson Medical College, Jefferson Alumni Hall, Room 461, 1020 Locust Street, Philadelphia, PA 19107-5541. E-mail address: zrahman{at}mail.jci.tju.edu

³ Abbreviations used in this paper: GC, germinal center; AFC, Ab-forming cell; IC, immune complex; FO, follicular; MZ, marginal zone; MOMA-1, metallophillic macrophage 1; Ars, p-azophenylarsonate; KLH, keyhole limpet hemocyanin; PNA, peanut lectin (agglutinin); RQ, relative quantification; TD, thymus dependent; ANA, antinuclear autoantibody; SA, streptavidin; BM, bone marrow; SRBC, sheep RBC; NP, 4-hydroxy-3-nitrophenyl acetyl; CGG, chicken -globulin; Tg, transgene.