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* Department of Medicine, Division of Rheumatology and
Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033;
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY 10461; and
¶ Research Division and Division of Rheumatology, Hospital for Special Surgery, Weill Medical College, Cornell University, New York, NY 10021
In otherwise non-autoimmune-prone C57BL/6 (B6) mice rendered genetically deficient in CD152 (CTLA-4), polyclonal hypergammaglobulinemia with increased levels of systemic lupus erythematosus (SLE)-associated IgG autoantibodies, glomerular IgG and C3 deposition, and interstitial nephritis all developed by 3–5 wk of age. Remarkably, superimposing genetic deficiency of BAFF (B cell-activating factor belonging to the TNF family) onto CD152 deficiency did not substantially attenuate humoral autoimmunity and immunopathology in these mice, despite the resulting marked reduction in B-lineage cells. Although superimposing a BAFF transgene (resulting in constitutive BAFF overexpression) onto CD152-deficient mice did lead to increases in B-lineage cells and serum levels of certain SLE-associated IgG autoantibodies, renal immunopathology remained largely unaffected. Taken together, these results demonstrate that global T cell dysregulation, even in an otherwise non-autoimmune-prone host, can promote systemic humoral autoimmunity and immunopathology in a BAFF-independent manner. Moreover, supraphysiologic expression of BAFF in the setting of ongoing autoimmunity does not necessarily lead to greater immunopathology. These findings may help explain the limited clinical efficacy appreciated to date of BAFF antagonists in human SLE.
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 This work was supported in part by National Institutes of Health Grants R01 AR050193 (to W.S.), R01 AI054488 (to M.P.C.), R01 AI073939 (to M.P.C.), R01 AR049765 (to L.P.), R01 AR048692 (to C.P.), and P01 AI051392 (to C.P.), a grant from the Mary Kirkland Center for Lupus Research (to L.P.), a Target Identification in Lupus Award from the Alliance for Lupus Research/Arthritis Foundation (to C.P.), and a Hulda Irene Duggan Arthritis Investigator Award from the Arthritis Foundation (to C.P.).
2 Address correspondence and reprint requests to Dr. William Stohl, Division of Rheumatology, University of Southern California, 2011 Zonal Avenue, HMR 711, Los Angeles, CA 90033. E-mail address: stohl{at}usc.edu
3 Abbreviations used in this paper: BAFF, B cell-activating factor belonging to the TNF family; Tg, transgenic; BTg, BAFF Tg; FO, follicular; GN, glomerulonephritis; MZ, marginal zone; SLE, systemic lupus erythematosus; T1, transitional 1; BM, bone marrow; PC, plasma cell.
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