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and Chemokines by Autoantibodies in the Cerebrospinal Fluid of Patients with Neuropsychiatric Lupus1
* Department of Immunology, University of Washington, Seattle, WA 98195;
Division of Rheumatology and Clinical Immunology, School of Medicine, Jichi Medical University, Tochigi-ken, Japan; and
Department of Neurology and
Division of Rheumatology, University of Washington, Seattle, WA 98195
Neuropsychiatric disease in systemic lupus erythematosus (NPSLE) is a poorly understood, but potentially fatal, disease manifestation. A pathogenetic role for autoantibodies is suspected, but the mechanism is unclear. Since immune complexes in SLE can stimulate IFN-
and there is strong evidence in humans and in mice that IFN- can cause neuropsychiatric manifestations, we asked whether NPSLE patient serum and/or cerebrospinal fluid (CSF) contain abnormally high IFN--inducing activity. In a bioassay containing plasmacytoid dendritic cells and a source of Ag, NPSLE CSF induced significantly higher IFN- compared with CSF from patients with multiple sclerosis or other autoimmune disease controls. When normalized for IgG concentration, NPSLE CSF was 800-fold more potent at inducing IFN- compared with paired serum due to inhibitors present in serum. Analysis of Ig-deficient patient serum, depletion of IgG from normal serum, as well as addition of purified IgG to NPSLE CSF and serum in the bioassays revealed that one inhibitor was contained within the IgG fraction itself. In addition to IFN-, immune complexes formed by CSF autoantibodies produced significantly increased levels of IFN-
-inducible protein 10 (IP-10/CXCL), IL-8, and MCP-1, all of which have been reported to be elevated in CSF from NPSLE patients. Taken together, these findings are consistent with a two-step model of NPSLE whereby CSF autoantibodies bind to Ags released by neurocytotoxic Abs or other brain cell injury, and the resulting immune complexes stimulate IFN- and proinflammatory cytokines and chemokines.
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 by grants from the National Institutes of Health (National Institute of Arthritis and Musculoskeletal and Skin Diseases; AR48796 and AR054980), the Lupus Research Institute, and the Dana Foundation. D.M.S. is supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) postgraduate scholarship.
2 Address correspondence and reprint requests to Dr. Keith B. Elkon, Division of Rheumatology, University of Washington, 1959 NE Pacific Street, Box 356428, Seattle, WA 98195. E-mail address: elkon{at}u.washington.edu
3 Abbreviations used in this paper: NPSLE, neuropsychiatric systemic lupus erythematosus; NMDAR, N-methyl-D-aspartate receptor; anti-P, anti-ribosomal P protein Abs; CSF, cerebrospinal fluid; pDC, plasmacytoid dendritic cell; IFG, interferogenic; IP-10, IFN--inducible protein 10; OAID, other autoimmune disease; MS, multiple sclerosis; CVID, common variable immune deficiency; XLA, X-linked agammaglobulinemia; RNP, ribonucleoprotein; NE, nuclear extract; BDCA-2, blood DC Ag-2; SLEDAI, systemic lupus erythematosus disease activity index; IVIG, intravenous immunoglobulin; IM, inflammatory mediators.
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