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-Actinin Immunization Elicits Anti-Chromatin Autoimmunity in Nonautoimmune Mice¹

Bisram Deocharan^*, Zhijie Zhou, Kochnaf Antar, Linda Siconolfi-Baez, Ruth Hogue Angeletti, John Hardin^*, and Chaim Putterman^2,*,

^* Department of Microbiology & Immunology, Laboratory for Macromolecular Analysis & Proteomics, and Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY 10461

Anti-dsDNA Abs are characteristic of lupus and can be found deposited in the kidneys of lupus mice. Previously, we have shown that pathogenic anti-dsDNA Abs as well as Ig eluted from the kidneys of nephritic lupus mice cross-react with -actinin. Moreover, cross-reactivity with -actinin characterizes nephritogenic anti-dsDNA Abs in humans with lupus as well. To determine whether Abs generated against -actinin in vivo cross-react with nuclear Ags, we s.c. immunized 10-wk-old female BALB/c mice (and several other nonautoimmune mice strains) with -actinin in adjuvant. Immunized but not control mice displayed high titers of anti-nuclear Abs and IgG anti-chromatin autoantibodies, hypergammaglobulinemia, renal Ig deposition, and proteinuria. The specificity of the anti-chromatin response was determined by Western blotting of purified chromatin with serum from -actinin immunized mice. By proteomic analysis, a 25-kDa doublet band was conclusively identified as high mobility group box (HMGB) proteins 1 and 3, and a 70-kDa band was identified as heat shock protein 70 (hsp70), both of which are known antigenic targets in murine lupus. Binding to purified HMGB1 and hsp70 by immunized mice sera was confirmed by ELISA and Western blot. Immunized mice sera binding to both 25- and 70-kDa bands were significantly inhibited by -actinin and chromatin. Importantly, a panel of nephritogenic mAbs had significantly higher affinity for -actinin, chromatin, HMGB, and hsp70 as compared with nonpathogenic Abs, suggesting a common motif in these Ags that is targeted by pathogenic autoantibodies.

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 RO1-AR-48692 and PO1-AI-51392 from the National Institutes of Health (to Dr. Putterman’s laboratory). B.D. is the recipient of a Predoctoral Training grant from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Chaim Putterman, Division of Rheumatology, Forchheimer 701N, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. E-mail address: putterma{at}aecom.yu.edu

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; ANA, anti-nuclear Ab; IGF, insulin-like growth factor; MS, mass spectrometry; hsp, heat shock protein; NZW, New Zealand White; NZB, New Zealand Black.