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Antibody Responses to Mycobacterial and Self Heat Shock Protein 65 in Autoimmune Arthritis: Epitope Specificity and Implication in Pathogenesis¹

Hong Ro Kim^*, Eugene Y. Kim^*, Jan Cerny^2,* and Kamal D. Moudgil^2,3,*,

^* Department of Microbiology and Immunology and Division of Rheumatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201

Many autoimmune diseases are believed to involve primarily T cell-mediated effector mechanisms. There is increasing realization, however, that Abs may also play a vital role in the propagation of T cell-driven disorders. In this study, on the rat adjuvant-induced arthritis (AA) model of human rheumatoid arthritis, we examined the characteristics of serum Ab response to mycobacterial heat shock protein (hsp) 65 (Bhsp65), self (rat) hsp65 (Rhsp65), and linear peptides spanning these two molecules. The AA-resistant WKY (RT.1^l) rat responded to the heat-killed Mycobacterium tuberculosis immunization with a rapid burst of Abs to both Bhsp65 and Rhsp65. These Abs reacted with numerous peptide epitopes; however, this response was reduced to a few epitopes with time. On the contrary, the susceptible Lewis (RT.1^l) rat developed a relatively lower Ab response to Bhsp65, and Abs to Rhsp65 did not appear until the recovery from the disease. The Ab response in Lewis rats diversified with progression of AA, and there was an intriguing overlap between the repertoire of Bhsp65-reactive B and T cells during the recovery phase of AA. Nonetheless, subsets of the repertoire of the late Abs in both rat strains became focused on the same epitope regions of Bhsp65 and Rhsp65. The functional relevance of these Abs was evident from the results showing that sera from recovery phase Lewis or WKY rats, but not that of naive rats, afforded protection against subsequent AA. These results are of significance in further understanding of the role of humoral immunity in the pathogenesis of autoimmune arthritis.

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 (AI47790 and AI059623), the Arthritis Foundation (Atlanta, GA and the Maryland Chapter, Baltimore, MD), and the Maryland Arthritis Research Center (Baltimore, MD).

² J.C. and K.D.M. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Kamal D. Moudgil, Department of Microbiology and Immunology, Howard Hall 323C, University of Maryland School of Medicine, 660 W. Redwood Street, Baltimore, MD 21201. E-mail address: kmoud001{at}umaryland.edu

⁴ Abbreviations used in this paper: MS, multiple sclerosis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; EAE, experimental autoimmune encephalomyelitis; AA, adjuvant arthritis; Mtb, Mycobacterium tuberculosis; hsp, heat shock protein; Bhsp65, mycobacterial hsp 65; BN, Brown Norway; CII, type II collagen; Rhsp65, rat hsp 65; WKY, Wistar Kyoto (WKY/NHsd); KLH, keyhole limpet hemocyanin; Inc, incubation; Ons, onset; Pk, peak; Rec, recovery.