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The T Cells Specific for the Carboxyl-Terminal Determinants of Self (Rat) Heat-Shock Protein 65 Escape Tolerance Induction and Are Involved in Regulation of Autoimmune Arthritis¹

Malarvizhi Durai^*, Radhey S. Gupta and Kamal D. Moudgil^2,*

^* Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201; and Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada

Immunization of Lewis rats with heat-killed Mycobacterium tuberculosis H37Ra leads to development of polyarthritis (adjuvant-induced arthritis; AA) that shares several features with human rheumatoid arthritis (RA). Immune response to the 65-kDa mycobacterial heat-shock protein (Bhsp65) is believed to be involved in induction of AA as well as in experimental modulation of this disease. However, the understanding of several critical aspects of the pathogenesis of AA in the Lewis rat has severely been hampered by the lack of information both regarding the level as well as epitope specificity of tolerance to the mammalian self (rat) homologue of Bhsp65, 65-kDa rat heat-shock protein (Rhsp65), and about the functional attributes of the T cell repertoire specific for this self protein. In this study, we established that tolerance to Rhsp65 in the Lewis rat is incomplete, and that the residual T cells primed upon challenge with this self hsp65 are disease regulating in nature. We also have defined the T cell epitopes in the C-terminal region within Rhsp65 that contribute predominantly to the immune reactivity as well as the AA-protective effect of this self protein. Furthermore, the T cells primed by peptides comprising these C-terminal determinants can be efficiently restimulated by the naturally generated epitopes from endogenous Rhsp65, suggesting that self hsp65 might also be involved in natural remission from acute AA. These novel first experimental insights into the self hsp65-directed regulatory T cell repertoire in AA would help develop better immunotherapeutic approaches for autoimmune arthritis.

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				H. R. Kim, E. Y. Kim, J. Cerny, and K. D. Moudgil Antibody Responses to Mycobacterial and Self Heat Shock Protein 65 in Autoimmune Arthritis: Epitope Specificity and Implication in Pathogenesis J. Immunol., November 15, 2006; 177(10): 6634 - 6641. [Abstract] [Full Text] [PDF]

				Md. Y. Mia, M. Durai, H. R. Kim, and K. D. Moudgil Heat Shock Protein 65-Reactive T Cells Are Involved in the Pathogenesis of Non-Antigenic Dimethyl Dioctadecyl Ammonium Bromide-Induced Arthritis J. Immunol., July 1, 2005; 175(1): 219 - 227. [Abstract] [Full Text] [PDF]

				M. Durai, H. R. Kim, and K. D. Moudgil The Regulatory C-Terminal Determinants within Mycobacterial Heat Shock Protein 65 Are Cryptic and Cross-Reactive with the Dominant Self Homologs: Implications for the Pathogenesis of Autoimmune Arthritis J. Immunol., July 1, 2004; 173(1): 181 - 188. [Abstract] [Full Text] [PDF]