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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 Arthritis¹

Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201

The 65-kDa mycobacterial heat shock protein (Bhsp65) has been invoked in the pathogenesis of both adjuvant arthritis (AA) in the Lewis rat (RT.1^l) and human rheumatoid arthritis. Arthritic Lewis rats in the late phase of AA show diversification of the T cell response to Bhsp65 C-terminal determinants (BCTD), and pretreatment of naive Lewis rats with a mixture of peptides representing these neoepitopes affords protection against AA. However, the fine specificity and physiologic significance of the BCTD-directed T cell repertoire, and the role of homologous self (rat) hsp65 (Rhsp65), if any, in spreading of the T cell response to Bhsp65 have not yet been examined. We observed that T cells primed by peptides comprising BCTD can adoptively transfer protection against AA to the recipient Lewis rats. However, these T cells can be activated by preprocessed (peptide) form of BCTD, but not native Bhsp65, showing that BCTD are cryptic epitopes. The BCTD-reactive T cells can be activated by the naturally generated (dominant) C-terminal epitopes of both exogenous and endogenous Rhsp65 and vice versa. Furthermore, certain individual peptides constituting BCTD and their self homologs can also induce protection against AA. These results support a model for the diversification of T cell response to Bhsp65 during the course of AA involving up-regulation of the display of cryptic BCTD coupled with spontaneous induction of T cell response to the cross-reactive dominant C-terminal epitopes of Rhsp65. The identification of disease-regulating cryptic determinants in Ags implicated in arthritis provides a novel approach for immunotherapy of rheumatoid 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]

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