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Diversification of T cell responses to carboxy-terminal determinants within the 65-kD heat-shock protein is involved in regulation of autoimmune arthritis.

Moudgil KD, Chang TT, Eradat H, Chen AM, Gupta RS, Brahn E, Sercarz EE - J. Exp. Med. (1997)

Bottom Line: We have defined the specificity of the proliferative T cell responses to Bhsp65 during the course of AA in the Lewis rat.These results suggest that the observed diversification is possibly triggered in vivo by induction of self(Rhsp65)-reactive T cells.Interestingly, another strain of rat, the Wistar Kyoto (WKY/NHsd) rat (RT-1(l)), with the same major histocompatibility complex class II molecules as the Lewis rat, was found to be resistant to AA.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90095, USA.

ABSTRACT
The T cell response to the 65-kD mycobacterial heat-shock protein (Bhsp65) has been implicated in the pathogenesis of autoimmune arthritis. Adjuvant arthritis (AA) induced in the Lewis rat (RT-1(l)) by injection of Mycobacterium tuberculosis serves as an experimental model for human rheumatoid arthritis (RA). However, the immunological basis of regulation of acute AA, or of susceptibility/resistance to AA is not known. We have defined the specificity of the proliferative T cell responses to Bhsp65 during the course of AA in the Lewis rat. During the early phase of the disease (6-9 d after onset of AA), Lewis rats raised T cell responses to many determinants within Bhsp65, spread throughout the molecule. Importantly, in the late phase of the disease (8-10 wk after onset of AA), there was evidence for diversification of the T cell responses toward Bhsp65 carboxy-terminal determinants (BCTD) (namely, 417-431, 441-455, 465-479, 513-527, and 521-535). Moreover, arthritic rats in the late phase of AA also raised vigorous T cell responses to those carboxy-terminal determinants within self(rat) hsp65 (Rhsp65) that correspond in position to the above BCTD. These results suggest that the observed diversification is possibly triggered in vivo by induction of self(Rhsp65)-reactive T cells. Interestingly, another strain of rat, the Wistar Kyoto (WKY/NHsd) rat (RT-1(l)), with the same major histocompatibility complex class II molecules as the Lewis rat, was found to be resistant to AA. In WKY rats, vigorous responses to the BCTD, to which the Lewis rat responded only in the late phase of AA, were observed very early, 10 d after injection of M. tuberculosis, Strikingly, pretreatment with the peptides comprising the set of BCTD, but not its amino-terminal determinants, provided significant protection to naive Lewis rats from subsequent induction of AA. Thus, T cell responses to the BCTD are involved in regulating inflammatory arthritis in the Lewis rat and in conferring resistance to AA in the WKY rat. These results have important implications in understanding the pathogenesis of RA and in devising new immunotherapeutic strategies for this disease.

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Response of AA-resistant Wistar Kyoto (WKY) rats to  Bhsp65 peptides after injection of M. tuberculosis. Rats were immunized  with M. tuberculosis subcutaneously and after 10 d, the draining LNC from  four rats were pooled and tested in a proliferation assay as described in  Fig. 1. The results are expressed as cpm. The T cell responses to the  unique carboxy-terminal determinants of Bhsp65 (to which arthritic Lewis  rats respond only in the late phase of AA; shown in Fig. 1 B) are indicated  by arrows. Although the highest proliferative responses correspond to the  peptides marked by arrows, comparable or even higher responses also  were raised to the adjacent overlapping peptides; namely, 417–431, 441– 455, 465–479, 513–527, and 521–535 in repeat experiments (data not  shown). Responses to the BCTD were observed in repeat experiments in  WKY rats tested 10–13 d after M. tuberculosis injection (data not shown).
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Figure 3: Response of AA-resistant Wistar Kyoto (WKY) rats to Bhsp65 peptides after injection of M. tuberculosis. Rats were immunized with M. tuberculosis subcutaneously and after 10 d, the draining LNC from four rats were pooled and tested in a proliferation assay as described in Fig. 1. The results are expressed as cpm. The T cell responses to the unique carboxy-terminal determinants of Bhsp65 (to which arthritic Lewis rats respond only in the late phase of AA; shown in Fig. 1 B) are indicated by arrows. Although the highest proliferative responses correspond to the peptides marked by arrows, comparable or even higher responses also were raised to the adjacent overlapping peptides; namely, 417–431, 441– 455, 465–479, 513–527, and 521–535 in repeat experiments (data not shown). Responses to the BCTD were observed in repeat experiments in WKY rats tested 10–13 d after M. tuberculosis injection (data not shown).

Mentions: The results given in Fig. 3 clearly demonstrate that 10 d after immunization with M. tuberculosis, WKY rats raised T cell responses to several determinants within Bhsp65. Interestingly, unlike Lewis rats in the early phase of AA (see Fig. 1 A), WKY rats could raise significant T cell responses to the BCTD; Lewis rats raised T cell responses to the BCTD only in the late phase of AA (see Fig. 1 B). Although the highest proliferative responses to Bhsp65 peptides in the carboxy-terminal region correspond to peptides 421– 435, 445–459, 469–483, 517–531, and 525–539, WKY rats also raised significant responses to the overlapping peptides immediately preceding these peptides in the pepscan, namely, 417–431, 441–455, 465–479, 513–527, and 521–535 (Fig. 3). In repeat experiments, the proliferative responses to the adjacent overlapping peptides comprising each of these five pairs of peptides either was comparable or the pattern was reversed compared with the above pattern (data not shown). Importantly, WKY rats were not deficient in raising responses to peptide 177–191, which contains the minimal arthritogenic determinant, 180–188, described for Lewis rats (4), and is cross-reactive with it. These results suggest that despite reactivity to a known (established) arthritogenic determinant within Bhsp65, efficient T cell responses to carboxy-terminal determinants of the same protein were successful in affording protection to WKY rats from development of AA.


Diversification of T cell responses to carboxy-terminal determinants within the 65-kD heat-shock protein is involved in regulation of autoimmune arthritis.

Moudgil KD, Chang TT, Eradat H, Chen AM, Gupta RS, Brahn E, Sercarz EE - J. Exp. Med. (1997)

Response of AA-resistant Wistar Kyoto (WKY) rats to  Bhsp65 peptides after injection of M. tuberculosis. Rats were immunized  with M. tuberculosis subcutaneously and after 10 d, the draining LNC from  four rats were pooled and tested in a proliferation assay as described in  Fig. 1. The results are expressed as cpm. The T cell responses to the  unique carboxy-terminal determinants of Bhsp65 (to which arthritic Lewis  rats respond only in the late phase of AA; shown in Fig. 1 B) are indicated  by arrows. Although the highest proliferative responses correspond to the  peptides marked by arrows, comparable or even higher responses also  were raised to the adjacent overlapping peptides; namely, 417–431, 441– 455, 465–479, 513–527, and 521–535 in repeat experiments (data not  shown). Responses to the BCTD were observed in repeat experiments in  WKY rats tested 10–13 d after M. tuberculosis injection (data not shown).
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Related In: Results  -  Collection

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Figure 3: Response of AA-resistant Wistar Kyoto (WKY) rats to Bhsp65 peptides after injection of M. tuberculosis. Rats were immunized with M. tuberculosis subcutaneously and after 10 d, the draining LNC from four rats were pooled and tested in a proliferation assay as described in Fig. 1. The results are expressed as cpm. The T cell responses to the unique carboxy-terminal determinants of Bhsp65 (to which arthritic Lewis rats respond only in the late phase of AA; shown in Fig. 1 B) are indicated by arrows. Although the highest proliferative responses correspond to the peptides marked by arrows, comparable or even higher responses also were raised to the adjacent overlapping peptides; namely, 417–431, 441– 455, 465–479, 513–527, and 521–535 in repeat experiments (data not shown). Responses to the BCTD were observed in repeat experiments in WKY rats tested 10–13 d after M. tuberculosis injection (data not shown).
Mentions: The results given in Fig. 3 clearly demonstrate that 10 d after immunization with M. tuberculosis, WKY rats raised T cell responses to several determinants within Bhsp65. Interestingly, unlike Lewis rats in the early phase of AA (see Fig. 1 A), WKY rats could raise significant T cell responses to the BCTD; Lewis rats raised T cell responses to the BCTD only in the late phase of AA (see Fig. 1 B). Although the highest proliferative responses to Bhsp65 peptides in the carboxy-terminal region correspond to peptides 421– 435, 445–459, 469–483, 517–531, and 525–539, WKY rats also raised significant responses to the overlapping peptides immediately preceding these peptides in the pepscan, namely, 417–431, 441–455, 465–479, 513–527, and 521–535 (Fig. 3). In repeat experiments, the proliferative responses to the adjacent overlapping peptides comprising each of these five pairs of peptides either was comparable or the pattern was reversed compared with the above pattern (data not shown). Importantly, WKY rats were not deficient in raising responses to peptide 177–191, which contains the minimal arthritogenic determinant, 180–188, described for Lewis rats (4), and is cross-reactive with it. These results suggest that despite reactivity to a known (established) arthritogenic determinant within Bhsp65, efficient T cell responses to carboxy-terminal determinants of the same protein were successful in affording protection to WKY rats from development of AA.

Bottom Line: We have defined the specificity of the proliferative T cell responses to Bhsp65 during the course of AA in the Lewis rat.These results suggest that the observed diversification is possibly triggered in vivo by induction of self(Rhsp65)-reactive T cells.Interestingly, another strain of rat, the Wistar Kyoto (WKY/NHsd) rat (RT-1(l)), with the same major histocompatibility complex class II molecules as the Lewis rat, was found to be resistant to AA.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90095, USA.

ABSTRACT
The T cell response to the 65-kD mycobacterial heat-shock protein (Bhsp65) has been implicated in the pathogenesis of autoimmune arthritis. Adjuvant arthritis (AA) induced in the Lewis rat (RT-1(l)) by injection of Mycobacterium tuberculosis serves as an experimental model for human rheumatoid arthritis (RA). However, the immunological basis of regulation of acute AA, or of susceptibility/resistance to AA is not known. We have defined the specificity of the proliferative T cell responses to Bhsp65 during the course of AA in the Lewis rat. During the early phase of the disease (6-9 d after onset of AA), Lewis rats raised T cell responses to many determinants within Bhsp65, spread throughout the molecule. Importantly, in the late phase of the disease (8-10 wk after onset of AA), there was evidence for diversification of the T cell responses toward Bhsp65 carboxy-terminal determinants (BCTD) (namely, 417-431, 441-455, 465-479, 513-527, and 521-535). Moreover, arthritic rats in the late phase of AA also raised vigorous T cell responses to those carboxy-terminal determinants within self(rat) hsp65 (Rhsp65) that correspond in position to the above BCTD. These results suggest that the observed diversification is possibly triggered in vivo by induction of self(Rhsp65)-reactive T cells. Interestingly, another strain of rat, the Wistar Kyoto (WKY/NHsd) rat (RT-1(l)), with the same major histocompatibility complex class II molecules as the Lewis rat, was found to be resistant to AA. In WKY rats, vigorous responses to the BCTD, to which the Lewis rat responded only in the late phase of AA, were observed very early, 10 d after injection of M. tuberculosis, Strikingly, pretreatment with the peptides comprising the set of BCTD, but not its amino-terminal determinants, provided significant protection to naive Lewis rats from subsequent induction of AA. Thus, T cell responses to the BCTD are involved in regulating inflammatory arthritis in the Lewis rat and in conferring resistance to AA in the WKY rat. These results have important implications in understanding the pathogenesis of RA and in devising new immunotherapeutic strategies for this disease.

Show MeSH
Related in: MedlinePlus