A mycobacterial 65-kD heat shock protein induces antigen-specific suppression of adjuvant arthritis, but is not itself arthritogenic.

Abstract

A nonapeptide epitope contained in the 65-kD species of heat shock protein of many mycobacterial species shares homology with a peptide on a mammalian cartilage link protein (1), with four of the amino acids identical. Structures containing this epitope, including proteoglycans extracted from human rheumatoid synovial effusions (2), induce proliferation ofan arthritogenic, rat T lymphocyte line (3) that has been subdivided into two clones, A2b and A2c, which, respectively, induce adjuvant arthritis or suppress the developing and established phases ofthis experimental model of autoimmunity (4, 5). Both clones proliferate in the presence of the epitope, as do T lymphocytes from some rheumatoid arthritis patients (6), but it is not established ifthe epitope plays a role in the pathogenesis of the arthritis. Administration of the recombinant (r) 65-kD shock protein antigen intraperitoneally did not induce arthritis in rats, but rendered such rats resistant to further attempts to induce arthritis with mycobacteria (1) or streptococcal cell walls (7). It is known, however, that adjuvant arthritis development requires the arthritogens to be administered in an oil vehicle by either the intradermal or subcutaneous routes (reviewed in reference 8), and that the peptidoglycan component of the mycobacterial cell wall is essential (8).Using high levels of the r65-kD protein in an oil vehicle, and even combining the protein with low levels of a synthetic, nonimmunogenic adjuvant, CP20961 (9), to mimic the peptidoglycan portion of mycobacteria, we have been unable to induce arthritis with the r65-kD shock protein, though the induction of resistance was confirmed. At high levels, the synthetic adjuvant CP20961, which is known to be arthritogenic (9), induced arthritis in rats rendered resistant to mycobacterial arthritis by the r65-kD shock protein. Type II collagen-induced arthritis also developed in r65-kD protein-pretreated rats. These results strongly suggest that the r65-kD shock protein produces an antigen-specific resistance to classical, mycobacterial adjuvant arthritis, since it is much less effective at inhibiting the arthritis induced by both CP20961 and type II collagen . Furthermore, the pathogenesis ofthe actual adjuvant arthritis does not appear to involve the 65-kD protein.

Evaluation of therapeutic targets in animal models of arthritis: How does it relate to rheumatoid arthritis?

“…The antigen that induces the immune response has been shown to be Hsp65, with the responsible epitope being peptide 180-186 (29). However, other components in CFA are important as well, because injection of only Hsp65 cannot trigger arthritis (30). Of note, the injection of mineral oil only can result in oil-induced arthritis; however, only a transient arthritis develops, in contrast to the chronic erosive arthritis seen in AIA (20,31).…”

Induction of IL-10 and Inhibition of Experimental Arthritis Are Specific Features of Microbial Heat Shock Proteins That Are Absent for Other Evolutionarily Conserved Immunodominant Proteins

“…However, most data collected to date do not support such antigenic mimicry to be a major trigger to autoimmune disease. In contrast, immunization with (mycobacterial) hsp60 has been found to protect animals from the development of arthritis in virtually all forms of experimental arthritis (7)(8)(9). Most evidence on the mechanism of the protective role of mycobacterial hsp60 has been obtained in adjuvant arthritis (AA) (10,11).…”

Prevention of adjuvant arthritis in rats by a nonapeptide from the 65-kD mycobacterial heat-shock protein

“…During the 35-day pretreatment period none of the rats showed any clinical symptoms of A A, indicating that SNP is not arthritogenic (Billingham et al, 1990;Yang et al, 1990). In two separate experiments, we found after induction of A A that 11 out of 16 rats were completely protected (Table 1); furthermore on radiographs no indication of arthritis was found in these rats (Table 2).…”

“…Recent studies have demonstrated that the dominant immunogenic epitopes of some T cell-mediated experimental autoimmune diseases can be precisely defined by using disease inducing T cell clones as tools (Zamvile;a/,, 1986;van Eden e^o/,, 1988), In adjuvant arthritis (AA), a model of autoimmune arthritis inducible in certain strains of rats such as in Lewis rats, by heatkilled Mycobacterium tuberculosis (Pearson, 1956;1964;Taurog, Argentieri & McReynolds, 1988), a 65-kD mycobacterial heat-shock protein (HSP) has been proposed to be involved in the pathogenesis of AA (van Eden et al, 1988), Administration of the 65-kD HSP led to protection against AA and streptococcal cell-wall-induced arthritis in Lewis rats (van Eden et al, 1988;van den Broek et al, 1989;Billingham et al, 1990). A nonapeptide (Thr-Phe-Gly-Leu-Gln-Leu-Glu-Leu-Thr), representing amino acid sequence 180-188 ofthe 65-kD mycobacterial HSP, has been suggested to carry the critical epitope(s) for A A because of its ability to stimulate the arthritis-inducing T cell clone A2b as well as the arthritis-protective T cell clone A2c in vitro (Holoshitz, Matitiau & Cohen, 1984;Cohen et at., 1985;van Eden et al, 1988;, Based on these observations, it was suspected that immunization with the Correspondence: Dr X,-D, Yang, R-1056.…”