T cell reactivity to an epitope of the mycobacterial 65‐kDa heat‐shock protein (hsp 65) corresponds with arthritis susceptibility in rats and is regulated by hsp 65‐specific cellular responses

Abstract

Adjuvant arthritis (AA) can be induced in genetically susceptible rats by immunization with heat-killed mycobacteria suspended in mineral oil. From our analysis of arthritogenic T cell clone A2b, obtained from an arthritic Lewis rat and specific for the 180-188 epitope of mycobacterial 65-kDa heat-shock protein (hsp 65), the possible origin of AA was explained by the existence of a molecular mimicry of the 180-188 epitope with a cartilage-associated self antigen. We now have shown that Lewis rats respond to the 180-188 epitope after Mycobacterium tuberculosis immunization and that arthritis-resistant Fisher and (Lewis x Fisher)F1 rats, although major histocompatibility complex class II identical with Lewis, do not respond to this epitope. However, in rare cases of arthritis in Fisher rats, responses to the epitope were seen. We obtained no evidence for a defect at the level of antigen processing and presentation or for suppression in Fisher rats. Thus, non-responsiveness in Fisher rats was likely due to a difference at the level of the T cell repertoire. Previously, we have reported that pretreatment with hsp 65 in experimental arthritis, and not only in AA, caused resistance to arthritis induction. We now present evidence that immunization with hsp 65 or in vitro stimulation with hsp 65 may lead to inhibition of responses specific for epitope 180-188. Thus the hsp 65-induced resistance to arthritis is probably caused by the induction of regulatory control specifically targeted at the 180-188 epitope. Especially in rats that tend to focus their responses on the critical 180-188 sequence, such as Lewis, regulation seems to develop following immunization with hsp 65. Since recent evidence suggests that hsp 65 and also the 180-188 epitope have a role in human arthritic conditions, the present findings are expected to contribute to further experimentation directed at exploiting hsp 65 or its epitopes for the development of new therapeutical approaches in humans.

Resistance to Adjuvant Arthritis Is Due to Protective Antibodies Against Heat Shock Protein Surface Epitopes and the Induction of IL-10 Secretion

“…The disease cannot be induced in resistant strains of rats (e.g., Brown-Norway (BN), Fisher) (3,4), and Lewis rats develop resistance to reinduction of the disease after recovery from arthritis (5,6).…”

“…Preimmunization of susceptible rats with the mycobacterial HSP65 leads to resistance to induction of the disease by MT. This protective effect is believed to be mediated by T cells specific for HSP65 (3,7,17,18). Likewise, although arthritic rats develop vigorous T cell responses to self-HSP and to peptide 180 -188 of the MT HSP65, neither of these molecules is arthritogenic when administered to arthritis-susceptible rats (19,20).…”

“…Likewise, although arthritic rats develop vigorous T cell responses to self-HSP and to peptide 180 -188 of the MT HSP65, neither of these molecules is arthritogenic when administered to arthritis-susceptible rats (19,20). This suggests that HSP65 may contain different epitopes, some of which are responsible for its pathogenicity, whereas others confer resistance to disease induction (3,19,(21)(22)(23)(24).…”

Regulation of resistance against adjuvant arthritis in the Fisher rat

“…Interestingly, however, depleting F344 rats in vivo of OX8 + cells did not make this strain susceptible to exacerbations [8]. In addition, Hogervorst et al [9] also found that in AA responsiveness to certain mycobacterial antigen epitopes could be related to susceptibility. However, in this study the nonresponsiveness of the F344 appeared not to be due to antigenspecific suppression.…”

Environmental Modulation of Autoimmune Arthritis Involves the Spontaneous Microbial Induction of T Cell Responses to Regulatory Determinants Within Heat Shock Protein 65

“…The mechanism by which BCTD bring about these effects is currently under investigation. However, because the nature of microbial flora in different conventional facilities might be different, it is likely that T cell responses to certain Bhsp65 determinant regions (6,38,39) other than, or in addition to, BCTD might be crucial in inducing suppressive effect on AA in F344 rats. In addition, microbial agents can also influence susceptibility to autoimmunity by mechanisms other than determinant mimicry, e.g., bystander activation of potentially autoreactive T cells (34,40), and by the action of superantigen (41).…”