In 1984 it became possible to study the complexities of AA using an etiologic agent of disease, a clone of T cells capable of adoptively transferring AA, called A2b. It was demonstrated that A2b recognized an MT antigen and an antigen in the proteoglycan moiety of joint cartilage. This supported the autoimmune theory: AA was caused by antigen mimicry between MT and a joint antigen.
The MT epitope recognized by clone A2b was later identified as the nine amino acids at positions 180-188 in the sequence of the 65 kDa heat shock protein (hsp65) molecule of MT. This molecule belongs to the hsp60 family and is closely homologous to the mammalian hsp60 molecules. The general importance of hsp65 to arthritis was suggested by the observation that T cells responsive to hsp65 could be detected in the synovial fluids of patients suffering from rheumatoid arthritis. Moreover, some patients with juvenile arthritis showed immunity to the human hsp60 molecule. Thus, immunity to hsp65/hsp60 could be associated with spontaneous forms of immunological arthritis in humans as well as with AA of rats.
Is T cell immunity to hsp65 the cause or only the result of AA? The answer awaits the resolution of four issues.
1. Identity of the joint antigen. The 180-188 peptide recognized by clone A2b is in a variable region of the hsp65 molecule of MT; despite an overall homology of 50%, the 180-186 amino acid sequence is not present in the known mammalian hsp60 molecules. Thus the epitope recognized by A2b in the joints is probably not on the endogenous hsp60 molecule but is likely to be present on another molecule. A very weak homology between the 180-188 peptide and a sequence in the link protein of cartilage proteoglycan exists. This is compatible with the earlier observation that clone A2b recognizes an element in cartilage proteoglycan. However, clone A2b does not proliferate in response to the link protein peptide, so some other cross-reactivity is probably responsible for AA. Cross-reactivity has been sought between hsp65 and chondrocyte and proteoglycan antigens, and between hsp65 and lactoferrin, but these studies have failed to shed any light on pathogenesis. AA seems to be distinct immunologically from the arthritis inducible by immunization to collagen type II, yet spleen cells from rats immunized to collagen type II could partially inhibit AA. Thus, the immunological connection between MT and AA, and between hsp65 and the joints, remains circumstantial.
2. Induction of A A. The fact that clone A2b caused arthritis ted to the hypothesis that the target epitope of AA must be present in the hsp65 molecule of MT. This idea would be more tenable if active immunization to hsp65 were to actually induce AA. However, immunization with hsp65 has as yet failed to induce arthritis. Nevertheless, hsp65 must be involved in the process responsible for arthritis because administration of whole hsp65 or the 180-188 nonapeptide to rats induces resistance to AA.
There is yet another problem: not only can hsp65 prevent AA, it can also prevent arthritis induced by streptococcal cell walls or arthritis induced by the oil pristane. These forms of arthritis are not related, at least superficially, to MT. Why then should administration of the hsp65 of MT influence them?
3. Specificity of hsp65 immunity. The immune response to hsp65 is not exclusive to arthritis. It appears that inflammatory exudates outside of the joints, pleural effusions for example, are also rich in T cells responsive to hsp65. Moreover, immunization of some strains of mice with hsp65 or hsp60 has been found to induce diabetes mellitus. The epitope of hsp60 associated with diabetes differs from the 180-188 epitope associated with arthritis. Nevertheless, it is clear that hsp65 immunity is not limited to the inflammation of immunological arthritis. In fact, immunity to hsp65 is not necessarily associated with immunopathology; the T cells of healthy humans respond very well to hsp65 and even to self hsp 60. Moreover, hsp65 is a dominant antigen in the immune response to infection or vaccination with Mycobacteria or other bacteria.
4. Regulation of AA. AA is a manifestation of the inflammatory reaction, so it is not surprising that AA can be suppressed by various anti-inflammatory treatments, particularly treatments that inhibit proinflammatory cytokines, such as tumor necrosis factor a (TNFa), or that block the T-cell receptor. Interestingly, AA can be inhibited by T cells that recognize specific epitopes from the T-cell receptor of an anti-hsp65 T cell. In addition to regulatory T cells, it appears that antibodies may be important in the regulation of AA. AA can be inhibited by normal immunoglobulin (IVIg) and by immunoglobulins from strains of rats resistant to AA. Furthermore, AA is marked by changes in the glyco-
sylation of antibodies of the IgGl and IgG2b isotypes.
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