Mechanisms of immune injury in rheumatoid arthritis: evidence for the involvement of T cells and heat-shock protein.
Evidence for the involvement of T cells, especially CD4+ T cells, in the pathogenesis of RA is substantial and includes 1) the correlation between prolonged CD4+ T-cell depletion and improvement in joint disease in the absence of observable changes in the levels of autoantibodies (rheumatoid factors) in the blood and joints, 2) the infiltration of the inflamed synovial tissues with T cells and, 3) the increased susceptibility of individuals to RA with certain HLA-DR haplotypes. The most direct evidence for the involvement of CD4+ T cells is provided by recent studies which demonstrate rapid improvement in the joint disease manifestations of RA following the infusion of anti-CD4 monoclonal antibodies (Herzog et al. 1989, Walker et al. 1989). It is unlikely that T cells alone are responsible for the joint injury in RA. Autoantibodies (rheumatoid factors) in the joint which contribute to the release of complement breakdown products, and to the secretion of cytokines such as IL-1 by macrophages must also play an important role. Indeed, depletion of CD4+ cells after TLI or therapy with monoclonal antibody reduces, but does not eliminate, joint disease activity. The residual joint disease activity is probably influenced by the continued contribution of autoantibodies to joint injury. Production of these autoantibodies may not be dependent on help from CD4+ cells, since little change is observed in autoantibody levels after CD4+ cell depletion. The mechanisms by which T cells mediate to the joint disease in RA are not clear. Little or no direct evidence of cytotoxic effects of T cells on autologous joint cells has been reported. Considerable evidence suggests that at least some T-cell cytokines (i.e., TNF alpha, IL-6) can contribute to the proliferation of synovial lining cells which results in the marked build-up of inflammatory tissue (pannus) in the joints of patients with RA (Firestein et al. 1990). In addition, T cells may recruit other joint cells, such as macrophages, to secrete cytokines (i.e., IL-1) which both contribute to synovial cell proliferation, and cartilage and bone degeneration. The marked reduction in the spontaneous secretion of IL-1 by synovial biopsies, and improvement in disease activity after TLI support this notion. Interestingly, the CD4+ T-cell lymphokines, IL-2 and IFN-gamma, were not spontaneously secreted in detectable quantities by synovial biopsies. This suggests that the pattern of lymphokines secreted by T cells in the joint in RA are not typical of that in delayed-type hypersensitivity reactions.(ABSTRACT TRUNCATED AT 400 WORDS)
Strober
S
S
Stanford University School of Medicine, Department of Medicine, CA 94305.
Holoshitz
J
J
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens; D002450:Cell Communication; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000276:immunology; D006360:Heat-Shock Proteins / Q000276:immunology*; D006801:Humans; D008221:Lymphoid Tissue / Q000528:radiation effects; D009161:Mycobacterium / Q000378:metabolism; D013582:Synovial Fluid / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D016827:CD8 Antigens; D006360:Heat-Shock Proteins