Importance of T cells in rheumatoid synovitis: Comment on the review by Firestein and Zvaifler (2002)

In 1990, Firestein and Zvaifler wrote a cogent editorial on the limited role of T cells in rheumatoid (RA) synovitis, which remains a landmark in our understanding of the disease (1). The sequel (2) reaffirms the evidence, but the conclusions fail on the central question: “why does she have RA and not he?” Firestein and Zvaifler show that rheumatoid synovitis is not due to a local T cell effector mechanism. They could add that there is little evidence for T cell autoreactivity in RA. Neither point, however, is incompatible with the evidence from HLA–DR4 studies that RA is a T cell–dependent adaptive immune response (3). A systemic T cell–dependent response can initiate distant inflammation through antibody. It is now generally accepted that immune complexes generate inflammation not through complement, but by inducing cytokine release via IgG Fcγ receptor type III (FcγRIII) (4). Unlike autoreactive T cells, immune complexes small enough to traverse endothelium are abundant in RA, and FcγRIII is selectively expressed in synovium (5). Many rodent models of RA have now been shown to be antibody and FcγRIII dependent (6, 7). That adjuvant used to boost an adaptive immune response may also have an early activating effect on synovial cells through Toll-like receptors is probably a red herring. Another red herring, as Firestein and Zvaifler effectively point out, is that synovial macrophage cytokine release tends to recruit bystander “Th1” cells. It is very difficult to explain the extraarticular manifestations of RA without immune complexes. The distribution of FcγRIII indicates that pericarditis, nodules, and synovitis should all have the same origin (5). Tissue-specific amplification mechanisms almost certainly apply in synovium and bone marrow (8), but it is difficult to justify two means of initiation where one will do. The flaw in the common assumption that T cell–dependent autoimmune responses require autoreactive T cells is more subtle. The most consistent immune response in RA, rheumatoid factor production, is almost certainly T cell dependent, but there is no T cell autoreactivity to IgG. This paradox is explained by the ability of rheumatoid factor B cells to obtain help from T cells recognizing foreign antigen (9, 10). Evidence from other disorders also suggests that T cell responses to autoantigens may not determine corresponding autoantibody production (11, 12). “Loss of T cell tolerance” may not apply. Stastny not only confirmed the role of genes in RA (3), but also pointed out that the other factors may be not environmental, but stochastic (random). Genes, and probably smoking, set thresholds, but the kinetics of disease initiation are of a sequence of internal stochastic events. Studies of monozygotic twins suggest that a rate-limiting event occurs approximately once in 200 woman-years (4 adult lifetimes) (13). Scandinavian studies of antibody profiles evolving over several years before diagnosis indicate that other random events, occurring every few months or years, are probably involved (14). They also confirm that an adaptive response comes before synovitis, and it is an antibody response. Firestein and Zvaifler suggest that B cell activation is due to “undefined processes.” These processes may have remained undefined because they are engineered by the B cells themselves. “Anti-foreign” B cells control their own activation by interacting with antigen through surface and secreted antibody. Autoreactive B cells should not, but if a rare subset can do so through abnormal means, including the way rheumatoid factor B cells obtain T cell help, they will be self-perpetuating, and the kinetics of autoimmunity become comprehensible. Plausible mechanisms are not hard to identify (10). The generation of all antibody species is random. Antibodies able to subvert all control mechanisms and initiate RA might well arise only once in 200 woman-years, being what survival pressures will allow. Recruitment of other clones to create clinical disease might well take months or years. In advanced RA, B cell depletion often lowers the C-reactive protein level to normal as autoantibody levels fall (15, 16). Relapse occurs following B cell return, but again, may evolve over many months. Firestein and Zvaifler are right to argue that T cells in rheumatoid synovitis are largely bystanders, but the answer to their question “what comes before T cells” is well documented (14): it is antibody. Jonathan C. W. Edwards MD*, * University College, London, UK.