The immunologic homunculus in rheumatoid arthritis - A new sight of immunopathogenesis of RA and its therapeutic implications

Autoreactivity plays a major role in the pathogenesis of RA. The rheumatoid factor has been and still is for now more than 50 years the only autoreact ivity that is clinically applied in the diagnosis of RA. This well reflects the current way of thinking that a single antigen or a single cause drives an individual into disease. Although by now many other autoantigens and au toreactivities have been described, their discovery was always on the searc h for the one and only autoreactivity that causes RA. This includes also im mune reactivities directed against xenogenic antigens. But, none of the kno wn RA-associated autoreactivities is present in all RA patients and none of them occurs exclusively in RA. Thus, the observed sensitivities and specif icities are well below 100%. Therefore, RA has often been postulated to con sist of various immunological subentities with similar clinical symptoms. N evertheless, none of the autoreactivities correlates with a distinct clinic al feature or course of disease. It is about time to say good-bye to the idea that a single antigen or immun oreactvity causes and maintains rheumatoid arthritis. In this paper we pres ent RA as the clinical outcome of an immune system that has shifted from a healthy to an autoimmune steady state. This is accomplished by many differe nt reactivities and autoreactivities that occur either in parallel or one a fter the other. The entirety of the known RA-associated reactivities and (a uto)antigens is presented in detail. The major RA-relevant autoantigens com prise BiP, citrulline, the Sa-antigen, hnRNP A2, p205, IgG, calpastatin, ca lreticulin, collagen and the shared HLA-DR epitope. The accumulation of fac tors - involving autoreactivities, cytokines, environmental and genetic fac tors - that challange the normal regulatory mechanisms of the immune system lead to a regulatory catastrophe. In individuals developing the clinical f eatures of RA the immune system has been regulated to a new - autoimmune - steady state. This attractor,,rheumatoid arthritis" has many features of wh at has originally been described by Irun Cohen as the immunological homuncu lus: The healthy immune system is configured such as to direct its attentio n to major self-antigens. Thus it creates an autoreactivity to many autoant igens as a prerequisite for regulatory mechanisms that are sufficient to co ntrol them. The shift from the normal to rheumatoid attractor involves the inflammatory cytokines TNF-alpha, IL-1 and IL-6, autoreactive T- and B cell s directed at a variety of synovial and systemic antigens, activated dendri tic cells and macrophages, tissue destruction and genetic factors such as t he association with shared epitope. Environmental factors involved may also , but do not necessarily, include infection. With the appearance of clinical features of RA, naive, potentially autoreac tive T cells infiltrate the synovial compartment and become activated by de ndritic cells and other APCs. The autoantigenic peptides that are presented to these T cells are derived from inflammatory cell and tissue destruction as well as from tissue repair and remodeling processes. These T cells prol iferate and either provide help to B cells with the specificity to the same antigens or cause direct cytopathic tissue damage. Thereby, more and novel antigens are generated, released and presented again to naive or primed au toreactive T cells. These processes involving cytokines, tissue destruction and autoreactive T cells are sufficient to maintain RA even without the pe rmanent presence of a triggering agent. The recursive autoimmune processes are well consistent with the finding of the many different autoreactivities in RA and their respective sensitivitie s and specificities. The massive influx of T cells into the arthritic joint is accompanied by the anergization of over 90% of T cells in this compartm ent - which further substantiates the concept of the RA attractor within th e self-regulating immune system. Thereby, the RA-attracted immune system is not able to completely downregulate the inflammation and the local tissue damage/repair Thus, the immune system is permanently stimulated and suddenl y by chance shifts to a stable state different from the healthy system - re aching the wide fields of rheumatoid arthritis which in itself is self-sust aining as the healthy state before disease onset.