Rheumatoid arthritis and the concept of autoimmune disease

Abstract

We critically review the concept of autoimmunity in Rheumatoid Arthritis (RA). To classify a disease as autoimmune, it is necessary to demonstrate that the immune response to a self-antigen causes the observed pathology. In RA, neither autoantigens nor autoreactive T-cell clones were found. Molecular mimicry exists in some cases, e.g. after Proteus mirabilis infection. In some patients, cross-reactivity between microbial DnaJ and human HSP40 can occur. However, none of the autoantibodies described in RA, with perhaps exception of Anti-Citrullinated Peptides Antibodies (ACPAs), are responsible for the onset of disease and tissue damage. ACPAs appeared early in the disease process and could activate macrophages. In turn, this leads to the release of pro-inflammatory cytokines that stimulate synovial fibroblasts. In this disease, neither autoantibodies, nor leucocytes destroy bone and cartilage. This is caused by aggressive epigenetically modified synovial fibroblasts. Current treatments did not directly target those cells. The term “autoimmune disease” for RA should be used with caution until the link between immune phenomena and joint damage has been elucidated. However, we have to be open and to accept that RA is a heterogeneous disease. This is reflected by the large variability of responses to immunosuppressive drugs or biologicals.