Autoimmune mechanisms involved in the pathogenesis of rheumatoid arthritis

Rheumatoid arthritis (RA) was one of the first systemic disorders to be considered an autoimmune disease. Two major aspects of RA suggest a fundamental immune-mediated derangement in the disease: (1) presence of often massive lymphocytic infiltrates and activated CD4(+) T cells within the inflamed hypertrophied synovium, and (2) production of large amounts of rheumatoid factor (RF) by B-cells and plasma cells in the involved synovium itself. The actual tissue damage to joints and extra-articular structures affected by the disease comes from the rheumatoid inflammatory pannus or granulomatous collections of cells called rheumatoid nodules. RF production has long been studied as a prime example of apparent autoantibody production in association with the basic underlying disease process. RA patients who belong to subtype HLA DR4, Dw4 (DR B1 or 0401, Dw14 (0404/0408), or Dw15 (0405/0410) are most likely to be seropositive for RF and to have severe progressive disease. RFs are felt to represent an autoantibody associated with RA, since they show principal specificity for structures on the C gamma 3 and C gamma 2 (Fc) domains of IgG. Recent work by our group has defined a number of solvent-exposed linear RF-reactive epitopes on C gamma 3 and C gamma 2 using a strategy of overlapping 7-mers of primary sequence. RFs also have been demonstrated to react with two different regions, SKDWSFY and LSQPKIVKWDR, on beta 2-microglobulin (beta 2m). Many of the RF-reactive sites on C gamma 2 and C gamma 3 as well as on beta 2m show common immunodominant valines, leucines, tryptophanes, arginines, lysines, and glutamines, thus comprising common reactive residues. In the future, this approach may provide more direct insight into the specificities of other autoantibodies.