Quantification of cross-reactive idiotype-positive rheumatoid factor produced in autoimmune rheumatic diseases. An indicator of clonality and B cell proliferative mechanisms

Abstract

The aetiology of sustained autoantibody production in human autoimmune diseases is unknown. Evidence for structural similarities and common clonal origin among autoantibodies have been demonstrated through the expression of cross-reactive idiotype (CRI). In the present study we use four monoclonal antibodies (MoAbs) with specificity for non-overlapping CRI on human rheumatoid factor (RF) autoantibodies to define the structural features of polyclonal RF characteristic of patients with autoimmune rheumatic diseases. The pattern of CRI expression in the serum of 12 patients with rheumatoid arthritis (RA), eight with systemic lupus erythematosus (SLE) and 20 with primary Sjögren's syndrome and 34 normal individuals were determined in parallel with the level of IgM RF, IgA RF and autoantibodies to the cellular antigens SS-A, SS-B, Sm, nRNP and dsDNA and cryoglobulins. The results demonstrate significant elevation in the level of IgM and IgA expressing VHI (G6 and G8) and VHIII (B6 and D12) associated CRI in the serum of patients with autoimmune rheumatic diseases compared with normal individuals. These increases paralleled, but did not equal the increase in the level of immunoglobulins and RF. However, when expressed as proportion of immunoglobulin, only the VHI-associated CRI were significantly elevated in patients compared with normal individuals. The proportion of IgM RF expressing the VHI-associated CRI was higher in patients with Sjögren's syndrome compared with SLE and RA. Furthermore, the proportion of IgA RF expressing the G6 CRI was higher than G6+ IgM RF. These findings imply that different mechanisms contribute to RF production in autoimmune diseases. It is suggested that polyconal B cell activation is likely to be a contributing mechanism. However, such polyclonal activation is unlikely to be random since a selective elevation in the level of specific autoantibodies and VHI-associated CRI is observed. Furthermore, the data demonstrate that a proportion of autoantibodies in autoimmune diseases are immunoglobulin germline gene encoded. This is more evident in some patients with primary Sjögren's syndrome, where RF is likely to be oligoclonal or monoclonal in individuals with lymphoproliferation.