Histopathology and molecular pathology of synovial B-lymphocytes in rheumatoid arthritis

B-cells of the rheumatoid synovial tissue are a constant part of and, in so me histopathological subtypes, the dominant population of the inflammatory infiltrate, located in the region of tissue destruction. The pattern of B-c ell distribution and the relationship to the corresponding antigen-presenti ng cells (follicular dendritic reticulum cells: FDCs) show a great variety. B-cells may exhibit (i) a follicular organization forming secondary follic les; (ii) follicle-like patterns with irregularly formed FDC networks, and (iii) a diffuse pattern of isolated FDCs. Molecular analysis of immunoglobu lin VH and VL genes from human synovial B-cell hybridomas and synovial tiss ue demonstrates somatic mutations due to antigen activation. The FDC format ions in the synovial tissue may therefore serve as an environment for B-cel l maturation, which is involved in the generation of autoantibodies. An aut oantibody is defined as "pathogenic" if it fulfills the Witebsky-Rose-Koch criteria for classical autoimmune diseases: definition of the autoantibody; induction of the disease by transfer of the autoantibody; and isolation of the autoantibody from the disease-specific lesion. B-cells from rheumatoid synovial tissue show specificity for FcIgG, type II collagen, COMP, sDNA, tetanus toroid, mitochondrial antigens (M2), filaggrin and bacterial HSPs. The contributions of these antigens to the pathogenesis of RA are still hyp othetical. A possible contribution could derive from crossreactivity and ep itope mimicry: due to crossreaction, an antibody directed originally agains t a foreign infectious agent could react with epitopes from articular tissu es, perpetuating the local inflammatory process. The characteristic distrib ution pattern, the localisation within the area of tissue destruction, the hypermutated IgVH and IgVL genes, and their exclusive function to recognize conformation-dependent antigens suggest a central role for B-cells in the inflammatory process of rheumatoid arthritis. Therefore, the analysis of sy novial B-cell hybridomas and experimental expression of synovial IgVH and I gVL genes will help to characterise the antigens responsible for the pathog enesis of rheumatoid arthritis.