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

Abstract

B-cells of the rheumatoid synovial tissue are a constant part of and, in some histopathological subtypes, the dominant population of the inflammatory infiltrate, located in the region of tissue destruction. The pattern of B-cell distribution and the relationship to the corresponding antigen-presenting cells (follicular dendritic reticulum cells: FOCs) show a great variety. Bcells may exhibit (i) a follicular organization forming secondary follicles; (ii) follicle-like patterns with irregularly formed FOC networks, and (iii) a diffuse pattern of isolated FOCs. Molecular analysis of immunoglobulin YH and YL genes from human synovial B-cell hybridomas and synovial tissue demonstrates somatic mutations due to antigen activation. The FOC formations in the synovial tissue may therefore serve as an environment for B-cell maturation, which is involved in the generation of autoantibodies. An autoantibody 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, sONA, tetanus toxoid , mitochondrial antigens (M2), filaggrin and bacterial HSPs. The contributions of these antigens to the pathogenesis of RA are still hypothetical. A possible contribution could derive from crossreactivity and epitope mimicry: due to crossreaction, an antibody directed originally against a foreign infectious agent could react with epitopes from articular tissues, perpetuating the local inflammatory process. The characteristic distribution pattern, the localisation within the area of tissue destruction, the hypermutated IgYH and IgYL genes, and their exclusive function to recognize conformation-dependent antigens suggest a central role for B-cells in the inflammatory Offprint requests to: Dr. Veit Krenn, MD., Institute for Pathology, University of Wurzburg. Josef-Schneider-Str. 2, 0-97080 Wurzburg, Germany. Fax: +49931 2013440. e-mail : path119@mail.uniwuerzburg.de process of rheumatoid arthritis. Therefore, the analysis of synovial B-cell hybridomas and experimental expression of synovial IgYH and IgYL genes will help to characterise the antigens responsible for the pathogenesis of rheumatoid arthritis.