The Identification of Germinal Centres and Follicular Dendritic Cell Networks in Rheumatoid Synovial Tissue

Abstract

We document here the identification of germinal centres with dark and light zones, a follicular dendritic cell network and clonal expansion in the synovium of rheumatoid arthritis patients. Synovial tissue from 24 patients suffering from rheumatoid arthritis or the polyarticular form of juvenile rheumatoid arthritis were screened for the presence of lymphoid follicles. The synovial tissues of 14 patients contained follicles and four of these had germinal centres and a follicular dendritic cell network. There was a statistically significant association between follicles in the synovium and the presence of rheumatoid factor autoantibodies in the patients' serum indicating a link between local germinal centre formation and the presence of pathological rheumatoid factors. Nucleotide sequencing of monoclonal rheumatoid factors from one of the patients' synovial tissue which contained germinal centres clearly supports the possibility that these rheumatoid factors have gone through a germinal centre reaction. While rheumatoid factors from healthy immunized donors are regulated through a tolerization mechanism which selects against replacement mutations and does not allow affinity maturation, synovial rheumatoid factors seem to lack this tolerization mechanism. The formation of germinal centres where B cells affinity mature and expand at the central site of disease in rheumatoid arthritis may explain why rheumatoid factors in rheumatoid arthritis develop into auto-aggressive antibodies.

Distinct Effector Cytokine Profiles of Memory and Naive Human B Cell Subsets and Implication in Multiple Sclerosis

“…Such ectopic lymph node structures have been described in the target organs of several other human autoimmune diseases, including Sjogren's syndrome, diabetes, gastritis, and rheumatoid arthritis (43)(44)(45)(46). Our present findings extend these reports and highlight the potential contribution of distinct subsets of B cells to ongoing inflammation, both within the target organs of human autoimmune diseases and in the periphery, where they may elaborate chemokines, produce factors that promote lymphoneogenesis, act as APCs, and regulate the local immune response through the expression of effector cytokines.…”

Evidence for a selected humoral immune response encoded by VH4 family genes in the synovial membrane of a patient with rheumatoid arthritis (RA)

“…An over-representation of one V H 4 gene, the V H 4.21, in the autoimmune repertoire has been described [15]. A high representation of members of the V H 4 family was also found within hybridomas derived from synovial Clin Exp Immunol 1996; 106: [5][6][7][8][9][10][11][12] tissue of one patient with RA [16]. Recently, it was postulated that a negative selection of V H 4 takes place in the peripheral blood lymphocytes (PBL) of healthy individuals as a means to avoid autoimmunity [17].…”

The B cell repertoire of patients with rheumatoid arthritis. II. Increased frequencies of IgG+ and IgA+ B cells specific for mycobacterial heat‐shock protein 60 or human type II collagen in synovial fluid and tissue

“…Interestingly, B cells in all stages of differentiation, from mature B cells to plasma cells, have been observed (16)(17)(18)(19)(20). There is some molecular evidence that B cells are specifically activated and clonally expanded in the synovium (21)(22)(23).…”

“…There is some molecular evidence that B cells are specifically activated and clonally expanded in the synovium (21)(22)(23). Organized structures resembling germinal centers have been described, which contain follicular dendritic cells and CD4+ T cells and reveal clonal expansion of B cells exhibiting isotype switching and somatic hypermutation (19,22). Numerous plasma cells have been found which produce IgM, IgG, and IgA (24); some of these also secrete RF or antibodies specific for type I1 collagen (CII) (17,(25)(26)(27).…”