Dendritic Cell Networks Lymphoid Germinal Centers and Follicular Memory B Lymphocytes via Effects on Therapy in Rheumatoid Arthritis Inhibits Cutting Edge: Anti-Tumor Necrosis Factor

Rheumatoid arthritis (RA) is mediated by a proinflam-matory cytokine network with TNF at its apex. Accordingly , drugs that block TNF have demonstrated significant efficacy in the treatment of RA. A great deal of experimental evidence also strongly implicates B cells in the pathogenesis of RA. Yet, it remains unclear whether these two important players and the therapies that target them are mechanistically linked. In this study we demonstrate that RA patients on anti-TNF (etanercept) display a paucity of follicular dendritic cell networks and germinal center (GC) structures accompanied by a reduction in CD38 ؉ GC B cells and peripheral blood memory B cell lymphopenia compared with healthy controls and RA patients on methotrexate. This study provides initial evidence in humans to support the notion that anti-TNF treatment disrupts GC reactions at least in part via effects on follicular dendritic cells. R heumatoid arthritis (RA) 3 is a systemic autoinflamma-tory disorder manifested by aggressive synovitis that over time causes bone, tendon, and cartilage damage. Although different cell types may play pathogenic roles in RA, a prominent participation of the B cell has been recently highlighted. Thus, rheumatoid factor (RF) and anti-cyclic citrulli-nated peptide (anti-CCP) autoantibodies are well-established indicators of disease and disease severity, and autoantibody-mediated models of RA have been described in the mouse (1–3). Moreover, B cells may provide a critical link between the development of tertiary lymphoid tissue within the inflamed syno-vium and the propagation of the autoimmune process. This contention is supported by the finding of germinal center (GC)-like structures within the inflamed RA synovium, the profound effect of B cell-borne lymphotoxin (LT) ␣ on lym-phoid architecture, and the observation that T cell activation in the RA synovium is dependent on the presence of B cells within these active GCs (4). Perhaps most strikingly, the key role of the B cell in disease pathogenesis has recently been demonstrated by the clinical efficacy of targeted B cell depletion with rituximab (5). TNF-␣ has also been established as a central player in the pathogenesis of RA. The pathogenic significance of TNF has been demonstrated by the clinical efficacy of TNF blockade in the treatment of RA (6). Interestingly, TNF and LT␣ (also blocked by some anti-TNF drugs) may exert powerful direct and indirect influences over B cells (which express TNFR1 and TNFR2) and through B cells that may produce TNF and constitute the main source of LT␣ (7–9). Of …