Abstract
The therapeutic benefit of B cell depletion in patients with rheumatoid arthritis has provided proof of concept that B cells are relevant for the pathogenesis of arthritis. It remains unknown which B cell effector functions contribute to the induction or chronification of arthritis. We studied the clinical and immunological effects of B cell depletion in glucose-6-phosphate isomerase-induced arthritis. We targeted CD22 to deplete B cells. Mice were depleted of B cells before or after immunization with glucose-6-phosphate isomerase (G6PI). The clinical and histological effects were studied. G6PI-specific antibody responses were measured by ELISA. G6PI-specific T helper (Th) cell responses were assayed by polychromatic flow cytometry. B cell depletion prior to G6PI-immunization prevented arthritis. B cell depletion after immunization ameliorated arthritis, whereas B cell depletion in arthritic mice was ineffective. Transfer of antibodies from arthritic mice into B cell depleted recipients did not reconstitute arthritis. B cell depleted mice harbored much fewer G6PI-specific Th cells than control animals. B cell depletion prevents but does not cure G6PI-induced arthritis. Arthritis prevention upon B cell depletion is associated with a drastic reduction in the number of G6PI-specific effector Th cells.
Highlights
The therapeutic success of the B cell–depleting drug Rituximab in treating patients with rheumatoid arthritis (RA) has induced intensified interest in how B cells contribute to the pathogenesis of autoimmune diseases
glucose-6-phosphate isomerase (G6PI) is the target autoantigen in the transgenic K/BxN mice, which develop high titers of anti-G6PI specific autoantibodies [8,9]. These autoantibodies are arthritogenic in the K/BxN transfer model, where transfer of serum or G6PI-specific mAbs generated from the transgenic K/BxN mice is sufficient to induce the disease in recipient mice [8,10]
SJL mice are susceptible to G6PI-induced arthritis To investigate the role of B cells in G6PI-induced arthritis at different disease stages, we wished to use a B cell depleting immunoconjugate
Summary
The therapeutic success of the B cell–depleting drug Rituximab (anti-CD20 antibody) in treating patients with rheumatoid arthritis (RA) has induced intensified interest in how B cells contribute to the pathogenesis of autoimmune diseases. B cells can produce autoantibodies and function as antigen-presenting cells (APC), which can profoundly influence T-helper (Th) cell proliferation and effector functions They produce cytokines and regulate lymphoid tissue architecture and neogenesis. G6PI is the target autoantigen in the transgenic K/BxN mice, which develop high titers of anti-G6PI specific autoantibodies [8,9]. These autoantibodies are arthritogenic in the K/BxN transfer model, where transfer of serum or G6PI-specific mAbs generated from the transgenic K/BxN mice is sufficient to induce the disease in recipient mice [8,10]. B cells and antibodies are necessary but not sufficient for the pathogenesis of G6PI-induced arthritis
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