Impaired early B cell tolerance in patients with rheumatoid arthritis.

Autoantibody production is a characteristic of most autoimmune diseases including rheumatoid arthritis (RA). The role of these autoantibodies in the pathogenesis of RA remains elusive, but they appear in the serum many years before the onset of clinical disease suggesting an early break in B cell tolerance. The stage of B cell development at which B cell tolerance is broken in RA remains unknown. We previously established in healthy donors that most polyreactive developing B cells are silenced in the bone marrow, and additional autoreactive B cells are removed in the periphery. B cell tolerance in untreated active RA patients was analyzed by testing the specificity of recombinant antibodies cloned from single B cells. We find that autoreactive B cells fail to be removed in all six RA patients and represent 35-52% of the mature naive B cell compartment compared with 20% in healthy donors. In some patients, RA B cells express an increased proportion of polyreactive antibodies that can recognize immunoglobulins and cyclic citrullinated peptides, suggesting early defects in central B cell tolerance. Thus, RA patients exhibit defective B cell tolerance checkpoints that may favor the development of autoimmunity.