Impaired early B cell tolerance in patients with rheumatoid arthritis

Abstract

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.

Antibody repertoire analysis in polygenic autoimmune diseases

“…B‐cell clones from patients with RA were enriched for longer CDR3 lengths in both the heavy‐chain92, 105, 106 and light‐chain (kappa, Igκ) 92, 106. B‐cells with BCRs containing long Igκ CDR3 regions (of ≥ 11 amino acids) were found to be autoreactive or polyreactive 92. Thus, a picture emerges in which B‐cells from patients with RA and particularly B‐cells from inflamed joints appear enriched for V gene usage that is associated with specificity for self‐antigen.…”

B cell tolerance: Putting the horse before the cart

“…In this issue of Arthritis & Rheumatism, Menard et al (1) provide an exceptional natural history of B lymphopoiesis, demonstrating that the defects in central B cell tolerance, which he and his colleagues previously noted in RA patients (19), are not resolved by effective treatment regimens (methotrexate or anti-tumor necrosis factor ␣ agents) that effectively reduce inflammation. Based on this simple, yet crucial finding, Menard et al were able to conclude that the impairment in central B cell tolerance is the cause of disease rather than a consequence.…”

“…Although the core methods of this approach were not novel (12-16), its scale was unprecedented, and consequently, great precision and much new insight has been brought to studies of human B cell biology. In particular, this experimental system has been used with great effect to enumerate self-reactive B cells in healthy subjects and in patients with systemic autoimmune disease (10,(17)(18)(19)(20). Interestingly, immature B cells in the BM of healthy subjects are frequently autoreactive, with as many as 75% of recovered IgH ϩ IgL pairs exhibiting self-binding (e.g., antinuclear antibody, DNA, or insulin reactivity) and/or polyreactivity (10).…”

“…The high frequency of poly-reactive membrane IgMϪ B cells in human BM is surprising, given the characteristic specificity (Յ5% polyreactivity) of mature peripheral B cell populations (10,18), and these cells are associated with BCRs bearing long IgH in the third complementarity-determining region, containing positively charged and/or aromatic amino acids (10,21,22). In humans, perhaps even more than in mice (3), random V-D-J rearrangements frequently generate autoreactive/polyreactive BCRs and B cells with a potential role in autoimmune disease (10,(17)(18)(19).…”

“…In contrast to the normally efficient tolerance checkpoints in healthy subjects, the central and peripheral tolerance checkpoints in patients with systemic lupus erythematosus (SLE) and patients with RA appear defective; patients with SLE and those with RA have significantly higher frequencies (25-50%) of autoand polyreactive naive, mature B cells as compared with normal healthy controls (18,19). These important results provide direct and convincing evidence that systemic autoimmunity, or at least SLE and RA, may be the direct result of (genetic) impairments in central B cell tolerance, rather than the indirect consequence of abnormal antigen exposure, inflammation, and/or immunoregulation.…”