Impaired early B cell tolerance in patients with rheumatoid arthritis

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Published 16 May 2005. doi:10.1084/jem.20042321

Impaired early B cell tolerance in patients with rheumatoid arthritis

s1, Yen-Shing Ng1, Coupillaud1, Paget1,

and Meffre1,2

1 Laboratory of Biochemistry and Molecular Immunology, Hospital for

Special Surgery

2 Weill Medical College of Cornell University, New York, NY 10021

CORRESPONDENCE Meffre: meffree@...

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.

http://www.jem.org/cgi/content/abstract/201/10/1659