The Journal of Experimental Medicine
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Published 4 October 2004. doi:10.1084/jem.20040920
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 7, 927-934
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Bruton's Tyrosine Kinase Is Essential for Human B Cell Tolerance

Yen-Shing Ng1, Hedda Wardemann3, James Chelnis1, Charlotte Cunningham-Rundles4, and Eric Meffre1,2

1 Laboratory of Biochemistry and Molecular Immunology, The Hospital for Special Surgery
2 Weill Medical College of Cornell University, New York, NY 10021
3 Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10021
4 Department of Medicine and Pediatrics, Mount Sinai Medical Center, New York, NY 10029

Address correspondence to Eric Meffre, The Hospital for Special Surgery, 535 E. 70th St., New York, NY 10021. Phone: (212) 774-2347; Fax: (212) 717-1192; email: meffree{at}hss.edu

Most polyreactive and antinuclear antibodies are removed from the human antibody repertoire during B cell development. To elucidate how B cell receptor (BCR) signaling may regulate human B cell tolerance, we tested the specificity of recombinant antibodies from single peripheral B cells isolated from patients suffering from X-linked agammaglobulinemia (XLA). These patients carry mutations in the Bruton's tyrosine kinase (BTK) gene that encode an essential BCR signaling component. We find that in the absence of Btk, peripheral B cells show a distinct antibody repertoire consistent with extensive secondary V(D)J recombination. Nevertheless, XLA B cells are enriched in autoreactive clones. Our results demonstrate that Btk is essential in regulating thresholds for human B cell tolerance.

Key Words: XLA • Bruton's tyrosine kinase • B lymphocytes • tolerance • autoantibody

Abbreviations used in this paper: ANA, antinuclear antibody; BCR, B cell receptor; Btk, Bruton's tyrosine kinase; RF, reading frame; XLA, X-linked agammaglobulinemia.


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