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Predominant Autoantibody Production by Early Human B Cell Precursors
Hedda Wardemann,1Sergey Yurasov,1,3Anne Schaefer,1James W. Young,4Eric Meffre,1,5*Michel C. Nussenzweig1,2*
During B lymphocyte development, antibodies are assembled byrandom gene segment reassortment to produce a vast number ofspecificities. A potential disadvantage of this process is thatsome of the antibodies produced are self-reactive. We determinedthe prevalence of self-reactive antibody formation and its regulationin human B cells. A majority (55 to 75%) of all antibodies expressedby early immature B cells displayed self-reactivity, includingpolyreactive and anti-nuclear specificities. Most of these autoantibodieswere removed from the population at two discrete checkpointsduring B cell development. Inefficient checkpoint regulationwould lead to substantial increases in circulating autoantibodies.
1 Laboratory of Molecular Immunology, Rockefeller University, New York, NY 10021, USA. 2 Howard Hughes Medical Institute, Rockefeller University, New York, NY 10021, USA. 3 Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. 4 Allogeneic Bone Marrow Transplant and Clinical Immunology Services, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. 5 Hospital for Special Surgery, Weill Medical College of Cornell University, New York, NY 10021, USA.
* To whom correspondence should be addressed. E-mail: meffree{at}hss.edu, nussen{at}mail.rockefeller.edu
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