The Journal of Experimental Medicine
Rockland Immunochemicals for Research
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Published online 30 January 2006 doi:10.1084/jem.20052033
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 2, 393-400
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ARTICLE

 A checkpoint for autoreactivity in human IgM+ memory B cell development

Makoto Tsuiji1, Sergey Yurasov1,2, Klara Velinzon1, Saskia Thomas4, Michel C. Nussenzweig1,3, and Hedda Wardemann1

1 Laboratory of Molecular Immunology, The Rockefeller University, 2 Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, and 3 Howard Hughes Medical Institute, New York, NY 10021
4 FU-Berlin, Department of Biology, Chemistry, and Pharmacy, 14195 Berlin, Germany

CORRESPONDENCE Hedda Wardemann: wardemh{at}rockefeller.edu

Autoantibodies are removed from the repertoire at two checkpoints during B cell development in the bone marrow and the periphery. Despite these checkpoints, up to 20% of the antibodies expressed by mature naive B cells in healthy humans show low levels of self-reactivity. To determine whether self-reactive antibodies are also part of the antigen-experienced memory B cell compartment, we analyzed recombinant antibodies cloned from single circulating human IgM+ memory B cells. Cells expressing antibodies specific for individual bacterial polysaccharides were expanded in the IgM+ memory compartment. In contrast, B cells expressing self-reactive and broadly bacterially reactive antibodies were removed from the repertoire in the transition from naive to IgM+ memory B cell. Selection against self-reactive antibodies was implemented before the onset of somatic hypermutation. We conclude that a third checkpoint selects against self-reactivity during IgM+ memory B cell development in humans.

Abbreviations used: ANA, antinuclear antibody; CVID, common variable immunodeficiency; FWR, framework region; HEL, Hen egg lysozyme; IFA, indirect immunofluorescence assay; MZ, marginal zone; mSpA, modified Staphylococcus aureus protein A; SpA, Staphylococcus aureus protein A; T-I, T cell–independent; T-D, T cell–dependent.

M.C. Nussenzweig and H. Wardemann contributed equally to this work.


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