The Journal of Experimental Medicine
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Published 19 July 2004. doi:10.1084/jem.20040818
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 2, 191-199
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Human Autoantibody Silencing by Immunoglobulin Light Chains

Hedda Wardemann1, Johanna Hammersen1, and Michel C. Nussenzweig1,2

1 Laboratory of Molecular Immunology, The Rockefeller University and 2 Howard Hughes Medical Institute, New York, NY 10021

Address correspondence to Michel C. Nussenzweig, The Rockefeller University, 1230 York Ave., Box 220, New York, NY 10021. Phone: (212) 327-8067; Fax: (212) 327-8370; email: nussen{at}mail.rockefeller.edu

Several newly arising human antibodies are polyreactive, but in normal individuals the majority of these potentially autodestructive antibodies are removed from the repertoire by receptor editing or B cell deletion in the bone marrow. To determine what proportion of naturally arising autoantibodies can be silenced by immunoglobulin (Ig) light chain receptor editing, we replaced the light chains in 12 such antibodies with a panel of representative Ig{kappa} and Ig{lambda} chains. We found that most naturally arising autoantibodies are readily silenced by light chain exchange. Thus, receptor editing may account for most autoreactive antibody silencing in humans. Light chain complementarity determining region (CDR) isoelectric points did not correlate with silencing activity, but Ig{lambda} genes were more effective than Ig{kappa} genes as silencers. The greater efficacy of Ig{lambda} chains as silencer of autoreactivity provides a possible explanation for the expansion and altered configuration of the Ig{lambda} locus in evolution.

Key Words: human • tolerance • B lymphocytes • receptor editing • autoantibodies

Abbreviations used in this paper: ANA, antinuclear antibody; CDR, complementarity determining region; D, diversity; IgH, Ig heavy; IgL, Ig light; J, joining; pI, isoelectric point; V, variable.


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