Human Autoantibody Silencing by Immunoglobulin Light Chains

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 Igkappa and Iglambda 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 Iglambda genes were more effective than Igkappa genes as silencers. The greater efficacy of Iglambda chains as silencer of autoreactivity provides a possible explanation for the expansion and altered configuration of the Iglambda locus in evolution.