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Human autoantibody silencing by immunoglobulin light chains
Hedda Wardemann1, Johanna Hammersen, Michel C Nussenzweig
1The Rockefeller University, 1230 York Ave., Box 220, New York, NY 10021, USA.
The Journal of Experimental Medicine
|July 21, 2004
Summary
Most potentially self-damaging human antibodies are silenced by receptor editing. Replacing antibody light chains effectively silenced autoreactivity, suggesting this mechanism accounts for most autoantibody silencing in humans.
Area of Science:
- Immunology
- Molecular Biology
Background:
- Newly arising human antibodies can be polyreactive, meaning they bind to multiple targets.
- In healthy individuals, potentially self-damaging antibodies are typically eliminated through receptor editing or B cell deletion in the bone marrow.
Purpose of the Study:
- To investigate the extent to which naturally occurring autoantibodies can be silenced by immunoglobulin (Ig) light chain receptor editing.
- To determine the efficacy of different Ig light chains in silencing autoreactivity.
Main Methods:
- Replaced light chains of 12 naturally arising autoantibodies with various Igkappa and Iglambda chains.
- Assessed the silencing activity of the modified antibodies.
Main Results:
- The majority of naturally arising autoantibodies were readily silenced by light chain exchange.
- Iglambda light chains were more effective than Igkappa light chains in silencing autoreactivity.
- No correlation was found between light chain complementarity determining region (CDR) isoelectric points and silencing activity.
Conclusions:
- Receptor editing, particularly via light chain exchange, likely accounts for the majority of autoantibody silencing in humans.
- The greater silencing efficacy of Iglambda chains may explain evolutionary changes in the Iglambda locus.