The Journal of Experimental Medicine
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Published online 21 February 2006 doi:10.1084/jem.20052438
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 3, 553-561
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ARTICLE

 TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE

Marc Ehlers1, Hidehiro Fukuyama1, Tracy L. McGaha1, Alan Aderem2, and Jeffrey V. Ravetch1

1 Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10021
2 The Institute for Systems Biology, Seattle, WA 98103

CORRESPONDENCE Jeffrey V. Ravetch: ravetch{at}rockefeller.edu

Loss of tolerance in systemic lupus erythematosus (SLE) leads to the generation of autoantibodies, which accumulate in end-organs where they induce disease. Here we show that immunoglobulin (Ig)G2a and 2b autoantibodies are the pathogenic isotypes by recruiting Fc{gamma}RIV expressing macrophages. Class switching, but not development, of IgM anti-self B cells to these pathogenic subclasses requires the innate immune receptor Toll-like receptor (TLR)9 and MyD88 signaling. In their absence, switching of autoreactive B cells to the IgG2a and 2b subclasses is blocked, resulting in reduced pathology and mortality. In contrast, switching of anti-self B cells to IgG1 is not perturbed and generation of nonautoreactive IgG2a and 2b antibodies is not impaired in TLR9-deficient mice. Thus, the TLR9 pathway is a potential target for therapeutic intervention in SLE.

Abbreviations used: GBM, antiglomerular basement membrane; GC, germinal center; SLE, systemic lupus erythematosus; TLR, Toll-like receptor.


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