TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE.
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 FcgammaRIV 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.
Ehlers
Marc
M
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10021, USA.
Fukuyama
Hidehiro
H
McGaha
Tracy L
TL
Aderem
Alan
A
Ravetch
Jeffrey V
JV
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000276:immunology*; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D017452:Receptors, IgG / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D001323:Autoantibodies; D007074:Immunoglobulin G; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D017452:Receptors, IgG; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9