Both FcγRIV and FcγRIII are essential receptors mediating type II and type III autoimmune responses via FcRγ-LAT-dependent generation of C5a
✍ Scribed by Shahzad N. Syed; Stephanie Konrad; Kristina Wiege; Bernhard Nieswandt; Falk Nimmerjahn; Reinhold E. Schmidt; J. Engelbert Gessner
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 591 KB
- Volume
- 39
- Category
- Article
- ISSN
- 0014-2980
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✦ Synopsis
FccRIV is a relatively new IgG Fc receptor (FccR) that is reported to contribute to the pathogenesis of autoimmune diseases, although its specific role in relation to FccRIII, complement and IgG2 subclasses remains uncertain. Here we define FccRIV on macrophages as a receptor for soluble IgG2a/b complexes but not for cellular bound IgG2a and show that simultaneous activation of FccRIV and FccRIII is critical to mediate certain type II/III autoimmune responses. FccRIII-deficient mice display compensatory enhanced FccRIV expression, are protected from lung inflammation after deposition of IgG complexes, and show reduced sensitivity to IgG2a/b-mediated hemolytic anemia, indicating that increased FccRIV alone is not sufficient to trigger these diseases in the absence of FccRIII. Importantly, however, blockade of FccRIV is also effective in inhibiting phagocytosis and cytokine production in IgG2b-induced anemia and acute lung injury, processes that display a further dependence on C5a anaphylatoxin receptor. Using gene deletion and functional inhibition studies, we found that FccRIII and FccRIV are each essential to trigger an FcRc-linker for activation of T-celldependent signal that drives C5a production in the Arthus reaction. Together, the results demonstrate a combined requirement for FccRIII and FccRIV in autoimmune injury, and identify the linker for activation of T cells adaptor as an integral component of linked FccR and C5a anaphylatoxin receptor activation to generate inflammation.