Both FcgammaRIV and FcgammaRIII are essential receptors mediating type II and type III autoimmune responses via FcRgamma-LAT-dependent generation of C5a.
FcgammaRIV is a relatively new IgG Fc receptor (FcgammaR) that is reported to contribute to the pathogenesis of autoimmune diseases, although its specific role in relation to FcgammaRIII, complement and IgG2 subclasses remains uncertain. Here we define FcgammaRIV on macrophages as a receptor for soluble IgG2a/b complexes but not for cellular bound IgG2a and show that simultaneous activation of FcgammaRIV and FcgammaRIII is critical to mediate certain type II/III autoimmune responses. FcgammaRIII-deficient mice display compensatory enhanced FcgammaRIV expression, are protected from lung inflammation after deposition of IgG complexes, and show reduced sensitivity to IgG2a/b-mediated hemolytic anemia, indicating that increased FcgammaRIV alone is not sufficient to trigger these diseases in the absence of FcgammaRIII. Importantly, however, blockade of FcgammaRIV 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 FcgammaRIII and FcgammaRIV are each essential to trigger an FcRgamma-linker for activation of T-cell-dependent signal that drives C5a production in the Arthus reaction. Together, the results demonstrate a combined requirement for FcgammaRIII and FcgammaRIV in autoimmune injury, and identify the linker for activation of T cells adaptor as an integral component of linked FcgammaR and C5a anaphylatoxin receptor activation to generate inflammation.
Laboratory for Molecular Immunology, Clinic for Immunology and Rheumatology, Hannover Medical School, Hannover, Germany.
Shahzad N
SN
Syed
Stephanie
S
Konrad
Kristina
K
Wiege
Bernhard
B
Nieswandt
Falk
F
Nimmerjahn
Reinhold E
RE
Schmidt
J Engelbert
JE
Gessner
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000744:Anemia, Hemolytic, Autoimmune / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010587:Phagocytosis / Q000276:immunology; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011014:Pneumonia / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D044087:Receptor, Anaphylatoxin C5a / Q000276:immunology* / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C485700:Fcgr3 protein, mouse; C522404:Fcgr4 protein, mouse; D007074:Immunoglobulin G; C491734:Lat protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D044087:Receptor, Anaphylatoxin C5a; D017452:Receptors, IgG