Immune complexes from vasculitis patients bind to endothelial Fc receptors independent of the allelic polymorphism of FcgammaRIIa.
Cutaneous leukocytoclastic vasculitis is characterized by the deposition of circulating immune complexes, neutrophil extravasation, and vessel destruction, but mechanisms of circulating immune complexes capture within postcapillary venules are unknown. We demonstrate that circulating immune complexes from sera of vasculitis patients bind to cultured endothelium in an Fc gamma receptor IIa-dependent fashion. In lesional skin, endothelial cells bind immunoglobulin G2 > immunoglobulin G3 and immunoglobulin G4, but not immunoglobulin G1, even before obvious neutrophil transmigration and vessel damage. As the human Fc gamma receptor IIa proteins exist in two allotypes (one with a histidine at position 131, which binds immunoglobulin G1, 2, 3 and the other with an arginine at position 131, which binds immunoglobulin G1, and 3, but is unable to bind immunoglobulin G2), we expected an altered prevalence of histidine 131 forms in vasculitis patients. Sequence analysis, however, revealed an equal distribution of allotypes in patients and controls. In conclusion, circulating immune complex binding to endothelial Fc gamma receptor IIa is among the initial steps in the development of vasculitis. Although immunoglobulin G2 is the predominant subtype precipitated at endothelial surfaces, it is not required for fixing circulating immune complexes to endothelium, because patients homozygote for Fc gamma receptor IIa-arginine 131 equally develop leukocytoclastic vasculitis as those bearing the Fc gamma receptor IIa-histidine 131 allele. As immunoglobulin G1 is virtually absent in leukocytoclastic vasculitis lesions and immunoglobulin G4 does not bind to both Fc gamma receptor IIa alleles, these complexes, in addition to immunoglobulin G2, should contain immunoglobulin G3 in order to fix to vascular Fc gamma receptor IIa, at least in persons homozygous for Fc gamma receptor IIa-arginine 131.


BACKGROUND
CD32/immunoglobulin G subtypes/leukocytoclastic vasculitis/microvessels.
Department of Dermatology, Division of General Dermatology, University of Vienna Medical School, Austria.
M
M
Gröger
G F
GF
Fischer
K
K
Wolff
P
P
Petzelbauer
D000483:Alleles; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007106:Immune Sera / Q000378:metabolism*; D007126:Immunoglobulin Allotypes / Q000235:genetics; D007074:Immunoglobulin G / Q000378:metabolism; D011110:Polymorphism, Genetic; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism*; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D017445:Skin Diseases, Vascular / Q000276:immunology / Q000378:metabolism*; D018366:Vasculitis, Leukocytoclastic, Cutaneous / Q000276:immunology / Q000378:metabolism*
D015703:Antigens, CD; C080568:Fc gamma receptor IIA; D007106:Immune Sera; D007126:Immunoglobulin Allotypes; D007074:Immunoglobulin G; D011961:Receptors, Fc; D017452:Receptors, IgG