Complement-independent, peroxide-induced antibody lysis of platelets in HIV-1-related immune thrombocytopenia.
Immunologic thrombocytopenia is seen commonly in HIV-1 infection. The pathogenesis of this problem has been unclear, but it is associated with circulating immune complexes that contain platelet membrane components and anti-platelet membrane GPIIIa49-66 IgG antibodies. These antibodies cause acute thrombocytopenia when injected into mice. We now show that purified anti-GPIIIa49-66 causes platelet fragmentation, in vitro in the absence of complement, and in vivo in wild-type and C3-deficient mice. The mechanism of complement-independent platelet lysis is shown to be caused by the antibody-induced generation of H202, as indicated by in vitro experiments with inhibitors of reactive oxygen species, and in vivo studies carried out with p47phox-deficient mice. Thus, a novel mechanism of immunologic platelet clearance is described in which an anti-platelet IgG causes platelet fragmentation via the induction of reactive oxygen species.
Nardi
M
M
Department of Pediatrics, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
Tomlinson
S
S
Greco
M A
MA
Karpatkin
S
S
D000818:Animals; D000936:Antigen-Antibody Complex / Q000737:chemistry / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism; D001792:Blood Platelets / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D003165:Complement System Proteins / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000150:complications* / Q000276:immunology / Q000378:metabolism; D015497:HIV-1; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D019255:NADPH Oxidases; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000209:etiology* / Q000276:immunology; D013917:Thrombin / Q000378:metabolism
D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D007140:Immunoglobulin Fab Fragments; D010446:Peptide Fragments; D010718:Phosphatidylserines; D010750:Phosphoproteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; C106958:platelet glycoprotein (GP)IIIa 49-66; D003165:Complement System Proteins; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D013917:Thrombin