FcgammaRIII (CD16)-deficient mice show IgG isotype-dependent protection to experimental autoimmune hemolytic anemia.
In autoimmune hemolytic anemia (AIHA), there is accumulating evidence for an involvement of FcgammaR expressed by phagocytic effector cells, but demonstration of a causal relationship between individual FcgammaRs and IgG isotypes for disease development is lacking. Although the relevance of IgG isotypes to human AIHA is limited, we could show a clear IgG isotype dependency in murine AIHA using pathogenic IgG1 (105-2H) and IgG2a (34-3C) autoreactive anti-red blood cell antibodies in mice defective for FcgammaRIII, and comparing the clinical outcome to those in wild-type mice. FcgammaRIII-deficient mice were completely resistent to the pathogenic effects of 105-2H monoclonal antibody, as shown by a lack of IgG1-mediated erythrophagocytosis in vitro and in vivo. In addition, the IgG2a response by 34-3C induced a less severe but persistent AIHA in FcgammaRIII knock-out mice, as documented by a decrease in hematocrit. Blocking studies indicated that the residual anemic phenotype induced by 34-3C in the absence of FcgammaRIII reflects an activation of FcgammaRI that is normally coexpressed with FcgammaRIII on macrophages. Together these results show that the pathogenesis of AIHA through IgG1-dependent erythrophagocytosis is exclusively mediated by FcgammaRIII and further suggest that FcgammaRI, in addition to FcgammaRIII, contributes to this autoimmune disease when other IgG isotypes such as IgG2a are involved.
Meyer
D
D
Departments of Clinical Immunology and Functional Anatomy, Hannover Medical School, Hannover, Germany.
Schiller
C
C
Westermann
J
J
Izui
S
S
Hazenbos
W L
WL
Verbeek
J S
JS
Schmidt
R E
RE
Gessner
J E
JE
D000744:Anemia, Hemolytic, Autoimmune / Q000276:immunology*; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004912:Erythrocytes / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D007132:Immunoglobulin Isotypes / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis; D017452:Receptors, IgG / Q000172:deficiency* / Q000235:genetics / Q000276:immunology
D001323:Autoantibodies; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D017452:Receptors, IgG