FcγRIII (CD16)-Deficient Mice Show IgG Isotype-Dependent Protection to Experimental Autoimmune Hemolytic Anemia

Abstract

In autoimmune hemolytic anemia (AIHA), there is accumulating evidence for an involvement of FcγR expressed by phagocytic effector cells, but demonstration of a causal relationship between individual FcγRs 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 FcγRIII, and comparing the clinical outcome to those in wild-type mice. FcγRIII-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 FcγRIII 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 FcγRIII reflects an activation of FcγRI that is normally coexpressed with FcγRIII on macrophages. Together these results show that the pathogenesis of AIHA through IgG1-dependent erythrophagocytosis is exclusively mediated by FcγRIII and further suggest that FcγRI, in addition to FcγRIII, contributes to this autoimmune disease when other IgG isotypes such as IgG2a are involved.

Insulin‐like growth factor‐binding protein‐2 in patients with prostate carcinoma and benign prostatic hyperplasia

“…This may easily account for the strong inhibition of in vitro erythrophagocytosis obtained in this study with human IgG1 and IgG3, but not with IgG2 and IgG4, and is consistent with the in vivo activity of IgG1 and IgG3 reported previously [36]. This efficiency of IgG1 and IgG3, but not of IgG2 and IgG4, may correspond to binding to Fc γ RIII that specifically recognizes these isotypes [41] and that is involved in antibody-mediated erythrophagocytosis, at least in the mouse [42]. Because the avidity of IgG oligomers to Fc γ receptors increases with their size [43], it could be postulated that large polymers would be more efficient to block these receptors and therefore to inhibit erythrophagocytosis.…”

Increased survival and reduced renal injury in MRL/lpr mice treated with a human Fcγ receptor II (CD32) peptide

“…5,6 Studies in mouse models lacking various Fc receptors have demonstrated the pivotal role of Fc receptors in many IC-mediated diseases. [7][8][9][10][11] Lupus-prone mice lacking Fcc receptors I and III as a result of targeted disruption of the Fc receptor c-chain (FccR )/) ), were completely protected from glomerulonephritis. 12 Complement-deficient mice mount a normal Arthus reaction, whereas FccR-deficient mice lack this ability.…”

Fc Receptors in Immune Responses

“…Each of these receptors was sufficient to induce ITP, suggesting a redundant role of activating FcgR . The involvement of FcgRI, FcgRIIIA, and FcgRIV was also reported in systemic lupus erythematosus (SLE) (Seres et al, 1998), experimental hemolytic anemia (Meyer et al, 1998;Syed et al, 2009), glomerulonephritis (Fujii et al, 2003), and arthritis (Bruhns et al, 2003;Ioan-Facsinay et al, 2002;Mancardi et al, 2011). The role of FcgRI in arthritis is however controversial as the blockade of FcgRIIIA and FcgRIV in wild type mice abolished symptoms and neutrophil infiltration in the joints .…”