Antiinflammatory Activity of IVIG Mediated through the Inhibitory FC Receptor

James E. Gern

Purpose of the Study. High-dose intravenous gamma globulin (IVIG) has proven effective for the treatment of autoimmune diseases such as immune thrombocytopenia (ITP), but the mechanism for its beneficial effects have not been clearly defined. In this study, the molecular basis for the antiinflammatory property of IVIG was investigated in a murine model of ITP.

Methods. ITP was induced in mice through the injection of an antiplatelet monoclonal antibody (mAb), and pretreatment with either IVIG or Fc antibody fragments (which bind to Fcγ receptors on cells, but cannot bind antigens) could prevent the resulting thrombocytopenia. Through the use of specific blocking antibodies and transgenic mice, the authors tested whether IgG receptors (FcγRIIB, FcγRIII) were involved in the protective effects of IVIG.

Results. The FcγRIIB receptor was required for protection, as demonstrated by genetic deletion or blocking with mAb. In addition, protection by IVIG was associated with the induction of FcγRIIB, which inhibits macrophage activation, and presumably also inhibits the phagocytosis of platelets in the spleen.

Conclusions. The authors concluded that IVIG inhibits autoantibody-mediated thrombocytopenia by inducing inhibitory FcγRIIB receptors on macrophages. The balance of inhibitory (FcγRIIB) and activating (FcγRIII) Fc receptors is likely to be a critical factor in the regulation of macrophage phagocytosis. These results suggest that autoantibody-triggered inflammatory diseases could be treated by new medications that inhibit macrophage phagocytosis.

Reviewer’s Comments. IVIG is an effective treatment for many diseases caused by autoantibodies, but its utility is limited by high cost, administration by prolonged intravenous infusion, and the occasional occurrence of side effects such as aseptic meningitis and renal insufficiency. This work suggests that new approaches could be developed that would utilize the same protective mechanism as IVIG, but be more easily administered and potentially have fewer side effects. This research also suggests that defects in the FcγRIIB inhibitory mechanism could underlie antibody-mediated autoimmunity. Although additional work is needed to determine whether the findings in this mouse model apply to human disease, these results are cause for optimism.