IVIg immune inhibitory activity: APC is key.

In this issue of Blood, Aubin and colleagues show that IVIg interacted with Fc Rs on APCs, resulting in reduced antigen presentation and inhibition of antigenspecific T-cell response.1 This finding suggests a key role for APCs in IVIg action. Recent evidence suggests that an essential step in the immunopathology of autoimmune disease (AD) involves antigenpresenting cells (APCs) presenting antigen to antigen-specific CD4 T helper cells,2 which, in turn, induce antigen-specific B cells to produce autoantibodies (see figure). Costimulatory molecules including CD40 and CD154 play an important role in these cellular interactions, which perpetuate the disease. Autoantibodies bind autoantigens to form immune complexes (ICs) that are taken up by APCs via Fc receptors (Fc Rs) for antigen processing and presentation, thus maintaining the pathogenic loop.3,4 Intravenous immunoglobulin (IVIg) has been used to treat AD for more than 2 decades. The precise mechanism(s) of action is still unclear.5 In this issue of Blood, Aubin and colleagues1 provide evidence suggesting that IVIg acts at the level of APC even though they found that IVIg inhibited antigen-specific T-cell and B-cell response. Mice immunized with ovalbumin (OVA) in the presence of IVIg generated reduced numbers of antigenspecific T cells compared with mice immunized with OVA in the absence of IVIg. IVIg treatment during OVA immunization significantly reduced OVA-specific antibody production. These suppressive activities of IVIg were not the result of decreased APC surface expression of MHCII and CD80/ CD86 costimulatory molecules, as previously postulated, but were the consequence of IVIg interfering with IC binding to activating Fc Rs expressed on APC. Three mechanisms have been proposed for the immune suppressive action of IVIg6 (see figure) in which pathogenic IgG/IC and Fc Rs on APC are believed have a role. Mechanism 1: IVIg competes with IC for activating Fc Rs. In this mechanism, high-dose IVIg competes with IC for activating Fc Rs on APC surface.6 Data of Aubin et al1 would favor this mechanism. First, these investigators showed that 2.4G2, Fc RIII–specific monoclonal antibody blocked OVA-IC binding to bone marrow dendritic cells (BM-DCs), used as APC in this study. Second, they found that intact IV IgG inhibited antigen-specific T-cell response but its F(ab ) fragments did not. Third, BM-DCs from chain– deficient mice (lacking Fc Rs) failed to activate CD4 T cells in the presence of IC. Altogether, their results suggest that IVIg via its Fc domain competes with IC for binding to activating Fc Rs expressed on APCs, consequently reduces APC antigen presentation, and inhibits CD4 T-cell activation and other downstream immune responses. One reservation in interpreting these data is that monomeric IgG in A model for the immunopathology of autoimmune disease. Some aspects such as the role of cytotoxic T cells and regulatory T cells are not included. Proposed mechanisms whereby IVIg interferes with immune complex–APC interaction are shown in the top 3 panels.