Although the presence of sialic acid on IVIg and SIGN-R1 were required, IVIg was still protective in splenectomized mice, indicating that a cell type
other than splenic macrophages mediated the anti-inflammatory FDA approved Drug Library effect of IVIg in this case . These findings are directly relevant to human ITP because some splenectomized patients with this disease still respond positively to IVIg therapy. Moreover, IVIg still inhibited the pathogenic effect of the anti-platelet antibody in the absence of IL-33, basophils, or IL-4 . These findings are important because they indicate that different mechanisms are at play in the protective effect of IVIg depending on the disease model. The two models of antibody-mediated diseases discussed, antibody-mediated arthritis and ITP, are markedly different from each other. For instance, mast cells and neutrophils are necessary for the development of antibody-mediated arthritis [25,
26], while they are dispensable for the development of ITP . These differences in mechanisms of pathogenesis are reflected in the kinetics of these diseases: arthritis induced by the injection of antibodies takes days to develop, while platelet depletion in ITP reaches AZD1208 purchase a maximum level 2–4 h after antibody administration, possibly due to immediate removal of autoantibody-opsonized platelet removal by CX3CR1hiLyC6loCD11cint monocytes in blood [27, Teicoplanin 28]. In their study published in this issue of the European Journal of Immunology, Schwab et al.  have added another layer of complexity to our understanding of the mode of action of IVIg toward autoantibody-mediated diseases. The novelty of their approach is in the utilization of IVIg in a therapeutic rather than in a preventive setting; the authors administrated IVIg to mice after, instead of before, the pathogenic antibodies. This might seem like a small difference, yet it is significant since IVIg is a therapy administered to humans who already have the disease and autoantibodies.
The therapeutic administration of IVIg turned out to have a major impact on the mode of action, as detailed below (Table 1). Another major strength of this study is the utilization of four distinct models of antibody-driven diseases, namely, two models of ITP (using two distinct antiplatelet monoclonal antibodies), one model of inflammatory arthritis, and a model of the skin blistering disease epidermolysis bullosa (EBA) . IVIg was administered to mice on day 2 after the first injection of the antiplatelet antibodies, or on day 3 or day 4 after induction of arthritis or EBA, respectively . Although these pathologies are all driven by the administration of antibodies, they differ in their underlying pathogenic mechanisms.