Can antibodies with specificity for soluble antigens mimic the therapeutic effects of intravenous IgG in the treatment of autoimmune disease?

Abstract

Intravenous Ig (IVIg) mediates protection from the effects of immune thrombocytopenic purpura (ITP) as well as numerous other autoimmune states; however, the active antibodies within IVIg are unknown. There is some evidence that antibodies specific for a cell-associated antigen on erythrocytes are responsible, at least in part, for the therapeutic effect of IVIg in ITP. Yet whether an IVIg directed to a soluble antigen can likewise be beneficial in ITP or other autoimmune diseases is also unknown. A murine model of ITP was used to determine the effectiveness of IgG specific to soluble antigens in treating immune thrombocytopenic purpura. Mice experimentally treated with soluble OVA + anti-OVA versus mice treated with OVA conjugated to rbcs (OVA-rbcs) + anti-OVA were compared. In both situations, mice were protected from ITP. Both these experimental therapeutic regimes acted in a complement-independent fashion and both also blocked reticuloendothelial function. In contrast to OVA-rbcs + anti-OVA, soluble OVA + anti-OVA (as well as IVIg) did not have any effect on thrombocytopenia in mice lacking the inhibitory receptor FcγRIIB (FcγRIIB-/-mice). Similarly, antibodies reactive with the endogenous soluble antigens albumin and transferrin also ameliorated ITP in an FcγRIIB-dependent manner. Finally, broadening the significance of these experiments was the finding that anti-albu-min was protective in a K/BxN serum-induced arthritis model. We conclude that IgG antibodies directed to soluble antigens ameliorated 2 disparate IVIg-treatable autoimmune diseases.

Suppression of Fcγ-Receptor-Mediated Antibody Effector Function during Persistent Viral Infection

“…Interestingly, using the platelet-depletion model of idiopathic thrombocytopenic purpura (ITP), we observe a suppression of autoAb-induced platelet reduction during persistent LCMV infection when high concentrations of ICs are present. Similar protection is observed with high dose IVIG in the treatment of Ab-mediated autoimmune diseases (Schwab and Nimmerjahn, 2013; Siragam et al, 2005) and is thought to work through a variety of mechanisms including the inhibitory FcγRIIB on macrophages (Anthony et al, 2011). However, in response to IC-mediated suppression of FcγR function during persistent infection, we did not observe a rescue of antibody activity in persistently infected FcγRIIB-deficient mice, although this type of regulation may be important for other aspects of the immune response including B cell antibody production.…”

Chapter 4 Multitasking by Exploitation of Intracellular Transport Functions

“…However, in addition to FcRn blockade, IVIG has multiple other possible modes of action that include FcγR-mediated effects (discussed in Clynes, 2007). For example, in mice the monomeric IgG component of IVIG can induce the upregulation of FcγRIIB expression (Bruhns et al ., 2003; Samuelsson et al ., 2001; Siragam et al ., 2005). IVIG treatment can also result in signaling by ICs through the activating receptor, FcγRIII, to inhibit IFN-γ responses or regulate dendritic cell activity in mice (Park-Min et al ., 2007; Siragam et al ., 2006).…”

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“…Interestingly, IVIG treament or anti-murine albumin antibodies protected mice against KBN serum-induced arthritis [139], suggesting the importance of FcR interactions in arthritis pathogenesis. Recently, anatomically restricted macromolecular vasopermeability dependent on vasoactive amines has been shown as one of the bases for the selectivity of the immune complex-facilitated antibody access to the joints [140].…”