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Abstract
AbstractIntravenous gamma globulin (IVIG) is used as an effective therapy for many different autoimmune and inflammatory diseases. The current paradigm for the mechanism underpinning anti-inflammatory effects links IVIG administration to increased expression and activity of the inhibitory Fc[gamma] receptor (Fc[gamma]RIIB) on splenic macrophages. This hypothesis has been disputed in the literature. Here we show that IVIG administered in the context of passive antibody-mediated thrombocytopenia to be therapeutically efficacious in both splenectomized and unmanipulated Balb/c mice despite no upregulation of Fc[gamma]RIIB mRNA in the spleen. Moreover, IVIG effectively ameliorated immune thrombocytopenia (ITP) in Fc[gamma]RIIB-deficient Balb/c mice, but not in Fc[gamma]RIIB-/- or Fc[gamma]RIIB+/+ control mice with a C57BL6/129S background. Our results demonstrate that Fc[gamma]RIIB is not relevant to the beneficial effects of IVIG. We anticipate that investigators will now shift their research focus away from Fc[gamma]RIIB and seek out other possible mechanism(s) to explain the plethora of diseases and conditions treatable with IVIG.
Highlights
Intravenous gamma globulin (IVIG) is used as an effective therapy for many different autoimmune and inflammatory diseases[1,2,3,4,5]
In 20016, it was reported that the inhibitory Fc receptor, FcγRIIB, is upregulated in the splenic macrophages of immune thrombocytopenic mice following administration of IVIG and that FcγRIIB knockout mice fail to respond to IVIG therapy
In human immune thrombocytopenia (ITP), platelet counts usually fall to very low levels and their levels remain low until therapeutic intervention
Summary
Using our mouse model of ITP, we have found the effects of IVIG on thrombocytopenia to be no different in FcγRIIB-deficient compared to wild-type mice on either the C57BL6/129S or Balb/c backgrounds (Fig. 3). A lack of FcγRIIB contribution to IVIG therapeutic effect is supported by our finding that FcγRIIB expression is unaltered in the spleen of wild-type Balb/c mice following IVIG treatment and the lack of any detectable difference in IVIG therapeutic effect in splenectomized compared to unmanipulated FcγRIIB-/- mice on the Balb/c background These findings are consistent with previous data showing that FcγRIIB is not upregulated in monocyte-macrophages obtained from Kawaski’s disease patients treated with IVIG16 and with data showing no differences in IVIG effect on ITP manifested by mice deficient for SHP-1 or SHIP-1, signaling effectors that are key to inhibitory activity of Fc receptors[18,19,20,21]. Further studies are required to pinpoint the key mechanisms accounting for IVIG beneficial effects in ITP and other autoimmune and inflammatory clinical conditions
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