Involvement of Virus-Induced Interferon Production in IgG Autoantibody-Mediated Anemia.

Sarah Legrain,Mélanie Gaignage,Jean-Paul Coutelier,J Sjef Verbeek,Shozo Izui,Dan Su,Cor Breukel,Jill Claassens,Margot M Linssen,Conny Brouwers

doi:10.3390/ijms22169027

Abstract

Infection with viruses, such as the lactate dehydrogenase-elevating virus (LDV), is known to trigger the onset of autoimmune anemia through the enhancement of the phagocytosis of autoantibody-opsonized erythrocytes by activated macrophages. Type I interferon receptor-deficient mice show enhanced anemia, which suggests a protective effect of these cytokines, partly through the control of type II interferon production. The development of anemia requires the expression of Fcγ receptors (FcγR) I, III, and IV. Whereas LDV infection decreases FcγR III expression, it enhances FcγR I and IV expression in wild-type animals. The LDV-associated increase in the expression of FcγR I and IV is largely reduced in type I interferon receptor-deficient mice, through both type II interferon-dependent and -independent mechanisms. Thus, the regulation of the expression of FcγR I and IV, but not III, by interferons may partly explain the exacerbating effect of LDV infection on anemia that results from the enhanced phagocytosis of IgG autoantibody-opsonized erythrocytes.

Highlights

Mouse infection with the lactate dehydrogenase-elevating virus (LDV) has been shown to exacerbate autoimmune diseases, such as antibody-mediated anemia [1,2] and thrombocytopenia [3,4]
To demonstrate the effect of viral infection on the establishment of autoimmune hemolytic anemia, 34-3C anti-Red Blood Cell (RBC) IgG2a mAb was injected into LDV-infected mice
The administration of 50 μg of this antibody to wild-type (WT) C57BL/6 mice induced moderate anemia after 4 and 5 days compared to WT animals treated with the control IgG2a (Figure 1A), and LDV infection worsened the anemia developed by 34-3C-treated mice (Figure 1A, p = 0.0005 and p < 0.0081, respectively)

Summary

Introduction

Mouse infection with the lactate dehydrogenase-elevating virus (LDV) has been shown to exacerbate autoimmune diseases, such as antibody-mediated anemia [1,2] and thrombocytopenia [3,4] This effect of LDV infection can be explained by the enhanced phagocytic activity of macrophages [1,3], leading to the engulfment and destruction of opsonized cells in response to the macrophage activation, which is mostly triggered by the gammainterferon (IFN-γ) secreted by natural killer cells upon infection [5]. The respective roles of Fc receptors (FcRs) and antibody isotypes in the phagocytosis of opsonized erythrocytes have been extensively analyzed in uninfected animals through the use of a large panel of anti-red blood cell antibody switch variants and mice deficient in one or several FcRs for IgG (FcγR) [6,7,8,9]. The present study was performed to analyze the effects of LDV infection on the expression of all activating FcγRs, their involvement in the exacerbated phagocytic activity, and the resulting anemia triggered by infection

Methods

Results

Conclusion