Abstract
Autophagy plays an important role in the regulation of autoimmune and autoinflammatory responses of the immune cells. Defective autophagy process is associated with various autoimmune and inflammatory diseases. Moreover, in many of these diseases, the therapeutic use of normal immunoglobulin G or intravenous immunoglobulin (IVIG), a pooled normal IgG preparation, is well documented. Therefore, we explored if IVIG immunotherapy exerts therapeutic benefits via induction of autophagy in the immune cells. Here we show that IVIG induces autophagy in peripheral blood mononuclear cells (PBMCs). Further dissection of this process revealed that IVIG-induced autophagy is restricted to inflammatory cells like monocytes, dendritic cells, and M1 macrophages but not in cells associated with Th2 immune response like M2 macrophages. IVIG induces autophagy by activating AMP-dependent protein kinase, beclin-1, class III phosphoinositide 3-kinase and p38 mitogen-activated protein kinase and by inhibiting mammalian target of rapamycin. Mechanistically, IVIG-induced autophagy is F(ab′)2-dependent but sialylation independent, and requires endocytosis of IgG by innate cells. Inhibition of autophagy compromised the ability of IVIG to suppress the inflammatory cytokines in innate immune cells. Moreover, IVIG therapy in inflammatory myopathies such as dermatomyositis, antisynthetase syndrome and immune-mediated necrotizing myopathy induced autophagy in PBMCs and reduced inflammatory cytokines in the circulation, thus validating the translational importance of these results. Our data provide insight on how circulating normal immunoglobulins maintain immune homeostasis and explain in part the mechanism by which IVIG therapy benefits patients with autoimmune and inflammatory diseases.
Highlights
Recent reports show that macroautophagy, hereafter referred to as autophagy, plays an important role in the regulation of autoimmune and autoinflammatory responses
intravenous immunoglobulin (IVIG) induces autophagy in peripheral blood mononuclear cells of healthy donors In order to investigate whether IVIG induces autophagy, we first resorted to peripheral blood mononuclear cells (PBMCs) of healthy donors
As LC3II was enhanced in cells treated with 10 mg concentration of IVIG, which correspond to IgG in the circulation of healthy individuals, this suggests that circulating normal IgG induces autophagy under physiological conditions
Summary
Recent reports show that macroautophagy, hereafter referred to as autophagy, plays an important role in the regulation of autoimmune and autoinflammatory responses. Autophagy involves lysosomal degradation of unnecessary or dysfunctional cellular components, Official journal of the Cell Death Differentiation Association. Das et al Cell Death and Disease (2020)11:50 machinery. P38 mitogen-activated protein kinase (p38 MAPK) has a dual role in regulating autophagy[3]. Autophagy was initially investigated as a process involved in the “cell survival” and nowadays is recognized as fundamental in the physiology of eukaryotic cells. Autophagy plays a fundamental role in the regulation of innate and adaptive immune responses[4], lymphocyte differentiation, survival and homeostasis[4,5]. In many of these diseases, the therapeutic use of intravenous and subcutaneous immunoglobulin (IVIG/SCIG), the normal human IgG preparations obtained from the pools of plasma of several thousand healthy donors is well documented[17,18,19,20]
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