Intravenous immunoglobulin mediates anti-inflammatory effects in peripheral blood mononuclear cells by inducing autophagy

Mrinmoy Das (1) , Anupama Karnam (1) , Emmanuel Stephen-Victor (1) , Laurent Gilardin (1, 2) , Bharat Bhatt (3) , Varun Kumar Sharma (1) , Naresh Rambabu (1) , Veerupaxagouda Patil (1) , Maxime Lecerf (1, 4) , Fabian Käsermann (5) , Patrick Bruneval (6) , Kithiganahalli Narayanaswamy Balaji (3) , Olivier Benveniste (7) , Srini V. Kaveri (1, 4) , Jagadeesh Bayry (1, 4)

1 Immuno-pathologie et immuno-intervention thérapeutique = Immunopathology and Therapeutic Immuno-intervention [CRC]
2 CHU Pitié-Salpêtrière [AP-HP]
3 IISc Bangalore - Indian Institute of Science [Bangalore]
4 UFR Médecine UPCité - UFR Médecine [Santé] - Université Paris Cité
5 CLS Behring AG, Bern
6 SACP - Service d'Anatomie et de Cytologie Pathologique
7 Centre de recherche en Myologie – U974 SU-INSERM

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.

Domaines: Immunologie

Mrinmoy Das, Anupama Karnam, Emmanuel Stephen-Victor, Laurent Gilardin, Bharat Bhatt, et al.. Intravenous immunoglobulin mediates anti-inflammatory effects in peripheral blood mononuclear cells by inducing autophagy. Cell Death and Disease, 2020, 11 (1), pp.50. ⟨10.1038/s41419-020-2249-y⟩. ⟨inserm-02553444⟩