Intravenous immunoglobulin remodels innate immune cell communication and induces differential autophagy pathways in Kawasaki disease

SURAJ SINGH¹Sruthi VIJAYA RETNAKUMAR²MRINMOY DAS^2,3Srini V Kaveri²Mano Joseph Mathew⁴Jagadeesh BAYRY^5*

• ¹Indian Institute of Technology Palakkad, Palakkad, India
• ²INSERM, Paris, France
• ³SRM Institute of Science and Technology Faculty of Medicine and Health Sciences, Kattankulathur, India
• ⁴Efrei Paris, Villejuif, France
• ⁵Unité 1138, INSERM, Centre de Recherche des Cordeliers, Indian Institute of Technology Palakkad, Palakkad, India

Intravenous immunoglobulin (IVIG), a therapeutic preparation of pooled normal IgG is extensively used as a first-line immunotherapy for many autoimmune and inflammatory diseases, including Kawasaki disease. IVIG provides therapeutic benefits through several non-exclusive mechanisms. Our recent data demonstrate that IVIG induces autophagy in inflammatory innate immune cells, a finding further supported by observations in IVIG-treated myopathy patients. In this study, we analysed single-cell transcriptomics data from IVIG-treated Kawasaki disease patients to investigate the specific autophagy pathways activated by IVIG across various innate immune cell subsets. We found that IVIG therapy in Kawasaki disease patients leads to global remodeling of innate immune cell communication. Further, IVIG therapy significantly upregulates macroautophagy-related genes in these cell subsets. Monocyte subsets especially intermediate monocytes showed enhanced expression of core autophagy genes with significant expression of ATG7 and UVRAG, which are crucial for autophagosome formation while NK cells, neutrophils and gamma delta (γδ) T cells also showed upregulation of several core autophagy genes. Additionally, we observed activation and enrichment of various selective autophagy and non-canonical LC3-associated phagocytosis (LAP) pathways in innate immune cell subsets of patients with Kawasaki disease. Importantly, IVIG-induced autophagy coincided with normalization of monocyte pseudotime states. Further mechanistic studies performed on peripheral blood mononuclear cells have revealed that IVIG-induced autophagy is not restricted to a particular formulation. However, Fc fragment and C-type lectin receptors were found to be dispensable for this process. These findings suggest that IVIG triggers multiple autophagy pathways in innate immune cells, which might contribute to its therapeutic benefits observed in Kawasaki disease and other autoimmune and inflammatory pathologies.