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

Introduction: 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 (KD). 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. However, whether IVIG selectively activates specific autophagy pathways across distinct innate immune cell subsets remains unclear. Methods: Single-cell RNA sequencing data from peripheral blood mononuclear cells (PBMC) of healthy controls, acute untreated KD patients, and IVIG-treated KD patients were analysed. Differential gene expression, cell-cell communication, functional pathway enrichment of autophagy-related pathways, and pseudotime trajectory analyses were performed. Mechanistic studies were conducted in vitro using PBMC and monocytes from healthy donors treated with different IVIG preparations, Fc fragments, or inhibitors, followed by immunoblotting for LC3-II. Results: KD was characterized by expansion of inflammatory monocytes and low-density neutrophils with reduced NK and γδ T cells. IVIG therapy reshaped innate immune composition and partially restored coordinated immune networks. IVIG upregulated core macroautophagy genes across innate immune subsets, particularly ATG7 and UVRAG in monocytes. It also induced non-canonical LC3-associated phagocytosis and multiple selective autophagy pathways in a cell-type-specific manner. Pseudotime analysis revealed normalization of monocyte trajectories following treatment. IVIG-induced autophagy occurred independently of Fc fragments and C-type lectin receptors. Discussion: IVIG remodels innate immune communication and activates differential autophagy programs, which may contribute to its therapeutic effects in KD and other autoimmune and inflammatory pathologies.