Background: Immunoglobulin G4-related disease (IgG4-RD) is a multisystem immune disorder characterized by fibroinflammatory lesions involving multiple organs. B cells play a pivotal role in IgG4-RD pathogenesis, and autophagy substantially influences their functional capacity. This study aimed to evaluate the role of B-cell autophagy in IgG4-RD.

Methods: Single-cell sequencing data were analyzed. Autophagy was assessed by flow cytometry with CYTO-ID® Autophagy Detection Kit 2.0 (CytoID) and by measuring autophagy-related proteins in peripheral blood mononuclear cell (PBMC) B cells from IgG4-RD patients and healthy controls (HCs) via polymerase chain reaction (PCR) and western blotting. Autophagy in B cells from IgG4-RD patients and HCs was inhibited, and B-cell activity was evaluated using Enzyme-linked immunoassay (ELISA) and flow cytometry.

Results: Altered autophagy levels and extracellular signal-regulated kinase (ERK) pathway activity were observed in total B cells, as well as in naïve B cells and plasmablasts. Autophagy in B cells was enhanced, as indicated by greater autophagosome formation and higher levels of autophagy-related proteins (p < 0.05). ERK phosphorylation was markedly reduced in IgG4-RD compared to HCs (p < 0.05). Following autophagy inhibition, B-cell metabolism, proliferation, antibody production, and cytokine secretion were significantly decreased in IgG4-RD (p < 0.05). Cell differentiation was similarly affected, with reduced memory B-cell and plasma cell proportions but elevated regulatory B-cell proportions (p < 0.05), whereas the reduction of memory B cells in HCs was not significant.

Conclusion: IgG4-RD patients exhibited defective B-cell autophagy and elevated autophagy levels associated with multiple serological and hematological markers, alongside impaired autophagy flux. Significantly reduced ERK1/2 phosphorylation was uniquely observed among signaling pathways, suggesting potential autophagy-apoptosis interactions. Upon autophagy inhibition, B cells exhibited a broad functional decline and anti-inflammatory features, highlighting an autophagy-B-cell activity relationship that may be valuable for disease monitoring.