Immunopathogenesis of IgG4-related disease in the era of single-cell RNA sequencing and highly multiplex immunofluorescence.

INTRODUCTION: IgG4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory disorder characterized by dense lymphoplasmacytic infiltration and storiform fibrosis, often resulting in organ dysfunction. Although glucocorticoids provide initial clinical improvement, relapse is common, underscoring the need for targeted therapies. B-cell depletion therapy has emerged as a promising approach, shedding light on the roles of plasmablasts and cytotoxic T lymphocytes in disease pathogenesis.

AREAS COVERED: This review summarizes recent advances in immunological mechanisms of IgG4-RD, focusing on plasmablasts, activated B cells, cytotoxic T lymphocytes, T follicular helper (Tfh) cells, macrophages, dendritic cells, other immune cells, and fibroblasts. We highlight how single-cell RNA sequencing and highly multiplex immunofluorescence have uncovered novel immune subsets and their interactions. These technologies have identified previously unrecognized populations, including GZMK+ cytotoxic Tfh cells, MKI67+ B cells, and double-negative type 3 B cells, offering unprecedented resolution into disease mechanisms.

EXPERT OPINION: Single-cell technologies have revolutionized our understanding of IgG4-RD immunopathogenesis and potentially revealed disease heterogeneity across clinical phenotypes. These insights hold promise for biomarker development and precision therapeutic strategies. Future directions should include spatial transcriptomics and proteomics, improved animal models, and translational efforts to bridge mechanistic discoveries with targeted treatment for this complex multi-organ disease.