From immune heterogeneity to targeted therapies in IgG4-related disease.

Purpose

OF REVIEW Recent advances in single-cell, spatial, and multiomic technologies have provided new insights into the immunopathogenesis and clinical heterogeneity of IgG4-related disease (IgG4-RD). At the same time, several mechanism-based therapies have entered clinical development. RECENT

Findings

Recent studies have identified distinct B-cell, T-cell, myeloid, and stromal populations and their interactions within affected tissues. Type 2 peripheral helper T-cell-associated, granzyme K+ cytotoxic T-cell-associated, and age-associated B-cell-related programs may contribute to tissue inflammation and immune dysregulation. Recent studies further suggest that immunopathogenesis varies across clinical phenotypes and may be shaped by additional axes such as allergy and malignancy. Clinical trials have demonstrated efficacy of the CD19-directed B-cell-depleting therapy with inebilizumab and the nondepleting B-cell modulator obexelimab, while Bruton tyrosin kinase inhibition and cellular therapies represent emerging therapeutic approaches. SUMMARY IgG4-RD is increasingly recognized as an immunologically heterogeneous fibroinflammatory disease. Integrating immune pathotypes with clinical phenotypes and dynamic biomarkers may enable more individualized treatment and accelerate development of mechanism-based therapies.