PRSS1 isoforms promote type 2 immune responses in IgG4-related disease.

Trypsin is commonly used as an adjunctive therapeutic agent for chronic inflammatory and autoimmune diseases. This study investigated the impact of trypsinogen (PRSS1) variants on type 2 immune responses mediated by M2 macrophage polarization in immunoglobulin G4-related disease (IgG4-RD). Whole-exome sequencing of affected tissue samples from patients with IgG4-RD, including two cases of IgG4-related autoimmune pancreatitis and one case of Mikulicz disease, identified novel PRSS1 variants, namely p.Lys70Asn and p.Phe73Leu. Activation of M2 macrophages was observed in these affected tissues. By integrating single-cell RNA sequencing datasets with spatial transcriptomic analysis of pancreatic tissues from mutation-positive cases, we found that molecules produced by M2 macrophages, including TGF-β, may promote type 2 immune responses. In conclusion, novel PRSS1 variants may contribute to the pathogenesis of IgG4-RD by activating type 2 immune responses.