Mechanistic Insights into Autoimmune Pancreatitis and IgG4-Related Disease.

Autoimmune pancreatitis (AIP) is a pancreatic manifestation of a recently defined disease form known as IgG4-related disease (AIP/IgG4-RD). AIP/IgG4-RD is characterized by elevated systemic IgG4 antibody concentrations and lesional tissues infiltrated by IgG4-expressing plasmacytes. In addition, recent studies have revealed that, in common with other autoimmune diseases, such as systemic lupus erythematosus (SLE) and psoriasis, AIP/IgG4-RD is associated with increased type I IFN (IFN-I) production by plasmacytoid dendritic cells (pDCs). However, unlike SLE, AIP/IgG4-RD is characterized by elevated IFN-I-dependent IL-33 production, the latter emerging as an important contributor to inflammation and fibrotic responses characterizing this disease. On this basis, we propose that blockade of the IFN-I/IL-33 axis might constitute a successful approach to treating this unique type of autoimmunity. Highlights AIP is a pancreatic manifestation of systemic AIP/IgG4-RD, a newly established disease entity in humans. AIP/IgG4-RD is characterized by enhanced IgG4 antibody responses, multiple organ involvement, and storiform fibrosis. IFN-I and pDCs have pathogenic roles in AIP/IgG4-RD as in SLE and psoriasis. In mice, IFN-I-dependent IL-33 production by pDCs mediates fibrosis as well as inflammation in AIP. IFN-I-dependent IL-33 production might have a pathogenic role in other diseases exhibiting both autoimmunity and fibrosis. The IFN-I/IL-33 axis in pDCs represents a new putative therapeutic target of AIP/IgG4-RD, although further studies in humans are warranted. [ABSTRACT FROM AUTHOR]