Plasmacytoid Dendritic Cells as a New Therapeutic Target for Autoimmune Pancreatitis and IgG4-Related Disease

Abstract

Although plasmacytoid dendritic cells (pDCs) able to produce large amounts of type 1 interferons (IFN-I) play beneficial roles in host defense against viral infections, excessive activation of pDCs, followed by robust production of IFN-I, causes autoimmune disorders including systemic lupus erythematosus (SLE) and psoriasis. Autoimmune pancreatitis (AIP), which is recognized as a pancreatic manifestation of systemic immunoglobulin G4-related disease (IgG4-RD), is a chronic fibroinflammatory disorder driven by autoimmunity. IgG4-RD is a multi-organ autoimmune disorder characterized by elevated serum concentrations of IgG4 antibody and infiltration of IgG4-expressing plasmacytes in the affected organs. Although the immunopathogenesis of IgG4-RD and AIP has been poorly elucidated, recently, we found that activation of pDCs mediates the development of murine experimental AIP and human AIP/IgG4-RD via the production of IFN-I and interleukin-33 (IL-33). Depletion of pDCs or neutralization of signaling pathways mediated by IFN-I and IL-33 efficiently inhibited the development of experimental AIP. Furthermore, enhanced expression of IFN-I and IL-33 was observed in the pancreas and serum of human AIP/IgG4-RD. Thus, AIP and IgG4-RD share their immunopathogenesis with SLE and psoriasis because in all these conditions, IFN-I production by pDCs contributes to the pathogenesis. Because the enhanced production of IFN-I and IL-33 by pDCs promotes chronic inflammation and fibrosis characteristic for AIP and IgG4-RD, neutralization of IFN-I and IL-33 could be a new therapeutic option for these disorders. In this Mini Review, we discuss the pathogenic roles played by the pDC-IFN-I-IL-33 axis and the development of a new treatment targeting this axis in AIP and IgG4-RD.

Keywords: IgG4-related disease; autoimmune pancreatitis; interferon-I; interleukin-33; plasmacytoid dendritic cells.

Figure 1

IFN-I produced by plasmacytoid dendritic cells mediates systemic lupus erythematosus and autoimmune pancreatitis/IgG4-related disease. Neutrophil extracellular traps (NETs) activate plasmacytoid dendritic cells (pDCs) to produce large amounts of IFN-I. pDC-mediated IFN-I responses underlie the immunopathogenesis of systemic lupus erythematosus (SLE). Myeloid differentiation primary response protein 88 (MyD88)-dependent activation of Toll-like receptor 7 (TLR7) and TLR9 induces IFN-I production through nuclear translocation of interferon regulatory factor 5 (IRF5) and IRF7 (top panel). Intestinal dysbiosis and NETs activate pDCs to produce large amounts of IFN-I through nuclear translocation of IRF7, which, in turn, results in the enhanced production of IL-33 by pDCs. The pDC-IFN-I-IL-33 axis underlies the immunopathogenesis of autoimmune pancreatitis (AIP) and IgG4-related disease (IgG4-RD) (bottom panel).

Figure 2

Development of new treatments targeting the plasmacytoid dendritic cell-IFN-I-IL-33 axis in autoimmune pancreatitis and IgG4-related disease. Intestinal dysbiosis activates endosomal Toll-like receptor 7 (TLR7) and TLR9 followed by nuclear translocation of IFN regulatory factor 7 (IRF7). pDCs produce IFN-I through the nuclear translocation of IRF7. IL-33 is produced by pDCs in an IFN-I-dependent manner. Antibiotics and probiotics may be useful for correction of intestinal dysbiosis. Chloroquine inhibits the activation of endosomal TLR7 and TLR9. Mycophenolate mofetil (MMF) suppresses nuclear translocation of IRF7. IFN-I-mediated signaling pathways are efficiently inhibited by Abs against IFN-I or IFN-I receptor. An anti-ST2 Ab, neutralizing the IL-33 receptor, blocks IL-33-mediated signaling pathways.