Figure 1.

Hypothesis for the pathogenesis of Type 1 autoimmune pancreatitis (AIP) in IgG4-related disease. In regard to central tolerance, naïve and natural regulatory T cells (Tregs) derived from the thymus suppress autoreactive CD4 or CD8 cells in the normal state. In IgG4-related disease, the basic concept is a biphasic mechanism of “induction” and “progression”. Initial response to self-antigens (e.g., lactoferrin (LF), carbonic anhydrase II (CA-II), CA-IV, pancreatic secretory trypsin inhibitor (PSTI), amylase-alpha, and plasminogen binding protein (PBP) peptide of Helicobacter pylori) might be induced by decreased naïve Tregs. Th2 immune responses are followed by a Th1-type immune response with the release of proinflammatory cytokines (interferon-γ (IFN-γ), interleukin (IL)-1β, IL-2, tumor necrosis factor-α (TNF-α)). Th2-type immune responses, producing IgG, IgG4, and autoantibodies may be involved in the pathophysiology of progression. The production of IgG4 may be regulated by increased IL-10 secreted from inducible co-stimulatory molecule (ICOS)⁺ effector Tregs. Fibrosis may be regulated by TGF-β secreted from ICOS⁻ Tregs. This figure modified from Okazaki et al. [54]. DC: dendritic cell, TE: effector T cell, nTreg: natural Tregs.