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To review studies that have examined underlying genetic and immunological aspects of IgG4-related disease.Genetic studies have suggested that several human leukocyte antigen (HLA) and non-HLA haplotypes/genotypes are associated with susceptibility to IgG4-related disease or to disease relapse after steroid therapy. Among several autoantibodies identified so far, autoantibodies against lactoferrin and carbonic anhydrase II are most frequently detected in serum of IgG4-disease patients. However, it has not been well clarified whether or not those autoantibodies belong to an IgG4 subclass. Studies that have demonstrated molecular mimicry between Helicobacter pylori and constituents of pancreatic epithelial cells suggest that gastric H. pylori infection triggers autoimmune pancreatitis in genetically predisposed individuals through antibody cross-reactivity. Recently, T-helper 2 immune reaction has been suggested to be predominant in IgG4-related disease. Interestingly, regulatory immune reactions are activated in IgG4-related disease, and regulatory cytokines interleukin-10 and transforming growth factor-β have been suggested, respectively, to play important roles in IgG4 class switch and fibroplasia.Autoimmunity has been considered the most probable pathogenesis of IgG4-related disease, but has not been completely proved so far. A breakthrough study to detect a specific autoantigen, autoantibody, or pathogen is necessary.