Pathophysiology of IgG4-Related Disease

It is still a mystery what is the role of immunoglobulin G4 (IgG4) in IgG4-related disease, or which kinds of immune responses are involved in the pathogenesis. Possible involvement of autoimmunity is supported by the fact that the patients commonly have antinuclear antibodies or hyper γ-globulinemia. The expression of human leukocyte DR antigen in epithelia of the affected organs, and possible reactivity of serum IgG4 of the patients with tissue specimens also support an autoimmune etiology. On the other hand, the Th2-dominant cytokine expression profile resembles allergic disorders rather than classical autoimmune diseases. Another unique point is that many regulatory T-cells infiltrate into the inflamed sites, being associated with the active expression of regulatory cytokines. IL-10 and TGF-β might be the key molecules involved in the two major histological findings of IgG4-related disease: IgG4 class switch and diffuse fibrosis, because IL-10 and TGF-β have a potent function in directing B cells to produce IgG4 and a strong fibrogenic function, respectively. The function of IgG4 in this disorder is still unknown. Unique characters of IgG4 might suggest that IgG4 is not a pathogenetic antibody, but acts as an anti-inflammatory factor by binding to other types of IgG. Recent proteomics studies have discovered possible autoantigens and autoantibodies. Several hypotheses have been proposed so far, but the consensus remains to be reached. Immunopathology in IgG4-related disease is not typical for known disease entities.