Involvement of cytokines in the pathogenesis of Mikulicz's disease

Objectives:Mikulicz's disease (MD) has been considered to be a subtype of Sjögren's syndrome (SS). However, recent studies have indicated that MD shows high serum IgG4 concentration, and suggest that MD is an IgG4 related disease and has been distinguished from SS. The IgG4 production is induced by T helper (Th) 2 cytokines such as IL-4. Recently, it has been reported that class switching of IgG4 is caused by the combination of IL-4 and IL-10. We thus investigated the expression of Th types and class switching related molecules in salivary glands (SGs) from the patients with MD and SS. Methods: Fifteen patients with MD, 18 patients with SS, and 18 healthy controls, referred to Kyushu University Hospital between 1993 and 2009, were included in the study. The following subjects were examined: 1) subsets of the infiltrating lymphocytes, 2) messenger RNA (mRNA) expression of Th1, Th2 and Treg types molecules and 3) relationship among of IgG4, class switching related molecules, and IL-4, IL-10. Results:In SS patients, the lymphocytes infiltration of various subsets were observed and mRNA expression of both Th1 and Th2 types molecules were significantly higher than that in controls. Meanwhile, in MD patients, the selective IgG4+ B cell and Treg infiltration were observed and mRNA expression of Th2, Tregs type and class switching related molecules were significantly higher than that in controls. Each IL-4 and IL-10 were correlated significantly with IgG4 and class switching related molecules. Conclusion: These results suggest that MD is an unique inflammatory disorder characterized by Th2 and regulatory immune reactions, and that combination of IL-4 and IL-10 induces class switching to IgG4.