title: Hypermethylation of MST1 in IgG4-related autoimmune pancreatitis and rheumatoid arthritis.
abstract: The serine/threonine kinase Mst1 plays important roles in the control of immune cell trafficking, proliferation, and differentiation. Previously, we reported that Mst1 was required for thymocyte selection and regulatory T-cell functions, thereby the prevention of autoimmunity in mice. In humans, MST1 null mutations cause T-cell immunodeficiency and hypergammaglobulinemia with autoantibody production. RASSF5C(RAPL) is an activator of MST1 and it is frequently methylated in some tumors. Herein, we investigated methylation of the promoter regions of MST1 and RASSF5C(RAPL) in leukocytes from patients with IgG4-related autoimmune pancreatitis (AIP) and rheumatoid arthritis (RA). Increased number of CpG methylation in the 5' region of MST1 was detected in AIP patients with extrapancreatic lesions, whereas AIP patients without extrapancreatic lesions were similar to controls. In RA patients, we detected a slight increased CpG methylation in MST1, although the overall number of methylation sites was lower than that of AIP patients with extrapancreatic lesions. There were no significant changes of the methylation levels of the CpG islands in the 5' region of RASSF5C(RAPL) in leukocytes from AIP and RA patients. Consistently, we found a significantly down-regulated expression of MST1 in regulatory T cells of AIP patients. Our results suggest that the decreased expression of MST1 in regulatory T cells due to hypermethylation of the promoter contributes to the pathogenesis of IgG4-related AIP.
authors.affiliation: Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, JST CREST, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
authors.forename: Takataro
authors.initials: T
authors.lastname: Fukuhara
authors.affiliation: Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, JST CREST, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tomiyama
authors.affiliation: Department of Urology and Andrology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
authors.forename: Kaneki
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Department of Molecular Genetics, Institute of Biomedical Science, and JST CREST, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Department of the First Department of Internal Medicine, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ozaki
authors.affiliation: Department of the First Department of Internal Medicine, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
authors.forename: Yonsu
authors.initials: Y
authors.lastname: Son
authors.affiliation: Department of the First Department of Internal Medicine, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
authors.forename: Shosaku
authors.initials: S
authors.lastname: Nomura
authors.affiliation: Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, JST CREST, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
authors.forename: Kazushige
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, JST CREST, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Okazaki
authors.affiliation: Department of Molecular Genetics, Institute of Biomedical Science, and JST CREST, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan. Electronic address: kinashi@takii.kmu.ac.jp.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kinashi
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D001483:Base Sequence; D018899:CpG Islands; D019175:DNA Methylation; D017931:DNA Primers; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D010195:Pancreatitis / Q000235:genetics* / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D000099317:Hippo Kinases
chemical_list: D017931:DNA Primers; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; C095566:STK4 protein, human; D000099317:Hippo Kinases
keywords: Autoimmune disease; DNA methylation; IgG4-related disease; MST1