title: Decreased Expression of Innate Immunity-Related Genes in Peripheral Blood Mononuclear Cells from Patients with IgG4-Related Disease.
abstract: BACKGROUND
  IgG4-related disease (IgG4-RD) is a new clinical entity of unknown etiology characterized by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells. Although aberrancies in acquired immune system functions, including increases in Th2 and Treg cytokines observed in patients with IgG4-RD, its true etiology remains unclear. To investigate the pathogenesis of IgG4-RD, this study compared the expression of genes related to innate immunity in patients with IgG4-RD and healthy controls.
  
  
  METHODS
  Peripheral blood mononuclear cells (PBMCs) were obtained from patients with IgG4-RD before and after steroid therapy and from healthy controls. Total RNA was extracted and DNA microarray analysis was performed in two IgG4-RD patients to screen for genes showing changes in expression. Candidate genes were validated by real-time RT-PCR in 27 patients with IgG4-RD and 13 healthy controls.
  
  
  RESULTS
  DNA microarray analysis identified 21 genes that showed a greater than 3-fold difference in expression between IgG4-RD patients and healthy controls and 30 genes that showed a greater than 3-fold change in IgG4-RD patients following steroid therapy. Candidate genes related to innate immunity, including those encoding Charcot-Leyden crystal protein (CLC), membrane-spanning 4-domain subfamily A member 3 (MS4A3), defensin alpha (DEFA) 3 and 4, and interleukin-8 receptors (IL8R), were validated by real-time RT-PCR. Expression of all genes was significantly lower in IgG4-RD patients than in healthy controls. Steroid therapy significantly increased the expression of DEFA3, DEFA4 and MS4A3, but had no effect on the expression of CLC, IL8RA and IL8RB.
  
  
  CONCLUSIONS
  The expression of genes related to allergy or innate immunity, including CLC, MS4A3, DEFA3, DEFA4, IL8RA and IL8RB, was lower in PBMCs from patients with IgG4-RD than from healthy controls. Although there is the limitation in the number of patients applied in DNA microarray, impaired expression of genes related to innate immunity may be involved in the pathogenesis of IgG4-RD as well as in abnormalities of acquired immunity.
authors.affiliation: Hematology and Immunology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Nakajima
authors.affiliation: Hematology and Immunology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Masaki
authors.affiliation: Hematology and Immunology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Hematology and Immunology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kawanami
authors.affiliation: Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Ishigaki
authors.affiliation: Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takegami
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Kanazawa University Hospital, Ishikawa 920-8641, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kawano
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Kanazawa University Hospital, Ishikawa 920-8641, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Tsukamoto
authors.affiliation: Health Administration Center University of Toyama, Toyama 930-0194, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Matsui
authors.affiliation: Department of Internal Medicine, Nagaoka Red Cross Hospital, Niigata 940-2085, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Saeki
authors.affiliation: Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, Osaka 573-1191, Japan.
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Okazaki
authors.affiliation: Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, Tokyo 113-8677, Japan.
authors.forename: Terumi
authors.initials: T
authors.lastname: Kamisawa
authors.affiliation: Department of Rheumatology, National Hospital Organization Nagasaki Medical center, Nagasaki 380-8582, Japan.
authors.forename: Taiichiro
authors.initials: T
authors.lastname: Miyashita
authors.affiliation: Department of Clinical Oncology, Ehime Graduate School of Medicine, Ehime 791-0295, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yakushijin
authors.affiliation: Department of Rheumatology, Japan Community Healthcare Organization, Isahaya General Hospital, Nagasaki 854-8501, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Fujikawa
authors.affiliation: Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Hokkaido 060-8543, Japan.
authors.forename: Motohisa
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Medical Informatics Division and Department of Internal Medicine, Gastroenterology, Shinshu University School Hospital, Nagano 390-8621, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hamano
authors.affiliation: First Department of Internal Medicine, Department of Immunology and Rheumatology, Nagasaki Graduate School of Health Sciences, Nagasaki 852-8520, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Origuchi
authors.affiliation: First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Fukuoka 807-8555, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Hirata
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Tsuboi
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sumida
authors.affiliation: Division of Nephrology, Mitoyo General Hospital, Kagawa 769-1695, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Morimoto
authors.affiliation: Hematology and Immunology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Hematology and Immunology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Iwao
authors.affiliation: Hematology and Immunology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Miki
authors.affiliation: Hematology and Immunology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Sakai
authors.affiliation: Hematology and Immunology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Hematology and Immunology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Hematology and Immunology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Fukushima
authors.affiliation: Hematology and Immunology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Okazaki
authors.affiliation: Hematology and Immunology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; Department of Clinical Immunology, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Umehara
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007074:Immunoglobulin G / Q000097:blood*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008245:Lysophospholipase / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D053700:Receptors, Interleukin-8 / Q000235:genetics / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D015854:Up-Regulation; D023084:alpha-Defensins / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D006023:Glycoproteins; D007074:Immunoglobulin G; C089821:MS4A3 protein, human; D008565:Membrane Proteins; D053700:Receptors, Interleukin-8; D023084:alpha-Defensins; C406427:human neutrophil peptide 3; C406428:human neutrophil peptide 4; D008245:Lysophospholipase; C011711:lysolecithin acylhydrolase