title: Decreased severity of experimental autoimmune arthritis in peptidylarginine deiminase type 4 knockout mice.
abstract: Peptidylarginine deiminase type 4 (PADI4) has been identified as a susceptibility gene for rheumatoid arthritis (RA) by genome-wide association studies. PADI4 is highly expressed in the bone marrow, macrophages, neutrophils, and monocytes. Peptidyl citrulline is an interesting molecule in RA because it is a target antigen for anti-citrullinated peptide antibodies, and only PADs (translated proteins from PADI genes) can provide peptidyl citrulline via the modification of protein substrates. The aim of this study was to evaluate the importance of the PADI4 gene in the progression of RA.
  
  
  
  We generated Padi4 knockout (Padi4(-/-)) DBA1J mice. The Padi4(-/-) DBA1J and wild-type mice were immunized with bovine type II collagen (CII) to develop collagen-induced arthritis (CIA). The expression of various inflammatory cytokines and Padi genes in immune cells was detected by the real-time TaqMan assay. Cytokine concentrations in sera were measured by enzyme-linked immunosorbent assays. Localization of the PAD4 and PAD2 proteins was indicated by immunohistochemistry.
  
  
  
  We demonstrated that the clinical disease score was significantly decreased in the Padi4(-/-) mice and Padi4 expression was induced by CII immunization. In the Padi4(-/-) mice, serum anti-type II collagen (CII) immunoglobulin M (IgM), IgG, and inflammatory cytokine levels were significantly decreased compared with those in the wild-type mice. Padi2 expression was induced in the immune cells of the Padi4(-/-) mice as a compensation for the defect in Padi4.
  
  
  
  Padi4 affected disease severity in the CIA mice and was involved in the enhancement of the collagen-initiated inflammatory responses.
authors.affiliation: Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), 1-7-22 Suehirocho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan. akaris@src.riken.jp.
authors.forename: Akari
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), 1-7-22 Suehirocho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kochi
authors.affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, the University, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Shoda
authors.affiliation: Department of Joint Disease and Rheumatism, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Seri
authors.affiliation: Department of Joint Disease and Rheumatism, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Fujio
authors.affiliation: Center for Genomic Medicine, Kyoto University, Yoshida-konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Sawada
authors.affiliation: Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), 1-7-22 Suehirocho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.affiliation: Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), 1-7-22 Suehirocho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|Department of Joint Disease and Rheumatism, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000097:blood / Q000235:genetics* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001327:Autoimmune Diseases / Q000097:blood / Q000235:genetics* / Q000276:immunology; D002956:Citrulline / Q000276:immunology* / Q000378:metabolism; D024043:Collagen Type II / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D006867:Hydrolases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000080002:Protein-Arginine Deiminase Type 4; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D001323:Autoantibodies; D024043:Collagen Type II; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D002956:Citrulline; D006867:Hydrolases; D000080002:Protein-Arginine Deiminase Type 4; C552151:peptidylarginine deiminase 4, mouse
keywords: Citrullination; Collagen-induced arthritis mice; Peptidylarginine deiminase type 4; Rheumatoid arthritis; TNF-α