title: A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22.
abstract: A unique feature of rheumatoid arthritis (RA) is the presence of anti-citrullinated protein antibodies (ACPA). Several risk factors for RA are known to increase the expression or activity of peptidyl arginine deiminases (PADs), which catalyze citrullination and, when dysregulated, can result in hypercitrullination. However, the consequence of hypercitrullination is unknown and the function of each PAD has yet to be defined. Th cells of RA patients are hypoglycolytic and hyperproliferative due to impaired expression of PFKFB3 and ATM, respectively. Here, we report that these features are also observed in peripheral blood mononuclear cells (PBMCs) from healthy at-risk individuals (ARIs). PBMCs of ARIs are also hypercitrullinated and produce more IL-2 and Th17 cytokines but fewer Th2 cytokines. These abnormal features are due to impaired induction of PTPN22, a phosphatase that also suppresses citrullination independently of its phosphatase activity. Attenuated phosphatase activity of PTPN22 results in aberrant expression of IL-2, ATM, and PFKFB3, whereas diminished nonphosphatase activity of PTPN22 leads to hypercitrullination mediated by PADs. PAD2- or PAD4-mediated hypercitrullination reduces the expression of Th2 cytokines. By contrast, only PAD2-mediated hypercitrullination can increase the expression of Th17 cytokines. Taken together, our data depict a molecular signature of preclinical RA that is triggered by impaired induction of PTPN22.
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
authors: Hui-Hsin
authors: HH
authors: Chang
authors: Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.|Division of Allergy, Immunology and Rheumatology, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors: Guang-Yaw
authors: GY
authors: Liu
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
authors: Nishant
authors: N
authors: Dwivedi
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
authors: Bo
authors: B
authors: Sun
authors: Division of Rheumatology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors: Yuko
authors: Y
authors: Okamoto
authors: Division of Rheumatology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors: Jennifer D
authors: JD
authors: Kinslow
authors: Division of Rheumatology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors: Kevin D
authors: KD
authors: Deane
authors: Division of Rheumatology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors: M Kristen
authors: MK
authors: Demoruelle
authors: Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, USA.
authors: Jill M
authors: JM
authors: Norris
authors: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Paul R
authors: PR
authors: Thompson
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
authors: Jeffrey A
authors: JA
authors: Sparks
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
authors: Deepak A
authors: DA
authors: Rao
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
authors: Elizabeth W
authors: EW
authors: Karlson
authors: Department of Life Sciences and.|Agricultural Biotechnology Center and Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan.
authors: Hui-Chih
authors: HC
authors: Hung
authors: Division of Rheumatology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors: V Michael
authors: VM
authors: Holers
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
authors: I-Cheng
authors: IC
authors: Ho
mesh_terms: D000328:Adult; D000075422:Anti-Citrullinated Protein Antibodies; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D002956:Citrulline / Q000378:metabolism*; D016207:Cytokines; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D025481:Phosphofructokinase-2 / Q000235:genetics; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D000080064:Protein-Arginine Deiminase Type 2; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases / Q000378:metabolism*; D012307:Risk Factors; D058504:Th17 Cells
chemical_list: D000075422:Anti-Citrullinated Protein Antibodies; D016207:Cytokines; C508594:IL2 protein, human; D007376:Interleukin-2; D002956:Citrulline; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C000620352:PADI2 protein, human; C000629235:PADI4 protein, human; D000080064:Protein-Arginine Deiminase Type 2; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases