← Back to Search
Peptidyl Arginine Deiminase Type 2 (PAD-2) And PAD-4 But Not PAD-1, PAD-3, And PAD-6 Are Expressed In Rheumatoid Arthritis Synovium In Close Association With Tissue Inflammation.
C. Foulquier, M. Sebbag, C. Clavel, S. Chapuy-Regaud, R. Al Badine, M. Mechin, C. Vincent, R. Nachat, M. Yamada, H. Takahara, Michel Simon, M. Guerrin, G. Serre
Published 2007 · Medicine
Download PDFAnalyze on Scholarcy
OBJECTIVE Autoantibodies to citrullinated proteins (ACPAs) are specific for rheumatoid arthritis (RA) and probably are involved in its pathophysiology. Citrullyl residues, posttranslationally generated by peptidyl arginine deiminase (PAD), are indispensable components of ACPA-targeted epitopes. The aim of this study was to identify which PAD isotypes are expressed in the synovial tissue (ST) of patients with RA and are involved in the citrullination of fibrin, the major synovial target of ACPAs. METHODS Expression of all PAD isotypes, including the recently described PAD type 6 (PAD-6), was explored by reverse transcription-polymerase chain reaction and immunoblotting, first in blood-derived mononuclear leukocytes from healthy donors, then in ST samples from 16 patients with RA and 11 control patients (4 with other arthritides and 7 with osteoarthritis [OA]). In ST samples from patients with RA, PADs were localized by immunohistochemistry. RESULTS In lymphocytic and monocytic cells and, similarly, in ST samples from patients with RA, the PAD-2, PAD-4, and PAD-6 genes were found to be transcribed, but only PAD-2 and PAD-4 enzymes were detected. PAD-2 was also expressed in ST from control patients, including those with OA, while PAD-4 was preferentially expressed in ST from patients with other arthritides. In RA, the expression levels of PAD-2 and PAD-4 were correlated with the intensity of inflammation (cell infiltration, hypervascularization, and synovial lining hyperplasia), and both enzymes were demonstrable within or in the vicinity of citrullinated fibrin deposits. CONCLUSION PAD-2 and PAD-4 are the only PAD isotypes expressed in the ST of patients with RA and those with other arthritides. Inflammatory cells are a major source, but PAD-4 also comes from hyperplastic synoviocytes. Both isotypes are probably involved in the citrullination of fibrin.
This paper references
The Major Synovial Targets of the Rheumatoid Arthritis-Specific Antifilaggrin Autoantibodies Are Deiminated Forms of the α- and β-Chains of Fibrin1
C. Masson-Bessière (2001)
The peptidylarginine deiminases expressed in human epidermis differ in their substrate specificities and subcellular locations
M. C. Méchin (2005)
Citrullinated proteins have increased immunogenicity and arthritogenicity and their presence in arthritic joints correlates with disease severity
K. Lundberg (2005)
Increased peptidylarginine deiminase type II in hypoxic astrocytes.
T. Sambandam (2004)
The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy.
M. Dougados (1991)
A family based study shows no association between rheumatoid arthritis and the PADI4 gene in a white French population.
L. Caponi (2005)
Peptidylarginine deiminase isoforms 1-3 are expressed in the epidermis and involved in the deimination of K1 and filaggrin.
R. Nachat (2005)
Fibrin Deimination in Synovial Tissue Is Not Specific for Rheumatoid Arthritis but Commonly Occurs during Synovitides1
S. Chapuy-Regaud (2005)
Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies.
G. A. Schellekens (1998)
Preferential deimination of keratin K1 and filaggrin during the terminal differentiation of human epidermis.
T. Senshu (1996)
Immunocytochemical localization of peptidylarginine deiminase in human eosinophils and neutrophils
H. Asaga (2001)
A functional haplotype of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in Koreans.
C. Kang (2006)
Protein Unfolding by Peptidylarginine Deiminase
E. Tarcsa (1996)
The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues.
E. Girbal-Neuhauser (1999)
Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association.
R. Altman (1986)
Abnormal accumulation of citrullinated proteins catalyzed by peptidylarginine deiminase in hippocampal extracts from patients with Alzheimer's disease
A. Ishigami (2005)
Peptidylarginine deiminase (PAD) is a mouse cortical granule protein that plays a role in preimplantation embryonic development
M. Liu (2005)
Comparative study of the synovial histology in rheumatoid arthritis, spondyloarthropathy, and osteoarthritis: influence of disease duration and activity
D. Baeten (2000)
Citrullination is an inflammation-dependent process.
D. Makrygiannakis (2006)
IgG subclass distribution of the rheumatoid arthritis‐specific autoantibodies to citrullinated fibrin
S. Chapuy-Regaud (2005)
Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages.
E. Vossenaar (2004)
Comparative analysis of the mouse and human peptidylarginine deiminase gene clusters reveals highly conserved non-coding segments and a new human gene, PADI6.
S. Chavanas (2004)
The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.
F. Arnett (1988)
PADI4 polymorphisms are not associated with rheumatoid arthritis in the Spanish population.
A. Martínez (2005)
Peptidylarginine deiminase isoforms are differentially expressed in the anagen hair follicles and other human skin appendages.
R. Nachat (2005)
Autoantibodies to citrullinated proteins: ACPA
C. Vincent (2005)
Synovial intracellular citrullinated proteins colocalizing with peptidyl arginine deiminase as pathophysiologically relevant antigenic determinants of rheumatoid arthritis-specific humoral autoimmunity.
L. De Rycke (2005)
Myelin in multiple sclerosis is developmentally immature.
M. Moscarello (1994)
Citrullination of synovial proteins in murine models of rheumatoid arthritis
E. Vossenaar (2003)
In the rheumatoid pannus, anti‐filaggrin autoantibodies are produced by local plasma cells and constitute a higher proportion of IgG than in synovial fluid and serum
C. Masson-Bessière (2000)
Nuclear Localization of Peptidylarginine Deiminase V and Histone Deimination in Granulocytes*
K. Nakashima (2002)
Human PAD4 Regulates Histone Arginine Methylation Levels via Demethylimination
Y. Wang (2004)
Human peptidylarginine deiminase type II: molecular cloning, gene organization, and expression in human skin.
A. Ishigami (2002)
Molecular Characterization of Peptidylarginine Deiminase in HL-60 Cells Induced by Retinoic Acid and 1α,25-Dihydroxyvitamin D3 *
K. Nakashima (1999)
ePAD, an oocyte and early embryo-abundant peptidylarginine deiminase-like protein that localizes to egg cytoplasmic sheets.
P. Wright (2003)
Association between PADI4 and rheumatoid arthritis: a replication study.
K. Ikari (2005)
Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis
A. Suzuki (2003)
Revised criteria for the classification of rheumatoid arthritis.
F. Arnett (1990)
Immunohistochemical Demonstration of Peptidylarginine Deiminase in Human Sweat Glands
Y. Urano (1990)
cDNA cloning, gene organization and expression analysis of human peptidylarginine deiminase type VI.
J. Zhang (2004)
Localization of peptidylarginine deiminase 4 (PADI4) and citrullinated protein in synovial tissue of rheumatoid arthritis.
X. Chang (2005)
Human peptidylarginine deiminase type III: molecular cloning and nucleotide sequence of the cDNA, properties of the recombinant enzyme, and immunohistochemical localization in human skin.
T. Kanno (2000)
Histone Deimination Antagonizes Arginine Methylation
Graeme L. Cuthbert (2004)
Epitopes of human fibrin recognized by the rheumatoid arthritis‐specific autoantibodies to citrullinated proteins
M. Sebbag (2006)
cDNA cloning, gene organization and expression analysis of human peptidylarginine deiminase type I.
M. Guerrin (2003)
Citrullination in extra-articular manifestations of rheumatoid arthritis.
T. Bongartz (2007)
Comparison of enzymatic properties between hPADI2 and hPADI4.
Makiko Nakayama-Hamada (2005)
Increased Citrullination of Histone H3 in Multiple Sclerosis Brain and Animal Models of Demyelination: A Role for Tumor Necrosis Factor-Induced Peptidylarginine Deiminase 4 Translocation
F. Mastronardi (2006)
Update on peptidylarginine deiminases and deimination in skin physiology and severe human diseases
M-C Méchin (2007)
Genetic and genomic studies of PADI4 in rheumatoid arthritis.
S. M. J. Harney (2005)
A functional haplotype of the PADI4 gene associated with rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population.
A. Barton (2004)
Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4.
R. Plenge (2005)
This paper is referenced by
Citrullination under physiological and pathological conditions.
Z. Baka (2012)
Upregulation of citrullination pathway: From Autoimmune to Idiopathic Lung Fibrosis
K. Samara (2017)
Identification of novel biomarker as citrullinated inter-alpha-trypsin inhibitor heavy chain 4, specifically increased in sera with experimental and rheumatoid arthritis
H. Kawaguchi (2018)
Differential ACPA Binding to Nuclear Antigens Reveals a PAD-Independent Pathway and a Distinct Subset of Acetylation Cross-Reactive Autoantibodies in Rheumatoid Arthritis
Katy A. Lloyd (2019)
An improved synthesis of haloaceteamidine-based inactivators of protein arginine deiminase 4 (PAD4).
C. Causey (2008)
Chronic administration of Cl‐amidine, a pan‐peptidylarginine deiminase inhibitor, does not reverse bone loss in two different murine models of osteoporosis
Virginia M Vargas-Muñoz (2019)
The Atypical Fibrin Fibre Network in Rheumatoid Arthritis and its Relation to Autoimmunity, Inflammation and Thrombosis
J. A. Bezuidenhout (2020)
Peptidylarginine deiminase and protein citrullination in prion diseases
B. Jang (2013)
MS analysis of rheumatoid arthritic synovial tissue identifies specific citrullination sites on fibrinogen
M. Hermansson (2010)
Galectin-9 Is a Possible Promoter of Immunopathology in Rheumatoid Arthritis by Activation of Peptidyl Arginine Deiminase 4 (PAD-4) in Granulocytes
V. R. Wiersma (2019)
Expression of citrulline and homocitrulline residues in the lungs of non-smokers and smokers: implications for autoimmunity in rheumatoid arthritis
Elena B. Lugli (2015)
Assessing the citrullinome in rheumatoid arthritis synovial fluid with and without enrichment of citrullinated peptides.
Astrid E V Tutturen (2014)
Review Rheumatoid arthritis and smoking: putting the pieces together
Zsuzsanna Baka (2009)
Targets Hidden by Fibrin Networks Still Need to Find Their Place in the Armamentarium for Rheumatoid Arthritis
Antonio Gabucio (2016)
This information is current as Citrullinated Protein Autoantibodies − Anti Effector Functions of the Disease-Specific and Complement-Dependent − Receptor from Rheumatoid Arthritis Sera Boost the Fc IgM and IgA Rheumatoid Factors Purified and Mireille Sebbag
Florence Anquetil (2015)
Antibodies to citrullinated proteins: molecular interactions and arthritogenicity
H. Uysal (2010)
Chapter 56 – Autoantibodies in Rheumatoid Arthritis
F. Andrade (2017)
Arthritic role of Porphyromonas gingivalis in collagen-induced arthritis mice
H. Jung (2017)
Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis
A. Quirke (2014)
From Citrullination to Specific Immunity and Disease in Rheumatoid Arthritis
A. Hensvold (2014)
LOOKING FOR ARTHRITIS REGULATING GENES ON MOUSE CHROMOSOME 6 & 14
M. Popovic (2008)
Investigating the tumourigenic aspects of the bone marrow microenvironment in multiple myeloma
Bessie Anne Ellis (2014)
Proteins derived from neutrophil extracellular traps may serve as self-antigens and mediate organ damage in autoimmune diseases
J. Knight (2012)
Outcomes of Influence of Dimethylarginine Derivats, PAD Isoenzymes, or both as Hallmark on Citrullinisation Process on Autoantigens ACPA/ Anti CCP Antibodies overall for Diagnosis in Rheumatoid Arthritis
Dejan Spasovski (2015)
eview itrullination under physiological and pathological conditions
suzsanna Bakaa (2012)
Predominance of IgG1 and IgG3 subclasses of autoantibodies to peptidylarginine deiminase 4 in rheumatoid arthritis
Wei Wang (2010)
Anti-Citrullinated Protein Antibodies in Patients with Rheumatoid Arthritis: Biological Effects and Mechanisms of Immunopathogenesis
Chao-Yi Wu (2020)
Unconventional post-translational modifications in immunological signaling
K. Mowen (2014)
Citrullination of autoantigens: Upstream of TNFα in the pathogenesis of rheumatoid arthritis
A. Quirke (2011)
4 HLA and Citrullinated Peptides in Rheumatoid Arthritis
I. Alvarez (2017)
Citrullination of TNF-α by peptidylarginine deiminases reduces its capacity to stimulate the production of inflammatory chemokines.
E. Moelants (2013)
Citrullination Alters the Antiviral and Immunomodulatory Activities of the Human Cathelicidin LL-37 During Rhinovirus Infection
V. Casanova (2020)See more