DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Association of Distinct Fine Specificities of Anti−Citrullinated Peptide Antibodies With Elevated Immune Responses to Prevotella intermedia in a Subgroup of Patients With Rheumatoid Arthritis and Periodontitis

Journal Article · · Arthritis & Rheumatology
DOI: https://doi.org/10.1002/art.40227 · OSTI ID:1405565
 [1];  [1];  [2];  [3];  [1];  [4];  [5];  [3];  [3];  [3];  [1];  [6];  [1];  [1];  [1];  [7];  [8];  [1]
  1. University of Oxford Oxford UK
  2. University of Oxford, Oxford, UK, and Jagiellonian University Krakow Poland
  3. Jagiellonian University Krakow Poland
  4. University of Nebraska Medical Center Omaha
  5. University of Bern Bern Switzerland
  6. Jagiellonian University, Krakow, Poland, and University of Louisville Louisville Kentucky
  7. University of Nebraska Medical Center Lincoln
  8. University of Nebraska Medical Center and Nebraska‐Western Iowa Health Care System Omaha

Objective In addition to the long‐established link with smoking, periodontitis ( PD ) is a risk factor for rheumatoid arthritis ( RA ). This study was undertaken to elucidate the mechanism by which PD could induce antibodies to citrullinated peptides ( ACPA s), by examining the antibody response to a novel citrullinated peptide of cytokeratin 13 ( CK ‐13) identified in gingival crevicular fluid ( GCF ), and comparing the response to 4 other citrullinated peptides in patients with RA who were well‐characterized for PD and smoking. Methods The citrullinomes of GCF and periodontal tissue from patients with PD were mapped by mass spectrometry. ACPA s of CK 13 ( cCK 13), tenascin‐C ( cTNC 5), vimentin ( cVIM ), α‐enolase ( CEP ‐1), and fibrinogen β ( cFIB β) were examined by enzyme‐linked immunosorbent assay in patients with RA (n = 287) and patients with osteoarthritis (n = 330), and cross‐reactivity was assessed by inhibition assays. Results A novel citrullinated peptide cCK 13‐1 ( 444 TSNASGR ‐Cit‐ TSDV ‐Cit‐ RP 458 ) identified in GCF exhibited elevated antibody responses in RA patients (24%). Anti– cCK 13‐1 antibody levels correlated with anti– cTNC 5 antibody levels, and absorption experiments confirmed this was not due to cross‐reactivity. Only anti– cCK 13‐1 and anti‐ cTNC 5 were associated with antibodies to the periodontal pathogen Prevotella intermedia ( P = 0.05 and P = 0.001, respectively), but not with antibodies to Porphyromonas gingivalis arginine gingipains. Levels of antibodies to CEP ‐1, cFIB β, and cVIM correlated with each other, and with smoking and shared epitope risk factors in RA. Conclusion This study identifies 2 groups of ACPA fine specificities associated with different RA risk factors. One is predominantly linked to smoking and shared epitope, and the other links anti– cTNC 5 and cCK 13‐1 to infection with the periodontal pathogen P intermedia .

Sponsoring Organization:
USDOE
OSTI ID:
1405565
Alternate ID(s):
OSTI ID: 1408157
Journal Information:
Arthritis & Rheumatology, Journal Name: Arthritis & Rheumatology Journal Issue: 12 Vol. 69; ISSN 2326-5191
Publisher:
Wiley Blackwell (John Wiley & Sons)Copyright Statement
Country of Publication:
Country unknown/Code not available
Language:
English

References (51)

The shared epitope hypothesis. an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis journal November 1987
Purification and Characterization of Gingipains journal August 2007
The american rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis journal March 1988
The rheumatoid arthritis synovial fluid citrullinome reveals novel citrullinated epitopes in apolipoprotein E, myeloid nuclear differentiation antigen, and β-actin journal December 2012
Antibodies to Porphyromonas gingivalis Indicate Interaction Between Oral Infection, Smoking, and Risk Genes in Rheumatoid Arthritis Etiology journal February 2016
Purification and characterisation of recombinant His-tagged RgpB gingipain from Porphymonas gingivalis journal April 2015
Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis journal September 2016
Periodontitis in RA—the citrullinated enolase connection journal September 2010
Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin journal February 2004
Identification of an immunodominant peptide from citrullinated tenascin-C as a major target for autoantibodies in rheumatoid arthritis journal December 2015
Case Definitions for Use in Population-Based Surveillance of Periodontitis journal July 2007
Expression of citrulline and homocitrulline residues in the lungs of non-smokers and smokers: implications for autoimmunity in rheumatoid arthritis journal January 2015
Fine specificity of the anti-citrullinated protein antibody response is influenced by the shared epitope alleles journal December 2007
Specific interaction between genotype, smoking and autoimmunity to citrullinated α-enolase in the etiology of rheumatoid arthritis journal November 2009
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 journal January 2007
Clinical Criteria for the Definition of “Established Periodontitis” journal March 1992
Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis journal September 2012
Immunity to Citrullinated Proteins in Rheumatoid Arthritis journal April 2008
Cigarette smoking increases the risk of rheumatoid arthritis: Results from a nationwide study of disease-discordant twins journal May 1996
Update of the Case Definitions for Population-Based Surveillance of Periodontitis journal December 2012
Release of Active Peptidyl Arginine Deiminases by Neutrophils Can Explain Production of Extracellular Citrullinated Autoantigens in Rheumatoid Arthritis Synovial Fluid: ENZYMATICALLY ACTIVE PADs AND AUTOANTIGEN PRODUCTION IN RA SF journal November 2015
A specific anti-citrullinated protein antibody profile identifies a group of rheumatoid arthritis patients with a toll-like receptor 4-mediated disease journal October 2016
Quantitative real-time PCR using TaqMan and SYBR Green for Actinobacillus actinomycetemcomitans , Porphyromonas gingivalis , Prevotella intermedia , tetQ gene and total bacteria journal October 2003
Identification of novel antiacetylated vimentin antibodies in patients with early inflammatory arthritis journal July 2015
Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis journal March 2013
Periodontitis: from microbial immune subversion to systemic inflammation journal December 2014
Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis: Anti-CCP Antibody and IgA-RF Predict RA journal October 2003
Purification, Characterization, and Sequence Analysis of a Potential Virulence Factor from Porphyromonas gingivalis, Peptidylarginine Deiminase journal July 1999
NETs Are a Source of Citrullinated Autoantigens and Stimulate Inflammatory Responses in Rheumatoid Arthritis journal March 2013
Cigarette smoking and the risk of rheumatoid arthritis among postmenopausal women: journal April 2002
Detection of antibodies to citrullinated tenascin-C in patients with early synovitis is associated with the development of rheumatoid arthritis journal December 2016
Gel-aided sample preparation (GASP)-A simplified method for gel-assisted proteomic sample generation from protein extracts and intact cells journal February 2015
Elevated levels of fibrinogen-derived endogenous citrullinated peptides in synovial fluid of rheumatoid arthritis patients journal January 2012
Expression of peptidylarginine deiminase-2 and -4, citrullinated proteins and anti-citrullinated protein antibodies in human gingiva journal September 2012
Porphyromonas gingivalis Facilitates the Development and Progression of Destructive Arthritis through Its Unique Bacterial Peptidylarginine Deiminase (PAD) journal September 2013
Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage journal October 2011
Performance of Self-Reported Measures for Periodontitis in Rheumatoid Arthritis and Osteoarthritis journal January 2015
Antibodies to citrullinated α-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase journal October 2008
Periodontitis and Porphyromonas gingivalis in Patients With Rheumatoid Arthritis : Periodontitis and journal April 2014
Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis journal January 2010
Citrullination in the periodontium—a possible link between periodontitis and rheumatoid arthritis journal August 2015
Bone loss, pain and inflammation: three faces of ACPA in RA pathogenesis journal January 2016
Citrullination is an inflammation-dependent process journal September 2006
Genetic and environmental determinants for disease risk in subsets of rheumatoid arthritis defined by the anticitrullinated protein/peptide antibody fine specificity profile journal June 2012
The Major Synovial Targets of the Rheumatoid Arthritis-Specific Antifilaggrin Autoantibodies Are Deiminated Forms of the α- and β-Chains of Fibrin journal March 2001
Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis journal December 2016
2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative journal August 2010
Hypothesis: The Humoral Immune Response to Oral Bacteria Provides a Stimulus for the Development of Rheumatoid Arthritis journal December 2004
The periodontium of periodontitis patients contains citrullinated proteins which may play a role in ACPA (anti-citrullinated protein antibody) formation journal April 2012
ATP Induces Protein Arginine Deiminase 2-Dependent Citrullination in Mast Cells through the P2X7 Purinergic Receptor journal September 2012
Smoking, Porphyromonas gingivalis and the immune response to citrullinated autoantigens before the clinical onset of rheumatoid arthritis in a Southern European nested case–control study journal November 2015