title: Bronchiectasis is a Model for Chronic Bacterial Infection Inducing Autoimmunity in Rheumatoid Arthritis.
abstract: OBJECTIVE
  To examine the potential of chronic severe bacterial infection to generate rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs), by studying patients with bronchiectasis (BR) alone and BR patients with rheumatoid arthritis (BR/RA).
  
  
  METHODS
  We studied 122 patients with BR alone, 50 patients with BR/RA, and 50 RA patients without lung disease, as well as 87 patients with asthma and 79 healthy subjects as controls. RF levels were measured using an automated analyzer, and cyclic citrullinated peptide 2 (CCP-2) was used to detect ACPAs. The fine specificities of citrullinated α-enolase peptide 1 (CEP-1), Cit-vimentin, and Cit-fibrinogen to their arginine-containing control peptides (arginine-containing α-enolase peptide 1 [REP-1], vimentin, and fibrinogen) were measured by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Among the BR patients and control subjects, 39% and 42%, respectively, were ever-smokers. The frequency of RF positivity in serum was increased in BR patients compared with controls (25% versus 10%), as were the frequencies of antibodies to CCP-2 (5% versus 0%), CEP-1 (7% versus 4%), Cit-vimentin (7% versus 4%), and Cit-fibrinogen (12% versus 4%), although only the differences for RF and Cit-fibrinogen were significant (P < 0.05). We observed a corresponding increase in the frequency of antibodies to the arginine-containing control peptides in BR patients compared with controls (for REP-1, 19% versus 4% [P < 0.01]; for vimentin, 16% versus 4% [P < 0.05]), demonstrating that the ACPA response in patients with BR is not citrulline specific. The lack of citrulline specificity was further confirmed by absorption studies. In BR/RA patients, all ACPA responses were highly citrulline specific.
  
  
  CONCLUSIONS
  Bronchiectasis is an unusual but potent model for the induction of autoimmunity in RA by bacterial infection in the lung. Our study suggests that the ACPA response is not citrulline specific during the early stages of tolerance breakdown but becomes more specific in patients with BR in whom BR/RA develops.
authors.affiliation: Kennedy Institute, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Quirke
authors.affiliation: Queen Elizabeth Hospital, Gateshead, UK, and University of Exeter Medical School, Exeter, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Perry
authors.affiliation: Kennedy Institute, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Cartwright
authors.affiliation: Queen Elizabeth Hospital, Gateshead, UK.
authors.forename: Clive
authors.initials: C
authors.lastname: Kelly
authors.affiliation: Newcastle University and The Freeman Hospital, Newcastle, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: De Soyza
authors.affiliation: University of Exeter Medical School, Exeter, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Eggleton
authors.affiliation: Royal Cornwall Hospital, Truro, UK.
authors.forename: David
authors.initials: D
authors.lastname: Hutchinson
authors.affiliation: Kennedy Institute, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Venables
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001249:Asthma / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D001424:Bacterial Infections / Q000276:immunology; D001987:Bronchiectasis / Q000276:immunology*; D016022:Case-Control Studies; D002908:Chronic Disease; D002956:Citrulline / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005340:Fibrinogen / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology; D010751:Phosphopyruvate Hydratase / Q000276:immunology / Q000378:metabolism; D012217:Rheumatoid Factor / Q000276:immunology; D012907:Smoking / Q000276:immunology*; D014746:Vimentin / Q000276:immunology / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D010456:Peptides, Cyclic; D014746:Vimentin; C487763:cyclic citrullinated peptide; D002956:Citrulline; D005340:Fibrinogen; D012217:Rheumatoid Factor; D010751:Phosphopyruvate Hydratase