title: Marked differences in fine specificity and isotype usage of the anti-citrullinated protein antibody in health and disease.
abstract: OBJECTIVE
  Anti-citrullinated protein antibodies (ACPAs) display high association with rheumatoid arthritis (RA) and are implicated in its pathogenesis. The presence of ACPAs is known to precede the onset of RA. In order to identify the features that could confer its pathogenicity, we extensively characterized this antibody response in a unique North American native population of patients with RA and their unaffected relatives.
  
  
  METHODS
  The levels of IgA, IgM, and IgG ACPAs, as well as IgM and IgA rheumatoid factor (RF), were measured in serum samples obtained from 81 patients with RA and 195 of their unaffected relatives. The isotype distribution, the fine specificity of the ACPA response, and its association with RF were compared in health and disease.
  
  
  RESULTS
  ACPA positivity was observed in 19% of the healthy relatives and approximately 91% of the patients with RA. ACPA isotype usage was strikingly lower in unaffected relatives than in patients with RA (1-2 versus 5-6 isotypes). Fine specificity studies showed that reactivity to citrullinated fibrinogen and vimentin was present in sera from patients with RA, while it was virtually absent in their unaffected relatives. Finally, the ACPA and RF responses were associated in patients with RA but were discordant in their healthy relatives. Extended analyses revealed that the presence of ACPAs was associated with RA irrespective of RF status, while the association of RF with disease relied on its interaction with ACPAs.
  
  
  CONCLUSIONS
  The fine specificity and isotype usage of the ACPA response are qualitatively different in health and disease. Epitope spreading and expansion of the isotype repertoire might be necessary for development of RA, and this could be facilitated by the presence of RF antibodies.
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Andreea
authors.initials: A
authors.lastname: Ioan-Facsinay
authors.forename: Annemiek
authors.initials: A
authors.lastname: Willemze
authors.forename: David B
authors.initials: DB
authors.lastname: Robinson
authors.forename: Christine A
authors.initials: CA
authors.lastname: Peschken
authors.forename: Janet
authors.initials: J
authors.lastname: Markland
authors.forename: Diane
authors.initials: D
authors.lastname: van der Woude
authors.forename: Brenda
authors.initials: B
authors.lastname: Elias
authors.forename: Henri A
authors.initials: HA
authors.lastname: Ménard
authors.forename: Marianna
authors.initials: M
authors.lastname: Newkirk
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Fritzler
authors.forename: René E M
authors.initials: RE
authors.lastname: Toes
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: Hani S
authors.initials: HS
authors.lastname: El-Gabalawy
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000208:ethnology / Q000276:immunology*; D015415:Biomarkers; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology*; D007198:Indians, North American; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*; D012217:Rheumatoid Factor / Q000276:immunology
chemical_list: D015415:Biomarkers; D007070:Immunoglobulin A; D007075:Immunoglobulin M; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D012217:Rheumatoid Factor