title: Expression of the inherently autoreactive idiotope 9G4 on autoantibodies to citrullinated peptides and on rheumatoid factors in patients with early and established rheumatoid arthritis.
abstract: BACKGROUND
  The pre-symptomatic stage of Rheumatoid arthritis (RA) is associated with pro-inflammatory cytokines and autoantibodies. High levels and epitope spread by Rheumatoid factors (RhF) and autoantibodies to citrullinated proteins signify progression towards disease expression. In established RA, the persistence of high autoantibody levels reflects production by both long-lived plasma cells and short-lived plasmablasts. Neither the relative contributions to pathogenesis by autoantibodies from either source, nor the factors responsible for deciding the fate of autoantigen specific 'parent' B-cells, is understood. Phenotypic markers identifying subsets of autoreactive B-cells are therefore of interest in understanding the origin and perpetuation of the autoimmune response in RA. One such phenotypic marker is the rat monoclonal antibody, 9G4, which recognises an idiotope on immunoglobuins derived from the inherently autoreactive VH-gene, VH4-34. We therefore investigated whether the 9G4 idiotope was expressed on autoantibodies in patients with RA.
  
  
  RESULTS
  Sera from 19 patients with established RA and those with <1year history of untreated polyarthritis either resolving into RA (n = 42) or non-RA diagnosis (n = 31) were included. Autoantibodies to cyclic citrullinated peptides (CCP), RhF and co-expression of the 9G4 idiotope were measured by ELISA. 9G4 recognised a population of anti-CCP antibodies in the majority of sera from patients with established disease and also in samples from patients with early disaese. 9G4+RhF levels were generally lower and not associated with positivity for, or levels of 9G4+CCP.
  
  
  CONCLUSIONS
  The persistence of 9G4+ immunoglobulins, of any isotype, in serum is rare. We describe here the novel finding of 9G4 expression on anti-CCP antibodies in patients from the earliest symptoms of RA through to established disease. Our results suggest that 9G4 expression on anti-CCP autoantibodies was not due to polyclonal expansion of VH4-34-encoded immunoglobulins. These studies may therefore provide a new focus for investigation into the evolution of the autoimmune response in RA patients.
authors.affiliation: Centre for Rheumatology, University College London, London, United Kingdom.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Cambridge
authors.affiliation: Centre for Rheumatology, University College London, London, United Kingdom; Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Rita A
authors.initials: RA
authors.lastname: Moura
authors.affiliation: Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Tania
authors.initials: T
authors.lastname: Santos
authors.affiliation: Centre for Rheumatology, University College London, London, United Kingdom; Centre for Inflammation and Tissue Repair, University College London, London, United Kingdom.
authors.forename: Akif A
authors.initials: AA
authors.lastname: Khawaja
authors.affiliation: Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal; Rheumatology Department, Centro Hospitalar de Lisboa Norte, EPE, Hospital de Santa Maria, Lisbon, Portugal.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Polido-Pereira
authors.affiliation: Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal; Rheumatology Department, Centro Hospitalar de Lisboa Norte, EPE, Hospital de Santa Maria, Lisbon, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Canhão
authors.affiliation: Centre for Rheumatology, University College London, London, United Kingdom.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Leandro
authors.affiliation: Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal; Rheumatology Department, Centro Hospitalar de Lisboa Norte, EPE, Hospital de Santa Maria, Lisbon, Portugal.
authors.forename: João E
authors.initials: JE
authors.lastname: Fonseca
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis* / Q000097:blood / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D007130:Immunoglobulin Idiotypes / Q000097:blood / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D051381:Rats; D012217:Rheumatoid Factor / Q000097:blood / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D007130:Immunoglobulin Idiotypes; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D012217:Rheumatoid Factor