title: Genetic control of antibody production during collagen-induced arthritis development in heterogeneous stock mice.
abstract: OBJECTIVE
  To identify genetic factors driving pathogenic autoantibody formation in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA), in order to better understand the etiology of RA and identify possible new avenues for therapeutic intervention.
  
  
  METHODS
  We performed a genome-wide analysis of quantitative trait loci controlling autoantibody to type II collagen (anti-CII), anti-citrullinated protein antibody (ACPA), and rheumatoid factor (RF). To identify loci controlling autoantibody production, we induced CIA in a heterogeneous stock-derived mouse cohort, with contribution of 8 inbred mouse strains backcrossed to C57BL/10.Q. Serum samples were collected from 1,640 mice before arthritis onset and at the peak of the disease. Antibody concentrations were measured by standard enzyme-linked immunosorbent assay, and linkage analysis was performed using a linear regression-based method.
  
  
  RESULTS
  We identified loci controlling formation of anti-CII of different IgG isotypes (IgG1, IgG3), antibodies to major CII epitopes (C1, J1, U1), antibodies to a citrullinated CII peptide (citC1), and RF. The anti-CII, ACPA, and RF responses were all found to be controlled by distinct genes, one of the most important loci being the immunoglobulin heavy chain locus.
  
  
  CONCLUSIONS
  This comprehensive genetic analysis of autoantibody formation in CIA demonstrates an association not only of anti-CII, but interestingly also of ACPA and RF, with arthritis development in mice. These results underscore the importance of non-major histocompatibility complex genes in controlling the formation of clinically relevant autoantibodies.
authors.affiliation: Karolinska Institutet, Stockholm, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Förster
authors.forename: Bruno
authors.initials: B
authors.lastname: Raposo
authors.forename: Diana
authors.initials: D
authors.lastname: Ekman
authors.forename: Dorota
authors.initials: D
authors.lastname: Klaczkowska
authors.forename: Marjan
authors.initials: M
authors.lastname: Popovic
authors.forename: Kutty S
authors.initials: KS
authors.lastname: Nandakumar
authors.forename: Therese
authors.initials: T
authors.lastname: Lindvall
authors.forename: Malin
authors.initials: M
authors.lastname: Hultqvist
authors.forename: Ivanka
authors.initials: I
authors.lastname: Teneva
authors.forename: Martina
authors.initials: M
authors.lastname: Johannesson
authors.forename: Emma
authors.initials: E
authors.lastname: Ahlqvist
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D024043:Collagen Type II / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D055106:Genome-Wide Association Study; D007074:Immunoglobulin G / Q000097:blood / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D010456:Peptides, Cyclic / Q000276:immunology; D040641:Quantitative Trait Loci / Q000276:immunology; D012217:Rheumatoid Factor / Q000276:immunology; D013045:Species Specificity
chemical_list: D001323:Autoantibodies; D024043:Collagen Type II; D007074:Immunoglobulin G; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D012217:Rheumatoid Factor