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Genetic control of antibody production during collagen-induced arthritis development in heterogeneous stock mice

Forster, Michael; Raposo, Bruno; Ekman, Diana; Klaczkowska, Dorota; Popovic, Marjan; Nandakumar, Kutty S.; Lindvall, Therese LU ; Hultqvist, Malin LU ; Teneva, Ivanka LU and Johannesson, Martina, et al. (2012) In Arthritis and Rheumatism 64(11). p.3594-3603
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... (More)
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. Conclusion. 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. (Less)
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published
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Arthritis and Rheumatism
volume
64
issue
11
pages
3594 - 3603
publisher
John Wiley & Sons
external identifiers
  • wos:000310544500013
  • scopus:84868104226
ISSN
1529-0131
DOI
10.1002/art.34658
language
English
LU publication?
yes
id
aa5edcd9-4c53-4fa3-a7fb-c1775ba611e7 (old id 3283464)
date added to LUP
2013-01-07 09:40:56
date last changed
2017-09-17 04:05:31
@article{aa5edcd9-4c53-4fa3-a7fb-c1775ba611e7,
  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. Conclusion. 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.},
  author       = {Forster, Michael and Raposo, Bruno and Ekman, Diana and Klaczkowska, Dorota and Popovic, Marjan and Nandakumar, Kutty S. and Lindvall, Therese and Hultqvist, Malin and Teneva, Ivanka and Johannesson, Martina and Ahlqvist, Emma and Holmdahl, Rikard},
  issn         = {1529-0131},
  language     = {eng},
  number       = {11},
  pages        = {3594--3603},
  publisher    = {John Wiley & Sons},
  series       = {Arthritis and Rheumatism},
  title        = {Genetic control of antibody production during collagen-induced arthritis development in heterogeneous stock mice},
  url          = {http://dx.doi.org/10.1002/art.34658},
  volume       = {64},
  year         = {2012},
}