Mr. Förster and Mr. Raposo contributed equally to this work.
Genetic control of antibody production during collagen-induced arthritis development in heterogeneous stock mice
Article first published online: 27 OCT 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 11, pages 3594–3603, November 2012
How to Cite
Förster, M., Raposo, B., Ekman, D., Klaczkowska, D., Popovic, M., Nandakumar, K. S., Lindvall, T., Hultqvist, M., Teneva, I., Johannesson, M., Ahlqvist, E. and Holmdahl, R. (2012), Genetic control of antibody production during collagen-induced arthritis development in heterogeneous stock mice. Arthritis & Rheumatism, 64: 3594–3603. doi: 10.1002/art.34658
- Issue published online: 27 OCT 2012
- Article first published online: 27 OCT 2012
- Accepted manuscript online: 8 AUG 2012 12:00PM EST
- Manuscript Accepted: 26 JUL 2012
- Manuscript Received: 21 FEB 2012
- Swedish Research Council
- Swedish Science Strategic Foundation
- European Union Seventh Framework Programme (project Masterswitch). Grant Number: HEALTH-F2-2008-223404
- Innovative Medicines Initiative, a public-private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations (BTCure program)
- Fundação para a Ciência e Tecnologia, Portugual. Grant Number: SFRH/BD/40658/2007
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.
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.
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.
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.