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Disease-promoting and -protective genomic loci on mouse chromosomes 3 and 19 control the incidence and severity of autoimmune arthritis

Genes & Immunity volume 13, pages 336–345 (2012)Cite this article

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Abstract

Proteoglycan (PG)-induced arthritis (PGIA) is a murine model of rheumatoid arthritis. Arthritis-prone BALB/c mice are 100% susceptible, whereas the major histocompatibility complex-matched DBA/2 strain is completely resistant to PGIA. To reduce the size of the disease-suppressive loci for sequencing and to find causative genes of arthritis, we created a set of BALB/c.DBA/2-congenic/subcongenic strains carrying DBA/2 genomic intervals overlapping the entire Pgia26 locus on chromosome 3 (chr3) and Pgia23/Pgia12 loci on chr19 in the arthritis-susceptible BALB/c background. Upon immunization of these subcongenic strains and their wild-type (BALB/c) littermates, we identified a major Pgia26a sublocus on chr3 that suppressed disease onset, incidence and severity via controlling the complex trait of T-cell responses. The region was reduced to 3 Mbp (11.8 Mbp with flanking regions) in size and contained gene(s) influencing the production of a number of proinflammatory cytokines. Additionally, two independent loci (Pgia26b and Pgia26c) suppressed the clinical scores of arthritis. The Pgia23 locus (∼3 Mbp in size) on chr19 reduced arthritis susceptibility and onset, and the Pgia12 locus (6 Mbp) associated with low arthritis severity. Thus, we have reached the critical sizes of arthritis-associated genomic loci on mouse chr3 and chr19, which are ready for high-throughput sequencing of genomic DNA.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (NIH/NIAMS) (R01 AR059356), Dr Glant's endowment chair (Rush University Medical Center, Chicago, IL) and, in part, by the Grainger Foundation (Lake Forest, IL). We thank a number of our colleagues and members of the Midwest Orthopedics (Rush University Medical Center, Chicago), especially Drs JJ Jacobs and M Tunyogi-Csapo, who helped in the collection of human cartilage samples, members of the Comparative Research Center (Rush University Medical Center, Chicago) and Dr. JM Oswald, and Drs O Tarjanyi, B Farkas, and G Hutas for scoring, Dr. Andras Kadar for additional cytokine assays, and Beata Tryniszewska for genotyping of animals (all in Departments of Orthopedic Surgery, Section of Molecular Medicine, Rush University Medical Center, Chicago, IL, USA.

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  1. V A Adarichev

    Present address: 5Current address: Departments of Medicine and Microbiology and Immunology, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, USA,

  2. F Boldizsar

    Present address: 6Current address: Department of Immunology and Biotechnology, University of Pecs, Pecs H-7635, Hungary,

  3. T T Glant and V A Adarichev: These two authors contributed equally to this work

Authors and Affiliations

  1. Department of Orthopedic Surgery, Section of Molecular Medicine, Rush University Medical Center, Chicago, IL, USA

    T T Glant, V A Adarichev, F Boldizsar, T Besenyei, A Laszlo, K Mikecz & T A Rauch

  2. Department of Internal Medicine, Section of Rheumatology, Rush University Medical Center, Chicago, IL, USA

    T T Glant & K Mikecz

  3. Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA

    T T Glant & K Mikecz

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  1. T T Glant
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Glant, T., Adarichev, V., Boldizsar, F. et al. Disease-promoting and -protective genomic loci on mouse chromosomes 3 and 19 control the incidence and severity of autoimmune arthritis. Genes Immun 13, 336–345 (2012). https://doi.org/10.1038/gene.2012.2

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