Email updates

Keep up to date with the latest news and content from Arthritis Research & Therapy and BioMed Central.

This article is part of the supplement: Proceedings of the 8th Global Arthritis Research Network (GARN) Meeting and 1st Bio-Rheumatology International Congress (BRIC)

Oral presentation

Therapeutic targets for rheumatoid arthritis: lessons from animal models

Yoichiro Iwakura12*, Shinobu Saijo1, Susumu Nakae1, Noriyuki Fujikado1, Harumichi Ishigame1 and Masanori Murayama1

  • * Corresponding author: Yoichiro Iwakura

Author affiliations

1 Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan

2 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan

For all author emails, please log on.

Citation and License

Arthritis Research & Therapy 2012, 14(Suppl 1):O18  doi:10.1186/ar3573

The electronic version of this article is the complete one and can be found online at: http://arthritis-research.com/content/14/S1/O18


Published:9 February 2012

© 2012 Iwakura et al.; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Oral presentation

We have generated two RA models, human T-cell leukemia virus type I (HTLV-I) transgenic mice and IL-1 receptor antagonist (Ra)-deficient (KO) mice, to elucidate the pathogenic mechanisms of the disease. Both models spontaneously developed arthritis closely resembling that of RA in humans. We found that TNF-, but not IL-6-, deficiency suppressed development of arthritis in IL-1Ra KO mice, while IL-6 but not TNF was involved in the HTLV-I transgenic mouse model [1]. IL-17 was important in both models. These observations suggest that pathogenic roles of IL-6 and TNF are different and both TNF, IL-6, and IL-17 are good targets for therapeutics.

We found that the expression of C-type lectin receptor (CLR) genes was augmented in the affected joints of these models using DNA microarrays. Dendritic cell immunoreceptor (DCIR) is one of such CLRs with a carbohydrate recognition domain in their extracellular carboxy terminus and an ITIM in its intracellular amino terminus. Because human shared syntenic locus containing the Dcir gene is linked to several autoimmune diseases including RA and SLE, we have generated Dcir KO mice to examine the roles of this gene in the immune system. We found that aged Dcir KO mice spontaneously developed sialadenitis and enthesitis associated with elevated serum autoantibodies [2]. DCs were excessively expanded in Dcir KO mice after aging. Dcir KO mouse-derived bone marrow cells (BMCs) differentiated into DCs more efficiently than did wild-type BMCs upon treatment with GM-CSF, owing to enhanced STAT-5 phosphorylation. These findings indicate that DCIR is crucial for maintaining the homeostasis of the immune system, suggesting that Dcir is one of novel targets for the treatment of RA.

We have also found that the expression of Muratin1, which encodes uncharacterized and secreted protein, is specifically up-regulated in affected joins of both models. Interestingly, the development of collagen-induced arthritis was markedly exacerbated in Muratin1 KO mice. I would like to discuss the roles of Muratin-1 in the development of arthritis.

References

  1. Iwakura Y, Nakae S, Saijo S, Ishigame H: The roles of IL-17A in inflammatory immune responses and host defense against pathogens.

    Immunol Rev 2008, 226:57-79. PubMed Abstract | Publisher Full Text OpenURL

  2. Fujikado N, Saijo S, Yonezawa T, Shimamori K, Ishii A, Sugai S, Kotaki H, Sudo K, Nose M, Iwakura Y: Dcir deficiency causes development of autoimmune diseases in mice due to excess expansion of dendritic cells.

    Nat Med 2008, 14:176-180. PubMed Abstract | Publisher Full Text OpenURL