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SP0003 Novel animal model in arthritis
  1. Y Iwakura
  1. Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan

Abstract

We have generated two rheumatoid arthritis (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 that closely resembles 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 development of arthritis in HTLV-I transgenic mouse model. IL-17 plays an important role in both models, suggesting the central role of IL-17 in these RA models.

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 syntenic locus for the CLR genes is linked to several autoimmune diseases including RA and SNPs in the Dcir gene is associated with RA, 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 autoimmune enthesitis and ankyloses accompanied by fibrocartilage proliferation and ectopic ossification. DCs were excessively expanded in Dcir KO mice, causing these mice autoimmunity and also highly susceptible to induced-autoimmune diseases. Dcir KO mouse–derived bone marrow cells differentiated into DCs more efficiently than did wild-type BMCs upon treatment with GM-CSF, due to enhanced STAT-5 phosphorylation. Furthermore, we found that IFN-g producing T cells were increased in Dcir KO mice and IFN-g enhanced bone and cartilage formation, resulting in the increase of bone volume and aberrant ossification in joints. DCIR is also expressed in osteoclasts and suppresses osteoclastogenesis upon activation. These findings suggest that DCIR plays important roles in both immune system and bone metabolism.

Disclosure of Interest None declared

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