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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.

Rheumatoid arthritis (RA) is an autoimmune disease affecting approximately 1% of the population worldwide. Previously, we showed that human T-cell leukemia virus type I-transgenic mice and interleukin-1 receptor antagonist-knockout mice develop autoimmunity and joint-specific inflammation that resembles human RA. To identify genes involved in the pathogenesis of arthritis, we analyzed the gene expression profiles of these animal models by using high-density oligonucleotide arrays. We found 1,467 genes that were differentially expressed from the normal control mice by greater than threefold in one of these animal models. The gene expression profiles of the two models correlated well. We extracted 554 genes whose expression significantly changed in both models, assuming that pathogenically important genes at the effector phase would change in both models. Then, each of these commonly changed genes was mapped into the whole genome in a scale of the 1-megabase pairs. We found that the transcriptome map of these genes did not distribute evenly on the chromosome but formed clusters. These identified gene clusters include the major histocompatibility complex class I and class II genes, complement genes, and chemokine genes, which are well known to be involved in the pathogenesis of RA at the effector phase. The activation of these gene clusters suggests that antigen presentation and lymphocyte chemotaxisis are important for the development of arthritis. Moreover, by searching for such clusters, we could detect genes with marginal expression changes. These gene clusters include schlafen and membrane-spanning four-domains subfamily A genes whose function in arthritis has not yet been determined. Thus, by combining two etiologically different RA models, we succeeded in efficiently extracting genes functioning in the development of arthritis at the effector phase. Furthermore, we demonstrated that identification of gene clusters by transcriptome mapping is a useful way to find potentially pathogenic genes among genes whose expression change is only marginal.

IL-17 is a T-cell-derived proinflammatory cytokine, which is suspected to be involved in the development of rheumatoid arthritis (RA) because this cytokine is found in sera and synovial tissues of RA patients. The pathogenic roles of IL-17 in the development of RA, however, still remain to be elucidated.

Chemokines and their receptors are potential therapeutic targets in rheumatoid arthritis (RA). Among these, several studies suggested the involvement of CXC chemokine 4 (CXCR4) and its ligand CXC ligand 12 (SDF-1) in RA pathogenesis. However, the role of these molecules in T-cell function is not known completely because of embryonic lethality of Cxcr4- and Cxcl12-deficient mice. In this report, we generated T cell-specific Cxcr4-deficient mice and showed that the CXCR4 in T cells is important for the development of collagen-induced arthritis (CIA). T cell-specific Cxcr4-deficient mice were generated by using the Cre-loxP system. Mice harboring loxP sites flanking exon 2 of the Cxcr4gene (Cxcr4 flox/flox ) were generated by homologous recombination and crossed with Cre transgenic mice expressing Cre recombinase under the control of Lck promoter (Cxcr4 +/+ /Lck-Cremice) to generate T cell-specific Cxcr4-deficient mice (Cxcr4 flox/flox /Lck-Cre mice). CIA was induced by immunization with chicken type II collagen and Complete Freund's Adjuvant (CFA). The incidence, but not the severity, of CIA was significantly reduced in Cxcr4 flox/flox /Lck-Cre mice compared with Cxcr4 +/+ /Lck-Cre mice. We found that the expression of CXCR4 was enhanced in activated T cells, and the migration of Cxcr4-deficient T cells toward SDF-1 was severely impaired. However, antibody production, cellular proliferative response, and cytokine production on treatment with type II collagen (IIC) were normal in these knockout mice, suggesting that CXCR4 is not involved in T-helper functions. Interestingly, the proportion of CXCR4-expressing T cells was much increased in affected joints compared with that in draining lymph nodes in CIA-induced mice, and distribution of Cxcr4 flox/flox /Lck-Cre mouse-derived T cells into affected joints was suppressed compared with that in Cxcr4 +/+ /Lck-Cre T cells. These results indicate that CXCR4 expression in T cells is important for the development of CIA, by recruiting activated T cells toward inflammatory sites, and suggest that CXCR4 is a good target for the treatment of RA in humans.