Professor Yoichiro Iwakrua, D. Sc.

Recent development of transgenic techniques made it possible to directly analyze the functions of a particular gene in a living animal. These techniques have also succeeded in producing various animal disease models as well as tools to analyze them. Immune disorders and infectious diseases are our major concerns, therefore we attempt to produce transgenic mouse models for these diseases.

1. Studies on the pathogenesis of rheumatoid arthritis and related autoimmune diseases using mouse models.

Tomo Yonezawa, Soo-Hyun Chung, Riho Kurata, Masanori Murayama, Aoi Akitsu, Kenji Shimizu, Yuriko Hashiguchi, Shinobu Saijo1, and Yoichiro Iwakura
1Medical Mycology Research Center, Chiba Univ.

Rheumatoid arthritis (RA) is one of the most serious medical problems worldwide with approximately 1% of the people in the world affected. The disease is autoimmune in nature and characterized by the chronic inflammation of synovial tissues in multiple joints that leads to joint destruction. High levels of inflammatory cytokine expression in the joints are a characteristic of the disease, although the pathogenesis has not been elucidated completely. We have been studying the pathogenesis of the disease using two arthritis models that we originally developed. One is HTLV-I transgenic (Tg) mice (Iwakura et al., Science, 1991) and the other is IL-1 receptor antagonist-deficient (Il1rn-/-) mice (Horai et al., J. Exp. Med., 2000). Both of these models develop autoimmunity and chronic inflammatory arthropathy closely resembling RA in humans.
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, and identified more than 500 genes which are overexpressed in the affected joints in the RA-related gene locus (Fujikado et al., Arthritis Res. Ther., 2006). Furthermore, we have also searched for pathogenesis-related genes by analyzing the effect of genetic backgrounds on arthritis development, because BALB/cA strain mice were highly susceptible to develop arthritis in these models, whereas C57BL/6J strain mice were resistant. We performed linkage-analysis using BALB/c-HTLV-I Tg backcross progenies into C57BL/6J, and identified several RA-related gene loci that affected the strain specificity of arthritis susceptibility. We are now analyzing the roles of these genes in the pathogenesis of arthritis and autoimmunity by generating the gene targeted mice of these genes.

2. Studies on the roles of C-type lectins in the homeostasis of the immune system

Tomonori Kaifu, Rikio Yabe, Takumi Maruhashi, Akimasa Seno, Natsumi Maeda, Kaori Yoshida, and Yoichiro Iwakura

A balance between positive and negative signals through cellular receptors with opposing functions is important for the homeostasis of the immune system and bone metabolism. The homeostasis of the immune system is maintained by counterbalancing signals between activation and inhibitory receptors, whereas bone homeostasis is maintained by an equilibrium between bone resorption by osteoclasts and bone formation by osteoblasts. Disturbance of the balance between these opposite signals may cause harmful effects. In fact, continuous activation of the immune system causes inflammation, resulting in tissue damage and loss of mineral components due to excess activation of osteoclasts.
DCIR is a member of the C-type lectin with an extracellular carbohydrate recognition domain (CRD) with an atypical Ca2+-dependent EPS motif and an intracellular cytoplasmic region with an immunoreceptor tyrosine-based inhibitory motif (ITIM). Gene disruption of this molecule in mice causes spontaneously development of autoimmune disorders such as enthesitis and sialadenitis due to over expansion of dendritic cells (Fujikado et al., Nat. Med., 2008). In this study, we further examined effects of DCIR deficiency on disease development and the physiology. We found that DCIR-deficient mice exacerbated experimental autoimmune encephalomyelitis, a mouse model for multiple sclerosis, and T cell proliferation of these mice was enhanced upon stimulation with myelin oligodendrocyte glycoprotein. Interestingly, DCIR-deficient mice developed ankylosing spondylitis-like joint disorder, suggesting that DCIR is involved in the regulation of bone metabolism. Given that defective DCIR is prone to autoimmune diseases and bone-related disorders, DCIR could be a potential therapeutic target that terminates excessive activation of immune responses through ITIM-mediated negative signaling. We are now trying to elucidate the roles of this molecule and related C-type lectins in the homeostasis of the immune system and bone metabolism.

3. Studies on the roles of innate immune receptors in the homeostasis of intestinal immunity

Ce Tang, Motohiko Kadoki, Tomonori Kamiya, Arifumi Hamada, and Yoichiro Iwakura

We have shown that Dectin-1 is the receptor for β-glucans and Dectin-2 is the receptor for α-mannans (Saijo et al., Nat. Immun., 2007; Immunity, 2010). These receptors are important for the host defense against fungal infection by inducing reactive oxygen species and differentiation of Th17 cells. Because various foods such as mushrooms, yeasts, or seaweeds, contain β-glucans, we are now investigating the roles of Dectin-1 and Dectin-2 signaling in the intestinal immune system.