Untitled

Abstract

���������������������������������������������������������������������������������������������������������������������������������� EMBO J. in 1988. Then, I generated Tg mice carrying the tax gene of HTLV-I, which is the causative agent of adult T cell leukemia. Because these transgenic mice spontaneously developed autoimmune arthritis resembling rheumatoid arthritis in humans, I suggested that HTLV-I is one of etiological agents of rheumatoid arthritis (Science, 1991). Through the analysis of these Tg mice, I found that Tax-induced IL-1 might play a critical role in the pathogenesis of arthritis. Then, we knocked out all ��������������������������������������������������������������������������������������������������������������������������������� in the febrile response and glucocorticoid induction under stress (J. Exp. Med., 1988). Furthermore, we found that IL-1Ra-����������������������������������������������������������������������������������������������������������J. Exp. Med., 2000; ����������������������������������������������������������������������������������������������������������������������������� TNF is a good candidate for the treatment of these diseases (J. Clin. Invest., ���������������������������������������������� because this gene expression was enhanced in both HTLV-I Tg and IL-1Ra KO mice. We showed that the development of arthritis was strongly suppressed in IL-17 KO mice, suggesting that IL-17 plays a critical role in the development of arthritis (Immunity, 2002; PNAS, 2003). Furthermore, we showed that IL-17F, the molecule with the highest homology with IL-17A in the same family, is important for the host defense against microbial mucoepithelial infection (Immunity, 2009; Immunity, 2011). To further analyze the mechanisms of the development of autoimmunity and arthritis, we knocked out genes which were highly expressed in arthritic joints. Among them, we showed that Dectin-1 and Dectin-2, C-type lectin receptors, is the receptor for �������������������������������������������������������������������������������������������������������������Nat. Immunol., 2007). Interestingly, Th17 cell differentiation was preferentially induced by these signals, suggesting that fungal infection may cause autoimmunity (Immunity, 2010). We also showed that KO mice of Dcir, another C-type lectin family member, develop autoimmune enthesitis and sialadenitis (Nat. Med., 2008). These results indicate that non-TLR innate immune molecules such as C-type lectins are important for the regulation of the acquired immune system and can be a good target for the treatment of autoimmune diseases. Taken together, I could show through these studies that gene manipulated mice are useful for the development of disease models and analysis of the pathogenic mechanisms.