Mechanisms and their regulation of autoimmune disorders

• Project Area: Immunological Self Recognition and its Disorders
• Project/Area Number: 19059005
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: YAMAMOTO Kazuhiko 東京大学, 医学部附属病院, 教授 (80191394)
• Co-Investigator(Kenkyū-buntansha): ISHII Naoto 東北大学, 医学系研究科, 教授 (60291267)
• Project Period (FY): 2007 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥157,500,000 (Direct Cost: ¥157,500,000); Fiscal Year 2011: ¥31,500,000 (Direct Cost: ¥31,500,000); Fiscal Year 2010: ¥31,500,000 (Direct Cost: ¥31,500,000); Fiscal Year 2009: ¥31,500,000 (Direct Cost: ¥31,500,000); Fiscal Year 2008: ¥31,500,000 (Direct Cost: ¥31,500,000); Fiscal Year 2007: ¥31,500,000 (Direct Cost: ¥31,500,000)
• Keywords: 遺伝学 / 生体分子 / 病理学 / 免疫学 / 臨床 / 遺伝子

Research Abstract

We have observed that in the presence of strong proliferation of antigen-X-specific T cells, co-existing T cells specific to antigen-Y exhibit activation in response to small amount of antigen-Y. We termed this phenomenon as 'Extended antigen presentation (EAP)', a new mechanism of naive T cell activation. This project revealed that the induction of EAP depends on cell-cell contact and the amount of EAP-inducing antigen is as small as that of physiological autoantigen. Moreover, the fact that EAP induction was observed in three different T cell receptor transgenic T cells suggested universal nature of this phenomenon. EAP may be an immunological basis for epitope-spreading in autoimmune disease, and our observation could contribute to the understanding of autoimmunity and the development of therapeutic strategy.

Research Products

• [Journal Article] Meta-analysis of genome-wide association studies identifies multiple novel loci associated with rheumatoid arthritis in the Japanese population. (2012)
  • Author(s): Okada Y, Terao C, Ikari K, et al
  • Journal Title: Nat. Genet. Volume: (e-pub) Pages: 511-516
  • DOI: 10.1038/ng.2231
  • Peer Reviewed
• [Journal Article] Regulation of histone modification and chromatin structure by the p53-PADI4 pathway. (2012)
  • Author(s): Tanikawa C, Espinosa M, Suzuki A, Masuda K, Yamamoto K, Tsuchiya E, Ueda K, Daigo Y, Nakamura Y, Matsuda K.
  • Journal Title: Nat Commun Volume: 3 Pages: 676-676
  • DOI: 10.1038/ncomms1676
  • Peer Reviewed
• [Journal Article] A Genome-Wide Association Study Identified (2012)
  • Author(s): 岡田随象
  • Journal Title: PLoS genetics Volume: (掲載確定) Pages: 1002455-1002455
  • DOI: 10.1371/journal.pgen.1002455
  • Peer Reviewed
• [Journal Article] Induction of human humoral immune responses in a novel HLA-DR-expressing transgenic NOD/Shi-scid/γcnull mouse. (2012)
  • Author(s): Suzuki M, Takahashi T, Katano I, Ito R, Ito M, Harigae H, Ishii N, Sugamura K.
  • Journal Title: Int. Immunol Volume: 24 Pages: 208-214
  • DOI: 10.1093/intimm/dxs045
  • Peer Reviewed
• [Journal Article] PADI4 polymorphism predisposes male smokers to rheumatoid arthritis (2011)
  • Author(s): Kochi Y, Thabet MM, Suzuki A, Okada Y, Daha NA, Toes REM, Huizinga TWJ, Myouzen K, Kubo M, Yamada R, Nakamura Y, Yamamoto K.
  • Journal Title: Ann Rheum Dis Volume: 70 Pages: 512-5
  • Peer Reviewed
• [Journal Article] Indispensable roles of OX40L-derived signal and epistatic genetic effect in immune-mediated pathogenesis of spontaneous pulmonary hypertension. (2011)
  • Author(s): Rabieyousefi M, Soroosh P, Satoh K, Date F, Ishii N, Yamashita M, Oka M,McMurtry IF, Shimokawa H, Nose M, Sugamura K, Ono M.
  • Journal Title: BMC Immunol. Volume: 12 Pages: 67-67
  • DOI: 10.1186/1471-2172-12-67
  • Peer Reviewed
• [Journal Article] Interaction between NK cells and dendritic cells generate MHC class II-dressed NK cells to regulate CD4^+ T cells (2011)
  • Author(s): Nakayama M, Takeda K, Kawano M, Takai T, Ishii N, Ogasawara K.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 108 Pages: 18360-5
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/22042851
  • Peer Reviewed
• [Journal Article] Involvement of osteopontin and its signaling molecule CD44 in clinic opathological features of adult T cell leukemia (2011)
  • Author(s): Chagan-Yasutan H, Tsukasaki K, Takahashi Y, Oguma S, Harigae H, Ishii N, Zhang J, Fukumoto M, Hattori T.
  • Journal Title: Leuk Res Volume: 35 Pages: 1484-1490
  • DOI: 10.1016/j.leukres.2011.05.011
  • Peer Reviewed
• [Journal Article] Interaction between NK cells and dendritic cells generate MHC class II-dressed NK cells to regulate CD4^+ T cells (2011)
  • Author(s): Nakayama M, Takeda K, Kawano M, Takai T, Ishii N, Ogasawara K
  • Journal Title: Proc.Natl.Acad.Sci.USA Volume: 108 Pages: 18360-5
  • Peer Reviewed
• [Journal Article] PADI4 polymorphism predisposes male smokers to rheumatoid arthritis. (2011)
  • Author(s): Kochi Y, Thabet MM, Suzuki A, Okada Y, Daha NA, Toes REM, Huizinga TWJ, Myouzen K, Kubo M, Yamada R, Nakamura Y, Yamamoto K.
  • Journal Title: Ann Rheum Dis Volume: 70 Pages: 512-515
  • Peer Reviewed
• [Journal Article] The family of IL-10 secreting CD4+ T cells (2010)
  • Author(s): Fujio K, Okamura T, Yamamoto K.
  • Journal Title: Advances in Immunology Volume: 05 Pages: 99-130
  • DOI: 10.1016/s0065-2776(10)05004-2
  • Peer Reviewed
• [Journal Article] A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility (2010)
  • Author(s): Kochi Y, Okada Y, Suzuki A, Ikari K, Terao C, Takahashi A, Yamazaki K, Hosono N, Myouzen K, Tsunoda T, Kamatani N, Furuichi T, Ikegawa S, Ohmura K, Mimori T, Matsuda F, Iwamoto T, Momohara S, Yamanaka H, Yamada R, Kubo M, Nakamura Y, Yamamoto K.
  • Journal Title: Nat Genet. Volume: 42 Pages: 515-9
  • DOI: 10.1038/ng.583
  • Peer Reviewed
• [Journal Article] OX40 ligand plays an important role in the development of atherosclerosis through vasa vasorum neovascularization (2010)
  • Author(s): Nakano M, Fukumoto Y, Satoh K, Ito Y, Kagaya Y, Ishii N, Sugamura K, Shimokawa H.
  • Journal Title: Cardiovasc Res Volume: 88 Pages: 539-46
  • DOI: 10.1093/cvr/cvq211
  • Peer Reviewed
• [Journal Article] Serial OX40 engagement on CD4+ T cells and natural killer T cells causes allergic airway inflammation (2010)
  • Author(s): Damayanti T, Kikuchi T, Zaini J, Daito H, Kanehira M, Kohu K, Ishii N, Satake M, Sugamura K, Nukiwa T.
  • Journal Title: Am J Respir Crit Care Med. Volume: 181 Pages: 688-98
  • DOI: 10.1164/rccm.200910-1598oc
  • Peer Reviewed
• [Journal Article] The association of a nonsynonymous single-nucleotide polymorphism in TNFAIP3 with systemic lupus erythematosus and rheumatoid arthritis in the Japanese population (2010)
  • Author(s): Shimane K, Kochi Y, Horita T, Ikari K, Amano H, Hirakata M, Okamoto A, Yamada R, Myouzen K, Suzuki A, Kubo M, Atsumi T, Koike T, Takasaki Y, Momohara S, Yamanaka H, Nakamura Y, Yamamoto K.
  • Journal Title: Arthritis Rheum. Volume: 62 Pages: 574-9
  • DOI: 10.1002/art.27190
  • Peer Reviewed
• [Journal Article] The family of IL-10 secreting CD4+ T cells. (2010)
  • Author(s): Fujio K, Okamura T, Yamamoto K.
  • Journal Title: Advances in Immunology. Volume: 105 Pages: 99-130
  • Peer Reviewed
• [Journal Article] A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility. (2010)
  • Author(s): Kochi Y, Okada Y, Suzuki A, Ikari K, Terao C, Takahashi A, Yamazaki K, Hosono N, Myouzen K, Tsunoda T, Kamatani N, Furuichi T, Ikegawa S, Ohmura K, Mimori T, Matsuda F, Iwamoto T, Momohara S, Yamanaka H, Yamada R, Kubo M, Nakamura Y, Yamamoto K.
  • Journal Title: Nat Genet. Volume: 42 Pages: 515-519
  • Peer Reviewed
• [Journal Article] OX40 ligand plays an important role in the development of atherosclerosis through vasa vasorum neovascularization. (2010)
  • Author(s): Nakano, M., et al
  • Journal Title: Cardiovasc.Res. Volume: 88 Pages: 539-546
  • Peer Reviewed
• [Journal Article] Serial OX40 engagement on CD4^+ T cells and NKT cells causes allergic airway inflammation. (2010)
  • Author(s): Damayanti, T., et al.
  • Journal Title: Am.J.Respir.Crit.Care.Med. Volume: 181 Pages: 688-698
  • Peer Reviewed
• [Journal Article] The association of a nonsynonymous single-nucleotide polymorphism in TNFAIP3 with systemic lupus erythematosus and rheumatoid arthritis in the Japanese population. (2010)
  • Author(s): Shimane K, Kochi Y, Horita T, Ikari K, Amano H, Hirakata M, Okamoto A, Yamada R, Myouzen K, Suzuki A, Kubo M, Atsumi T, Koike T, Takasaki Y, Momohara S, Yamanaka H, Nakamura Y, Yamamoto K.
  • Journal Title: Arthritis Rheum. 62 Pages: 574-579
• [Journal Article] The association of a nonsynonymous single-nucleotide polymorphism in TNFAI P3 with systemic lupus erythematosus and rheumatoid arthritis in the Japanese population (2010)
  • Author(s): Shimane K, Kochi Y, Horita T, Ikari K, Amano H, Hirakata M, Okamoto A, Yamada R, Myouzen K, Suzuki A, Kubo M, Atsumi T, Koike T, Takasaki Y, Momohara S, Yamanaka H, Nakamura Y, Yamamoto K.
  • Journal Title: Arthritis Rheum 62 Pages: 574-79
  • Peer Reviewed
• [Journal Article] A single nucleotide polymorphism in the IRF5 promoter region is associated with susceptibility to rheumatoid arthritis in the Japanese population (2009)
  • Author(s): Shimane K, Kochi Y, Yamada R, Okada Y, Suzuki A, Miyatake A, Kubo M, Nakamura Y, Yamamoto K.
  • Journal Title: Ann Rheum Dis. Volume: 68 Pages: 377-83
  • DOI: 10.1136/ard.2007.085704
  • Peer Reviewed
• [Journal Article] A single nucleotide polymorphism in the IRF5 promoter region is associated with susceptibility to rheumatoid arthritis in the Japanese population. (2009)
  • Author(s): Shimane K, Kochi Y, Yamada R, Okada Y, Suzuki A, Miyatake A, Kubo M, Nakamura Y, Yamamoto K.
  • Journal Title: Ann Rheum Dis. 68 Pages: 377-83
• [Journal Article] FCRL3, an autoimmune susceptibility gene, has inhibitory potential on B-cell receptor-mediated signaling. (2009)
  • Author(s): Kochi Y, Myouzen K, Yamada R, Suzuki A, Kurosaki T, Nakamura Y, Yamamoto K.
  • Journal Title: J Immunol. 183 Pages: 5502-10
• [Journal Article] Contribution of a haplotype in the HLA region to anti-cyclic citrullinated peptide antibody positivity in rheumatoid arthritis, independently of HLA-DRB1. (2009)
  • Author(s): Okada Y, Yamada R, Suzuki A, Kochi Y, Shimane K, Myouzen K, Kubo M, Nakamura Y, Yamamoto K.
  • Journal Title: Arthritis Rheum. 60 Pages: 3582-3590
• [Journal Article] CD4+CD25-LAG3+ regulatory T cells controlled by the transcription factor Egr-2. (2009)
  • Author(s): Okamura T, Fujio K, Shibuya M, Sumitomo S, Shoda H, Sakaguchi S, Yamamoto K.
  • Journal Title: Proc Natl Acad Sci USA. 106 Pages: 13974-79
• [Journal Article] A single nucleotide polymorphism in the IRF5 promoter region is associated with susceptibility to rheumatoid arthritis in the Japanese population (2009)
  • Author(s): Shimane K, Kochi Y, Yamada R, Okada Y, Suzuki A, Miyatake A, Kubo M, Nakamura Y, Yamamoto K.
  • Journal Title: Ann Rheum Dis 68 Pages: 377-83
  • Peer Reviewed
• [Journal Article] Functional SNPs in CD244 gene increase the risk of rheumatoid arthritis in a Japanese population (2008)
  • Author(s): Suzuki A,Yamada R, Kochi Y, Sawada T, Okada Y, Matsuda K, Kamatani Y, Mori M, Shimane K, Takahashi A, Tsunoda T, Miyatake A, Kubo M, Kamatani N, Nakamura Y, Yamamoto K
  • Journal Title: Nat Genet. Volume: 40 Pages: 1224-9
  • Peer Reviewed
• [Journal Article] OX40 costimulatory signals potentiate the memory commitment of effector CD8+ T cells (2008)
  • Author(s): Mousavi SF, Soroosh P, Takahashi T, Yoshikai Y, Shen H, Lefrancois L, Borst J, Sugamura K, Ishii N.
  • Journal Title: J Immunol. Volume: 181 Pages: 5990-6001
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/18941188
  • Peer Reviewed
• [Journal Article] Splenic phagocytes promote responses to nucleosomes in (NZB x NZW) F1 mice. (2008)
  • Author(s): Okamoto A, Fujio K, van Rooijen N, Tsuno NH, Takahashi K, Tsurui H, Hirose S, Elkon KB, Yamamoto K.
  • Journal Title: J Immunol. 181 Pages: 5264-71
• [Journal Article] Functional SNPs in CD244 gene increase the risk of rheumatoid arthritis in a Japanese population. (2008)
  • Author(s): Suzuki A, Yamada R, Kochi Y, Sawada T, Okada Y, Matsuda K, Kamatani Y, Mori M, Shimane K, Takahashi A, Tsunoda T, Miyatake A, Kubo M, Kamatani N, Nakamura Y, Yamamoto K
  • Journal Title: Nat Genet. 40 Pages: 1224-9
• [Journal Article] Lessons from a Genomewide Association Study of Rheumatoid Arthritis. (2007)
  • Author(s): Yamamoto K, Yamada R.
  • Journal Title: N. Engl. J. Med. 357 Pages: 1250-1251
• [Journal Article] Hepatocyte growth factor significantly suppresses collagen-induced Hepatocyte growth factor significantly suppresses collagen-induced arthritis in mice arthritis in mice. (2007)
  • Author(s): Okunishi K, Dohi M, Fujio K, Nakagome K, Yamamoto K, 他7名
  • Journal Title: J Immunol. 179 Pages: 5504-5513
  • Peer Reviewed
• [Journal Article] Lessons from a Genomewide Association Study of Rheumatoid Arthritis. (2007)
  • Author(s): Yamamoto K, Yamada R.
  • Journal Title: N.Engl J.Med 357 Pages: 1250-1251
  • Peer Reviewed
• [Journal Article] Interleukin-17B and interleukin-17C are associated with TNF-alpha Production and contribute to the exacerbation of inflammatory arthritis. (2007)
  • Author(s): Yamaguchi Y, Fujio K, Shoda H, Okamoto A, Yamamoto K., 他2名
  • Journal Title: J Immunol 179 Pages: 7128-7136
  • Peer Reviewed
• [Presentation] OX40 contributes to the generation and maintenance of memory CD4+ T cells (2011)
  • Author(s): Ishii N.
  • Organizer: 第40回日本免疫学会学術集会国際シンポジウム
  • Place of Presentation: 千葉市
  • Year and Date: 2011-11-29