1993 Fiscal Year Annual Research Report

自己・非自己識別分子MHCの起源と進化

Research Project

Project/Area Number	05304003
Research Institution	The Graduate University for Advanced Studies
Principal Investigator	高畑尚之総合研究大学院大学, 教育研究交流センター, 教授 (30124217)
Co-Investigator(Kenkyū-buntansha)	堀寛名古屋大学, 理学部, 教授 (60116663) 池村淑道国立遺伝学研究所, 集団遺伝研究系, 教授 (50025475) 笠原正典北海道大学, 医学部, 助教授 (30241318) 小幡裕一愛知県がんセンター, 免疫学部, 室長 (30177290) 笹月健彦九州大学, 生体防御医学研究所, 教授 (50014121)
Keywords	クローニング / 下等脊椎動物MHC / 非古典的MHC / HLA / 自己免疫 / MHC拘束 / 起源と進化 / T細胞レパートリー
Research Abstract	項目別にみた本年度の実績概要を記す。(1)脊椎動物、とくに両生類、魚類で新しいMHC遺伝子のクローニングや塩基配列の決定ができた他、MHC領域の遺伝子構成や遺伝子発現に新しい知見を得た。両生類では倍数性が普遍的な現象としてあるが、重複したMHCは部分的に欠失しやすいことが明らかになった。そのため、MHCの遺伝子群は通常とは異なり、複数の染色体に分散している。下等脊椎動物のMHCの分子構造は、高等脊椎動物のそれと類似している知見を得た他に、HSP70分子から進化してきた可能性が指摘された(笠原、橋本、堀)。(2)マウス特有の非古典的MHC分子TLは、器官特異的発現をする。これまでTLは機能をもたないといわれてきたが、TL特異的に誘導されるCD8^+T細胞が存在すること、またTLは限られた抗原だけを提示する知見を得た。これらは、TL様分子がマウス以外にも存在する可能性が高いことを示す。TLの腸内での高い発現は、免疫系が働くのに最も効率がよい場所がどこであるかを示唆している(小幡、森脇、高畑)。(3)ヒトHLA領域の解析が進み、新しい遺伝子座や新しいHLA対立遺伝子の発見があった。これと共に大切な課題は、HLA対立遺伝子やハプロタイプと病気との相関であり、自己免疫疾患に関する基礎的な知見を得た。このような知見は、近い将来新しい免疫療法の開発に役立つものと期待できる。(笹月、猪子、池村、堀)。(4)MHC拘束を受けるT細胞レパートリーの大きさと1個体がもつMHC分子の抗原レパートリーの大きさは、微妙なバランスの上で決まっている。このバランスが破れると自己免疫不全に陥る。これは、MHCがなぜ限られた数の遺伝子座だけで異常に多型的であるかという問題と関係している。この問題を胸線内クローン選択と個体選択の観点から理論的に説明した。対立遺伝子によるMHC拘束が強い程、多型的MHC遺伝子座の数は少なくなる。また異なる遺伝子座のMHC分子による拘束のため、多数の機能的MHC遺伝子座をもつようには進化できなかったと結論された(高畑)。

Research Products

(49 results)

All Other

All Publications (49 results)

[Publications] Klein,J.: "The molecular descent of the major histocompatibility complex." Ann.Rev.Immuno.11. 269-295 (1993)
[Publications] Takahata,N.: "Allelic genealogy and human evolution." Mol.Biol.Evol.10. 2-22 (1993)
[Publications] Satta,Y.: "The synonymous substitution rate at the major histocompatibility complex loci(Mhc)in primates." Proc.Natl.Acad.Sci.USA. 90. 7480-7484 (1993)
[Publications] Klein,J.: "Mhc polymorphism and human origins." Sci.Amer.269. 46-51 (1993)
[Publications] Klein,J.: "Trans-specific Mhc polymorphism and the origin of species." J.Med.Primatol.22. 57-64 (1993)
[Publications] Okamura,K.: "Expansion of genes that encode MHC class I molecules in cyprinid fishes." The Journal of Immunology. 151. 188-200 (1993)
[Publications] Hoshino,S.: "A simple and practical test of HLA-DRB and DQB matching in transplantation." Transplant.Proc.25. 199-202 (1993)
[Publications] 堀寛: "ボディプランと対称性の進化" 科学. 63. 222-229 (1993)
[Publications] Morita,A.: "TL antigen as a transplantation antigen trecognized by TL-restricted cytotoxic T cells." J.Exp.Med.179. 777-784 (1994)
[Publications] Watanabe,H.: "Generalized expansion of extrathymic cells in various immune organs TL-transgenic mice." Biomed.Res.14. 273-288 (1993)
[Publications] 小幡裕一: "非典型的MHCクラスI分子による抗原提示" 臨床免疫. 25. 1556-1556 (1993)
[Publications] 小幡裕一: "マウスTL抗原" 免疫Immunology Frontier. 3. 169-178 (1993)
[Publications] Sugimura,K.: "Analysis of genes within the HLA region affecting susceptibility to Ulcerative Colitis." Hum.Immuno.36. 112-118 (1993)
[Publications] Seki,T.: "Association of Primary biliary cirrhosis with human leukocyte antigen-DPB1^+ 0501 in Japanese Patients." Hepatol. 18. 73-78 (1993)
[Publications] Horiki,T.: "HLA-DPB1 allele associates with early-onset Myathenia Graves in Japan" Neurol.43. 771-774 (1993)
[Publications] Nakanishi K.: "Association of HLA-A24 with complete β cell destruction in IDDM." Diabetes. 42. 1086-1093 (1993)
[Publications] Mizuki N.: "Identification of a new HLA-DPB1 allele detected by PCR-RFLP and its nucleotide sequence determination by directsequencing after PCR amplification." Tissue Antigens. 41. 259-262 (1993)
[Publications] Ando A.: "Cloning of a new kinesin-related gene located at the centromeric end of the human MHC region." Immunogenetics. 39. 194-200 (1994)
[Publications] Ando,A.: "Cloning of a new kinesin-related gene located at the centromeric end of the human MHC region." Immunogenetics. 39. 194-200 (1994)
[Publications] Kimura,A.: "PCR-SSCP analysis of HLA-DP genes and its application in taransplantation." Transplant.Proc.25. 199-202 (1993)
[Publications] Nass,S.J.: "Mapping of the Mod-1 locus on mouse chromosome 9." Mammalian Genome. 4. 333-337 (1993)
[Publications] Hayashi,T.: "A variant family of mouse minor satellite located on the centromeric region of chromosome 2." Genomics. 17. 490-492 (1993)
[Publications] Yoshiki,A.: "Histological studies on male sterility of hybrids between laboratory and wild mouse strains." Develop.Growth & Differ. 35. 271-281 (1993)
[Publications] Nonaka,M.: "Molecular cloning of the b subunit of mouse coagulation factor XIII and assignment of the gene to chromosome 1:close evolutionary relationship to complement factor H." Genomics. 15. 535-542 (1993)
[Publications] Dong,R.P.: "Difference in HLA-linked genetic background between mixed connective tissue disease and systemic lupus erythematosus." Eur J Immunol. 41. 20-25 (1993)
[Publications] Fukui,Y.: "T cell repertoire in a taransgenic C5 7BL/6 mice expressing the HLA-DRA gene on the X chromosome." Immunogenetics. 37. 204-211 (1993)
[Publications] Hoshino,S.: "A practical HLA-DRB and -DQB matching test in kidney transplantation." Transpl Proc. 25. 191-193 (1993)
[Publications] Kimura,A.: "PCR-SSCP analysis of HLA-DP genes and its application to matching study in transplantation." Transplant.Proc.25. 100-202 (1993)
[Publications] Honda,K: "Immunogenetic analysis of silicosis in Japan." Am J Respir Cell Mol Biol. 8. 106-111 (1993)
[Publications] Fukui,Y: "Kestricted expression or transgenic HLA-DRA gene in thymic epithelial cells and its role in aquistion of T cell tolerance to self-su perantigens and processed DR α-derived pepitde." Eur J Immunol. 23. 1678-1686 (1993)
[Publications] Flajnik,M.F.: "A novel type of class I gene organization in vertebrates:A large family of non-MHC-linked class I genes is expressed at the RNA level in the amphibian Xenopus." EMBO J.12. 4385-4396 (1993)
[Publications] Sato,K.: "Evolution of the MHC:Isolation of class II β-chain cDNA clones from the amphibian Xenopus laevis." J.Immunol.150. 2831-2843 (1993)
[Publications] Greenberg,A.: "Isolation of a shark immunoglobulin light chain cDNA clone encoding a protein resembling mammalian k light chains:Implications for the evolution of light chains." Proc.Natl.Acad.Sci.U.S.A.90. 10603-10607 (1993)
[Publications] Kasahara,M.: "The evolutionary origin of the major histocompatibility complex:Polymorphism of class II α-chain genes in the cartilaginous fish." Eur.J.Immunol.23. 2160-2165 (1993)
[Publications] Shum,B.P.: "Isolation of classical MHC class I cDNA from an amphibian:Evidence for only one class I locus in the Xenopus MHC." J.Immunol.151. 5376-5386 (1993)
[Publications] Salter-Cid,L.: "HSP70 genes are linked to the Xenopus major histocompatibility complex." Immunogenetics. 39. 1-7 (1994)
[Publications] Yoshizumi,H.: "Generation of a novel CD8^+ cytotoxic T lymphocyte that requires soluble factor to lyse autologous antigen-pressenting cells." Eur J Immunol. 23. 3173-3180 (1993)
[Publications] de la Paz Bettinotti M: "Polymorphism of the 5' flanking region of the HLA-DQA1 gene in Coeliac disease." Eur J Immunogenet. 20. 399-407 (1993)
[Publications] Yoshida,M.: "DNA typing of HLA-B gene in Takayasu's arteritis." Tissue Antigens. 42. 87-90 (1993)
[Publications] Shirasawa,S: "Altered growth of human colon cancer cell lines disruprted at activated Ki-ras." Science. 260. 85-88 (1993)
[Publications] Tamai,H: "Resistance to autoimmune thyroid disease is associated with HLA-DQ." J Clin Endocrinol Metab. 78. 94-97 (1994)
[Publications] 小針布実子: "TAP遺伝子の構造と機能" Medical Immunology. 26. 283-289 (1993)
[Publications] Takahata,N.: "Progress in Immunology VIII" Springer/Verlag eds.J.Gergely et al., 153-158 (1993)
[Publications] Takahata,N.: "Human Population Genetics:A centennial tribute to J.B.S.Haldane." Plenum Press ed.Partha P.Majumder, 49-65 (1993)
[Publications] Ikemura,T.: "CODON USAGE.In “Plant Molecular Biology LABFAX"(ed.Croy,R.R.D.)." Blackwell Scientific Publications,UK, 37-48 (1993)
[Publications] Wada,K.: "A sensitive and efficient homology search method to find protein-coding regions using protein-coding region DNA database.In “Proceedings of Genome Informatics Workshop IV" (eds.Takagi,T.,et al.)" Universal Academy Press,Inc.Tokyo,Japan., 347-351 (1993)
[Publications] Inoko,H.: "Handbook for HLA Tissue-Typing Laboratories(eds.Bidwell J.,Hui KM),PCR-RFLP" CRC Press,Boca Raton, 1-70 (1993)
[Publications] 猪子英俊: "免疫学ブックレット第7巻(猪子英俊編著)移植と免疫" 中外医学社、東京, 1-182 (1993)
[Publications] Sasazuki,T.: "Immunogenetics of Hashimoto's thyroiditis." 80 years of Hashimoto Disease,Nagataki S et al (eds) Elsevier,Amsterdam, 13-18 (1993)

1993 Fiscal Year Annual Research Report

自己・非自己識別分子MHCの起源と進化

Principal Investigator

高畑 尚之 総合研究大学院大学, 教育研究交流センター, 教授 (30124217)

Research Products

[Publications] Klein,J.: "The molecular descent of the major histocompatibility complex." Ann.Rev.Immuno.11. 269-295 (1993)

[Publications] Takahata,N.: "Allelic genealogy and human evolution." Mol.Biol.Evol.10. 2-22 (1993)

[Publications] Satta,Y.: "The synonymous substitution rate at the major histocompatibility complex loci(Mhc)in primates." Proc.Natl.Acad.Sci.USA. 90. 7480-7484 (1993)

[Publications] Klein,J.: "Mhc polymorphism and human origins." Sci.Amer.269. 46-51 (1993)

[Publications] Klein,J.: "Trans-specific Mhc polymorphism and the origin of species." J.Med.Primatol.22. 57-64 (1993)

[Publications] Okamura,K.: "Expansion of genes that encode MHC class I molecules in cyprinid fishes." The Journal of Immunology. 151. 188-200 (1993)

[Publications] Hoshino,S.: "A simple and practical test of HLA-DRB and DQB matching in transplantation." Transplant.Proc.25. 199-202 (1993)

[Publications] 堀 寛: "ボディプランと対称性の進化" 科学. 63. 222-229 (1993)

[Publications] Morita,A.: "TL antigen as a transplantation antigen trecognized by TL-restricted cytotoxic T cells." J.Exp.Med.179. 777-784 (1994)

[Publications] Watanabe,H.: "Generalized expansion of extrathymic cells in various immune organs TL-transgenic mice." Biomed.Res.14. 273-288 (1993)

[Publications] 小幡 裕一: "非典型的MHCクラスI分子による抗原提示" 臨床免疫. 25. 1556-1556 (1993)

[Publications] 小幡 裕一: "マウスTL抗原" 免疫Immunology Frontier. 3. 169-178 (1993)

[Publications] Sugimura,K.: "Analysis of genes within the HLA region affecting susceptibility to Ulcerative Colitis." Hum.Immuno.36. 112-118 (1993)

[Publications] Seki,T.: "Association of Primary biliary cirrhosis with human leukocyte antigen-DPB1^+ 0501 in Japanese Patients." Hepatol. 18. 73-78 (1993)

[Publications] Horiki,T.: "HLA-DPB1 allele associates with early-onset Myathenia Graves in Japan" Neurol.43. 771-774 (1993)

[Publications] Nakanishi K.: "Association of HLA-A24 with complete β cell destruction in IDDM." Diabetes. 42. 1086-1093 (1993)

[Publications] Mizuki N.: "Identification of a new HLA-DPB1 allele detected by PCR-RFLP and its nucleotide sequence determination by directsequencing after PCR amplification." Tissue Antigens. 41. 259-262 (1993)

[Publications] Ando A.: "Cloning of a new kinesin-related gene located at the centromeric end of the human MHC region." Immunogenetics. 39. 194-200 (1994)

[Publications] Ando,A.: "Cloning of a new kinesin-related gene located at the centromeric end of the human MHC region." Immunogenetics. 39. 194-200 (1994)

[Publications] Kimura,A.: "PCR-SSCP analysis of HLA-DP genes and its application in taransplantation." Transplant.Proc.25. 199-202 (1993)

[Publications] Nass,S.J.: "Mapping of the Mod-1 locus on mouse chromosome 9." Mammalian Genome. 4. 333-337 (1993)

[Publications] Hayashi,T.: "A variant family of mouse minor satellite located on the centromeric region of chromosome 2." Genomics. 17. 490-492 (1993)

[Publications] Yoshiki,A.: "Histological studies on male sterility of hybrids between laboratory and wild mouse strains." Develop.Growth & Differ. 35. 271-281 (1993)

[Publications] Nonaka,M.: "Molecular cloning of the b subunit of mouse coagulation factor XIII and assignment of the gene to chromosome 1:close evolutionary relationship to complement factor H." Genomics. 15. 535-542 (1993)

[Publications] Dong,R.P.: "Difference in HLA-linked genetic background between mixed connective tissue disease and systemic lupus erythematosus." Eur J Immunol. 41. 20-25 (1993)

[Publications] Fukui,Y.: "T cell repertoire in a taransgenic C5 7BL/6 mice expressing the HLA-DRA gene on the X chromosome." Immunogenetics. 37. 204-211 (1993)

[Publications] Hoshino,S.: "A practical HLA-DRB and -DQB matching test in kidney transplantation." Transpl Proc. 25. 191-193 (1993)

[Publications] Kimura,A.: "PCR-SSCP analysis of HLA-DP genes and its application to matching study in transplantation." Transplant.Proc.25. 100-202 (1993)

[Publications] Honda,K: "Immunogenetic analysis of silicosis in Japan." Am J Respir Cell Mol Biol. 8. 106-111 (1993)

[Publications] Fukui,Y: "Kestricted expression or transgenic HLA-DRA gene in thymic epithelial cells and its role in aquistion of T cell tolerance to self-su perantigens and processed DR α-derived pepitde." Eur J Immunol. 23. 1678-1686 (1993)

[Publications] Flajnik,M.F.: "A novel type of class I gene organization in vertebrates:A large family of non-MHC-linked class I genes is expressed at the RNA level in the amphibian Xenopus." EMBO J.12. 4385-4396 (1993)

[Publications] Sato,K.: "Evolution of the MHC:Isolation of class II β-chain cDNA clones from the amphibian Xenopus laevis." J.Immunol.150. 2831-2843 (1993)

[Publications] Greenberg,A.: "Isolation of a shark immunoglobulin light chain cDNA clone encoding a protein resembling mammalian k light chains:Implications for the evolution of light chains." Proc.Natl.Acad.Sci.U.S.A.90. 10603-10607 (1993)

[Publications] Kasahara,M.: "The evolutionary origin of the major histocompatibility complex:Polymorphism of class II α-chain genes in the cartilaginous fish." Eur.J.Immunol.23. 2160-2165 (1993)

[Publications] Shum,B.P.: "Isolation of classical MHC class I cDNA from an amphibian:Evidence for only one class I locus in the Xenopus MHC." J.Immunol.151. 5376-5386 (1993)

[Publications] Salter-Cid,L.: "HSP70 genes are linked to the Xenopus major histocompatibility complex." Immunogenetics. 39. 1-7 (1994)

[Publications] Yoshizumi,H.: "Generation of a novel CD8^+ cytotoxic T lymphocyte that requires soluble factor to lyse autologous antigen-pressenting cells." Eur J Immunol. 23. 3173-3180 (1993)

[Publications] de la Paz Bettinotti M: "Polymorphism of the 5' flanking region of the HLA-DQA1 gene in Coeliac disease." Eur J Immunogenet. 20. 399-407 (1993)

[Publications] Yoshida,M.: "DNA typing of HLA-B gene in Takayasu's arteritis." Tissue Antigens. 42. 87-90 (1993)

[Publications] Shirasawa,S: "Altered growth of human colon cancer cell lines disruprted at activated Ki-ras." Science. 260. 85-88 (1993)

[Publications] Tamai,H: "Resistance to autoimmune thyroid disease is associated with HLA-DQ." J Clin Endocrinol Metab. 78. 94-97 (1994)

[Publications] 小針 布実子: "TAP遺伝子の構造と機能" Medical Immunology. 26. 283-289 (1993)

[Publications] Takahata,N.: "Progress in Immunology VIII" Springer/Verlag eds.J.Gergely et al., 153-158 (1993)

[Publications] Takahata,N.: "Human Population Genetics:A centennial tribute to J.B.S.Haldane." Plenum Press ed.Partha P.Majumder, 49-65 (1993)

[Publications] Ikemura,T.: "CODON USAGE.In “Plant Molecular Biology LABFAX"(ed.Croy,R.R.D.)." Blackwell Scientific Publications,UK, 37-48 (1993)

[Publications] Wada,K.: "A sensitive and efficient homology search method to find protein-coding regions using protein-coding region DNA database.In “Proceedings of Genome Informatics Workshop IV" (eds.Takagi,T.,et al.)" Universal Academy Press,Inc.Tokyo,Japan., 347-351 (1993)

[Publications] Inoko,H.: "Handbook for HLA Tissue-Typing Laboratories(eds.Bidwell J.,Hui KM),PCR-RFLP" CRC Press,Boca Raton, 1-70 (1993)

[Publications] 猪子 英俊: "免疫学ブックレット第7巻(猪子英俊編著)移植と免疫" 中外医学社、東京, 1-182 (1993)

[Publications] Sasazuki,T.: "Immunogenetics of Hashimoto's thyroiditis." 80 years of Hashimoto Disease,Nagataki S et al (eds) Elsevier,Amsterdam, 13-18 (1993)

高畑尚之総合研究大学院大学, 教育研究交流センター, 教授 (30124217)

[Publications] 堀寛: "ボディプランと対称性の進化" 科学. 63. 222-229 (1993)

[Publications] 小幡裕一: "非典型的MHCクラスI分子による抗原提示" 臨床免疫. 25. 1556-1556 (1993)

[Publications] 小幡裕一: "マウスTL抗原" 免疫Immunology Frontier. 3. 169-178 (1993)

[Publications] 小針布実子: "TAP遺伝子の構造と機能" Medical Immunology. 26. 283-289 (1993)

[Publications] 猪子英俊: "免疫学ブックレット第7巻(猪子英俊編著)移植と免疫" 中外医学社、東京, 1-182 (1993)