自己反応性B細胞の寛容破綻に関わる遺伝的機構とその制御

• Project/Area Number: 13140205
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Juntendo University
• Principal Investigator: 広瀬 幸子 順天堂大学, 医学部, 助教授 (00127127)
• Co-Investigator(Kenkyū-buntansha): 中村 和裕 順天堂大学, 医学部, 助手 (10327835)
• Project Period (FY): 2001 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥131,900,000 (Direct Cost: ¥131,900,000); Fiscal Year 2005: ¥24,700,000 (Direct Cost: ¥24,700,000); Fiscal Year 2004: ¥24,700,000 (Direct Cost: ¥24,700,000); Fiscal Year 2003: ¥27,000,000 (Direct Cost: ¥27,000,000); Fiscal Year 2002: ¥27,000,000 (Direct Cost: ¥27,000,000); Fiscal Year 2001: ¥28,500,000 (Direct Cost: ¥28,500,000)
• Keywords: 全身性エリテマトーデス / New Zealand マウス / 感受性遺伝子 / 遺伝子多型 / FcγRIIB / IL-4Rα / recombinant congenic マウス / 主要組織適合遺伝子複合体 / New Zealandマウス / LTK / PI3 kinase / FCγRIIB / 自己感応性B細胞 / 連鎖解析 / 制御領域多型 / gain-of-function型多型 / プロモーター領域多型 / 転写制御

Research Abstract

自己免疫疾患発症には、免疫応答調節に関わる複数の感受性遺伝子が関与している。抗体依存性自己免疫疾患における自己反応性B細胞の出現の原因を遺伝的に解析することで、B細胞免疫寛容破綻の原因を捉えられる。本年度は、全身性エリテマトーデス(SLE)自然発症マウス系を用いた遺伝的解析により得られた、第1染色体上のFcgr2b遺伝子のプロモーター多型、第7染色体上のIL-4Rα鎖の遺伝子多型、第17染色体上の主要組織適合遺伝子複合体(MHC)の多型と自己反応性B細胞の出現との関わりについて解析した。
1.Fcgr2b遺伝子プロモーター領域多型:SLEマウス系に共通して存在するFcgr2bのプロモーター領域のAp-4結合部位の欠損を伴う多型が、実際にSLEの感受性遺伝子であることを、SLE自然発症B×SBマウスのプロモーター多型を正常マウス型に入れ替えることで証明した。また、FcγRIIB分子は、B細胞のみでなく、樹状細胞の増殖と活性化にも働いていると考えられ、現在、その機序を解析中である。
2.IL-4Rα鎖遺伝子多型:IL-4はB細胞を活性化して、抗体産生を亢進させる。IL-4産生能には、マウス間で大きな差がみられ、T細胞によるIL-4産生能の違いは、IL-4Ra鎖のアミノ酸置換を伴う遺伝子多型に起因することを見出した。
3.MHCクラスII領域には、自己反応性B細胞の活性および抑制に働く部位が存在することを、recombinant congenicマウス系の樹立により明らかにした。具体的には、クラスIIのE分子の存在は、SLEを高度に抑制し、その機序の一つに、胸腺での自己反応性T細胞の負の選択にE分子が働いていることを見出した。一方、A分子においては、そのα鎖とβ鎖の遺伝子型の組み合わせの違いは、SLE病態を左右するのみでなく、SLE病態を関節リウマチ(RA)に変換させる可能性を得た。

Research Products

• [Journal Article] Genome-wide scan in novel IgA nephropathy model identifies susceptibility locus on murine chromosome 10, in a region sytenic to human IGAN1 on chromosome 6q22-23. (2005)
  • Author(s): H.Suzuki, et al.
  • Journal Title: J.Am.Soc.Nephrol. 16 Pages: 1289-1299
• [Journal Article] Chromosomal mapping of a quantitative trait locus for the development of albuminuria in diabetic KK/Ta mice. (2005)
  • Author(s): T.Shike, et al.
  • Journal Title: Nephrol.Dial.Transplant. 20 Pages: 879-885
• [Journal Article] Fas ligand and TNF-related apoptosis-inducing ligand induction on infiltrating lymphocytes in bladder carcinoma by bacillus Calmette-Guerin treatment. (2005)
  • Author(s): M.Mehmut, et al.
  • Journal Title: Urol.Int. 75 Pages: 80-87
• [Journal Article] Polymorphism of the mouse gene for the interleukin 10 receptor alpha chain (Il10ra) and its association with the autoimmune phenotype. (2005)
  • Author(s): Z.Qi, et al.
  • Journal Title: Immunogenetics 57 Pages: 697-702
• [Journal Article] Correlation of aggression with serum IgM level in autoimmune-prone NZB mice. (2005)
  • Author(s): K.Nakamura, et al.
  • Journal Title: Developmental Brain Research1 59 Pages: 145-148
• [Journal Article] Gain-of-function polymorphism in mouse and human Ltk : implications for the pathogenesis of systemic lupus erythematosus. (2004)
  • Author(s): N.Li, et al.
  • Journal Title: Hum.Mol.Genet. 13 Pages: 171-179
• [Journal Article] Transgene-mediated over-expression of interleukin-5 suppresses autoimmune disease, but increases the risk of B cell chronic lymphocytic leukemia. (2004)
  • Author(s): X.Wen, et al.
  • Journal Title: Eur.J.Immunol. 34 Pages: 2740-2749
• [Journal Article] Nucleosome-specific regulatory T cells engineered by triple gene trasfer suppress a systemic autoimmune disease. (2004)
  • Author(s): K.Fujio, et al.
  • Journal Title: J.Immunol. 173 Pages: 2118-2125
• [Journal Article] Dissection of the role of MHC class II A and E genes in autoimmune susceptibility inmurine lupus models with intragenic recombination. (2004)
  • Author(s): D.Zhang, et al.
  • Journal Title: Proc.Natl.Acad.Sci.USA 101 Pages: 13838-13843
• [Journal Article] Genome-wide scan in novel IgA nephropathy model identifies susceptibility locus on murine chromosome 10, in a region syntenic to human IGAN1 on chromosome 6q22-23. (2004)
  • Author(s): H.Suzuki, et al.
  • Journal Title: J.Am.Soc.Neph. (in press)
• [Publications] K.Nakamura et al.: "Genetic dissection of anxiety in autoimmune disease."Hum.Mol.Genet.. 12. 1079-1086 (2003)
• [Publications] S.Fujimura, et al.: "Spontaneous increase of _plasma-like cells with high GAMP expression in the extrafollicular region of lymphoid organs of autoimmune-prone mice."Autoimmunity. 20. 291-301 (2003)
• [Publications] S.Matsuoka, et al.: "A monoclonal antibody to the α2 domain of murine major histocompatibility complex class I that specifically kills activated lymphocytes and blocks liver damage in the concanavalin A hepatitis model."J.Exp.Med.. 198. 497-503 (2003)
• [Publications] H.Iwai, et al.: "Involvement of inducible costimulator-B7 homologous protein costimulatory pathway in murine lupus nephritis."J.Immunol.. 171. 2848-2854 (2003)
• [Publications] N.Li, et al.: "Gain-of-function polymorphism in mouse and human Ltk : implications for the pathogenesis of systemic lupus erythematosus."Hum.Mol.Genet.. 13. 171-179 (2004)
• [Publications] X.Wen, et al.: "Transgene-mediated over-expression of interleukin-5 suppresses autoimmune disease, but increases the risk of B cell chronic lymphocytic leukemia. Blood, submitted for publication."J.Immunol.. (In press). (2004)
• [Publications] Miyamoto A, et al.: "Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ"Nature. 416. 865-869 (2002)
• [Publications] Miura-Shimura Y, et al.: "Clq regulatory region polymorphism down-regulating murine Clq protein levels with linkage to lupus nephritis"J.Immunol.. 169. 1334-1339 (2002)
• [Publications] XieY, et al.: "Transcriptional regulation of Fcgr2b gene by polymorphic promoter region and its contribution to humoral immune responses"J.Immunol.. 169. 4340-4346 (2002)
• [Publications] Iwai H, et al.: "Amelioration of collagen-induced arthritis by brokade of inducible costimulator-b7 homologous protein costimulation"J.Immunol.. 169. 4332-4339 (2002)
• [Publications] Shirai T, et al.: "Genome screening for susceptibility loci in systemic lupus erythematosus"Am.J.Pharmacogenomics. 2. 1-12 (2002)
• [Publications] Hirose S, et al.: "Genetic basis of systemic lupus erythematosus"Drugs of Today. 38. 167-184 (2002)
• [Publications] Takasaki Y., et al.: "Reactivity of anti-PCNA murine monoclonal antibodies and human autoantibodies to the PCNA multiprotein complexes involved in cell proliferation"J. Immunol.. 166. 4780-4787 (2001)
• [Publications] Shike T. et al.: "Susceptibility and negative epistatic loci contributing to type 2 diabetes mellitus and related phenotypes in a KK/Ta mouse models"Diabetes. 50. 1943-1948 (2001)
• [Publications] Hirose S., et al.: "Genetic study of SLE : lessons from mouse models"Mod. Rheumatol.. 11. 262 (2001)
• [Publications] Jiang Y., et al.: "Polymorphism and chromosomal mapping of the murine gene for B cell activating factor belonging to the TNF family (BAFF) and association with the autoimmune phenotype"Immunogenetics. 53. 810-813 (2001)
• [Publications] Shirai T., et al.: "Genome screening for susceptibility loci in systemic lupus erythematosus"Am. J. Pharmacogenomics. 2. 1-12 (2002)
• [Publications] Hirose S., et al.: "Genetic basis of systemic lupus erythematosus"Drug of Today. (in press). (2002)