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2002 Fiscal Year Final Research Report Summary

Analysis of genetic polymorphisms which effects on tuberculosis

Research Project

Project/Area Number 12670428
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 内科学一般
Research InstitutionKyushu University

Principal Investigator

NAKASHIMA Hitoshi  Kyushu University Hospital Assistant professor, 医学部附属病院, 助手 (70188960)

Co-Investigator(Kenkyū-buntansha) OTSUKA Takeshi  Kyushu University Hospital, Lecturer, 医学部附属病院, 講師 (50213773)
Project Period (FY) 2000 – 2002
KeywordsTh1 / Th2 / tuberculosis / IL-12 / IFN-γ / IL-4 / genetic polymorphism / susceptibility
Research Abstract

CD4+ helper T (Th) cells can be classified into two different subsets based on their patterns of cytokine production. Th1 cells produce mainly interferon-γ (IFN-γ) and interleukin-2 (IL-2) and promote cell-mediated immunity, whereas Th2 cells secreting IL-4, IL-5, IL-6 and IL-10, are associated with humoral immune responses and induce antibody production. It has been demonstrated that an imbalance between Th1 and Th2 cytokine production is very much concerned with the induction and development of several autoimmune diseases, a correction of this Th1/Th2 balance has in fact led to the prophylaxis and therapy of such diseases in various models of autoimmunity.
Tuberculosis is the leading single infectious cause of death worldwide, claiming about 3 million lives annually, and approximately one-third of the world's population is infected with Mycobacterium tuberculosis. Twin, adoption and ethnic studies have indicated that host genetic differences in immune response may affect susceptibilit … More y to mycobacterial infection. Earlier genetic association studies have shown that severe pulmonary tuberculosis was associated with both HLA-DR2 and haptoglobin 2-2. Recently, other studies have revealed polymorphisms in the IL-1 locus, human NRAMP1 gene, vitamin D receptor gene, and HLA-DQ allele also contribute to susceptibility to tuberculosis.
To date, genetic deficiencies in five genes involved in the type 1 cytokine cascade (IL-12p40, IFN-gR1, IFN-gR2, IL-12Rb1 and STAT1) have been shown to render hosts susceptible to poorly pathogenic mycobacteria, such as bacillus Calmette Guerin (BCG) and environmental nontuberculous mycobacteria (NTM). These reports highlighted the critical role of IFN-γ-mediated immunity in protection against intracellular pathogens. The absence of such key cytokine or cytokine receptors results in a dramatic clinical phenotype, usually lethal in early childhood, while more subtle polymorphisms which result in only partial impairment of the type-1 cytokine cascade may play a role in susceptibility to tuberculosis among the general population. Here we have searched for polymorphisms in both the β1 and β2 subunits of the IL-12 receptor. We then determined whether IL-12 receptor polymorphisms are associated with susceptibility to tuberculosis by performing a case-control study comparing the frequency of IL12RB1 genotypes in Japanese subjects with tuberculosis and healthy controls. We also confirmed the effect of human IL-12R polymorphisms on IL-12-induced biologic activities, using several functional assays. Less

  • Research Products

    (30 results)

All Other

All Publications (30 results)

  • [Publications] Horiuchi T: "Mannose binding lectin (MBL) gene mutation is not a risk factor for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Japanese"Genes Immun. 1. 464-466 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Masutani K: "Th1/Th2 balance of peripheral T helper cells in ANCA associated glomerulonephritis"Clinical Nephrol. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ishikura R: "Factors correlated with emotional instability in SLE outpatients"Mod Rheumatol. 10. 31-37 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Akahoshi M: "Reply to the comment by Reuss Borst et al."Arthritis Rheum. 43(3). 711-712 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Masutani K: "Predominance of Th1 type immune responses in human diffuse proliferative lupus nephritis"Arthritis Rheum. 44. 2097-2106 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ishikura R: "Factors associated with anxiety, depression and suicide ideation in female outpatients with SLE in Japan"Clinical Rheumatol. 20. 394-400 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ahmed K: "Association of CTLA-4 but not CD28 gene polymorphisms with systemic lupus erythematosus in the Japanese population"Rheumatology. 40. 662-667 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakashima H: "Association between IL-4 genotype and IL-4 production in the Japanese population"Genes Immun. 3. 107-109 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Miyake K: "Genetically determined interferon-gamma production influences on the histological phenotype of lupus nephritis"Rheumatology. 41. 518-524 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nagano S: "Dysregulation of PGE2 production by polymorphonuclear leukocytes in rheumatoid arthritis"Int Immunol. 14. 733-740 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakashima H: "Porcelain gallbladder"J Gastroenterology and Hepatology. 17. 1228 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Imamura R: "Development of rheumatoid arthritis following autologous peripheral blood stem cell transplantation"Bone Marrow Transplantation. 30. 527-529 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Akahoshi M: "Influence of interleukin-12 receptor β1 polymorphisms on tuberculosis"Hum Genet. 112. 237-243 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Masutani K: "Impact of interferon-γ and interleukin-4 gene polymorphisms on development and progression of IgA nephropathy in Japan"Am J Kidney Dis. 41(2). 371-379 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takii Y: "Systemic Vasculitis Associated with al-arititrypsin Deficiency"Intern Med. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Akahoshi M, Nakashima H, Otsuka T: "Reply to the comment by Reuss Borst et al."Arthritis Rheum. 43(3). 711-712 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ishikura R, Morimoto N, Tanaka K, Kinukawa N, Yoshizawa S, Horiuchi T, Nakashima H, Otsuka T: "Factors correlated with emotional instability in SLE outpatients"Mod Rheumatol. 10. 31-37 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Horiuchi T, Tsukamoto H, Morita C, Sawabe T, Harashima S, Nakashima H, Miyahara H, Hashimura C, Kondo M: "Mannose binding lectin (MBL) gene mutation is not a risk factor for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Japanese"Genes Immun. 1. 464-466 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Masutani K, Akahoshi M, Ninomiya T, Tokumoto M, Tsuruya K, Kohsaka T, Fukuda K, Kanai H, Nakashima H, Otsuka T, Hirakata H: "Predominance of Th1 type immune responses in human diffuse proliferative lupus nephritis"Arthritis Rheum. 44. 2097-2106 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ishikura R, Morimoto N, Tanaka K, Kinukawa N, Yoshizawa S, Horiuchi T, Nakashima H, Otsuka T: "Factors associated with anxiety, depression and suicide ideation in female outpatients with SLE in Japan"Clinical Rheumatol. 20. 394-400 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ahmed K, Ihara S, Kanemitsu H, Nakashima H, Otsuka T, Tsuzaka K, Takeuchi T, Hara T: "Association of CTLA-4 but not CD28 gene polymorphisms with systemic lupus erythematosus in the Japanese population"Rheumatology. 40. 662-667 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakashima H, Miyake K, Inoue Y, Shimizu S, Akahoshi M, Tanaka Y, Otsuka T, Harada M: "Association between IL-4 genotype and IL-4 production in the Japanese population"Genes Immun. 3. 107-109 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Miyake K, Nakashima H, Akahoshi M, Inoue Y, Nagano S, Tanaka Y, Masutani K, Hirakata H, Gondo H, Otsuka T, Harada M: "Genetically determined interferon-gamma production influences on the histological phenotype of lupus nephritis"Rheumatology. 41. 518-524 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nagano S, Otsuka T, Niiro H, Ohshima K, Yamaoka K, Ogami E, Arinobu Y, Akahoshi M, Nakashima H, Harada M: "Dysregulation of PGE2 production by polymorphonuclear leukocytes in rheumatoid arthritis"Int Immunol. 14. 733-740 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakashima H, Tanaka Y: "Porcelain gallbladder"J. Gastroenterology and Hepatology. 17. 1228 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Imamura R, Inoue H, Kato K, Kobayashi S, Tsukamoto H, Nagafuji K, Shimoda K, Nakashima H, Otsuka T, Gondo H, Harada M: "Development of rheumatoid arthritis following autologous peripheral blood stem cell transplantation"Bone Marrow Transplantation. 30. 527-529 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Masutani K, Miyake K, Nakashima H, Hirakawa M, Hirano T, Tsuruya K, Fukuda K, Kanai H, Otsuka T, Hirakata H, Iida M: "Impact of interferon-γ and interleukin-4 gene polymorphisms on development and progression of IgA nephropathy in Japan"Am J Kidney Dis. 41(2). 371-379 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Akahoshi M, Nakashima H, Miyake K, Inoue Y, Shimizu S, Tanaka Y, Okada K, Otsuka T, Harada M: "Influence of interleukin-12 receptor b1 polymorphisms on tuberculosis"Hum Genet. 112. 237-243 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Masutani K, Tokumoto M, Nakashima H, Tsuruya K, Kashiwagi M, Kosaka T, Fukuda K, Kanai H, Akahoshi M, Otsuka T, Hirakata H, Iida M: "Th1/Th2 balance of peripheral T helper cells in ANCA associated glomerulonephritis"Clinical Nephrol. in press.

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takii Y, Inoue H, Karashima K, Akahoshi M, Furugo I, Hattori S, Yamanaka M, Kinoshita S, Hamasaki N, Shimoda K, Nakashima H, Tsukamoto H, Horiuchi T, Otsuka T, Harada M: "Systemic Vasculitis associated with a1-antitrypsin Deficiency"Intern Med. in press.

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2004-04-14  

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