| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2001: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2000: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| 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
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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
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