ROLE OF KILLER INHIBITORY RECEPTOR GENES IN AUTOIMMUNE AND INFECTIOUS DISEASES

自然杀伤细胞（NK）是一种独特的淋巴细胞群，通过NK细胞表面极其多样化的受体识别HLA分子的机制，参与监视和杀死外来或感染细胞。杀伤抑制受体基因（KIRs）与其他相关基因一起定位于染色体19q13.4。其中一些基因编码识别HLA- C配体的分子，而另一些则结合HLA- a和- b分子。与细胞毒性T淋巴细胞（CTL）对I类肽的识别不同，NK细胞破坏缺乏I类表达的靶标，并被细胞表面的I类识别所抑制。NK细胞在防御抑制I类分子表达的病毒中发挥重要作用，从而避免被CTL识别。例如，HIV-1下调细胞表面HLA- a和-B分子的表达（但不下调-C分子），解释某些HLA类型的个体快速发展为艾滋病的一种机制可能涉及NK细胞活性的改变。通过Nef下调HLA-A和-B来降低CTL活性，同时通过不影响HLA-C的表达来降低NK活性，宿主防御系统可能被有效地削弱。人类乳头瘤病毒（HPV）下调I类蛋白的证据也有报道。我们已经开发了KIR基因的分子分型技术，以研究这些基因在自身免疫性疾病（银屑病关节炎[PSA]，强直性脊柱炎和多发性硬化症）和传染性疾病（与HIV-1，丙型肝炎病毒和乙型肝炎病毒相关的疾病）中的潜在作用。KIR基因复合体的单倍型在存在的KIR基因数量上有所不同，其中一些基因具有轻微的多态性。我们最初的方法是确定每个KIR基因的存在与否，但我们也开始开发在每个位点上分型等位基因的方法。我们的方案包括聚合酶链反应（PCR）扩增，使用每个位点特异性的引物（PCR- ssp）。我们对所有基因座使用相同的扩增条件，大大提高了检测效率。DRB1第三内含子796 bp片段的内控引物也包含在每个PCR反应中。为了确定特定位点的存在与否，每个位点设计了两组引物。整个类型协议可以以96井格式执行，从而为半自动化提供了潜在的手段。几种KIR基因产物对HLA- c分子的识别使我们推测HLA和KIR基因之间的协同相互作用可能在从HLA- c相关疾病中获得的数据集中最为明显。HLA与自身免疫性疾病的关系似乎没有与感染性疾病的关系复杂。因此，我们对一组患有（PSA）的个体进行了分型，这种疾病已被证明与HLA-Cw*06相关。还将确定PSA组中Cw*06的个体中KIR基因的频率，并与对照数据集进行比较。目前正在对这些数据进行分析。我们也已经开始使用一组强直性脊柱炎患者和一组hiv -1感染者的样本对这些基因进行分型。杀伤抑制受体基因在艾滋病中的作用-自然杀伤细胞，杀伤抑制受体，HLA， -人体组织，液体，细胞等。

Natural killer (NK) cells are a unique group of lymphocytes involved in surveillance and killing of foreign or infected cells through a mechanism involving recognition of HLA molecules by an extremely diverse set of receptors on the NK cell surface. The killer inhibitory receptor genes (KIRs) map to chromosome 19q13.4 along with other related genes. Some of these genes encode molecules that recognize HLA- C ligands, whereas others bind HLA-A and -B molecules. In contrast to cytotoxic T lymphocyte (CTL) recognition of peptide as presented by class I, NK cells destroy targets that lack expression of class I, and they are inhibited by recognition of class I on the cell surface. NK cells play an important role in defense against viruses that inhibit class I molecule expression and thereby avoid recognition by CTL. For example, HIV-1 downregulates cell surface expression of HLA-A and -B molecules (but not -C) and one mechanism to explain rapid progression to AIDS in individuals with certain HLA types may involve alteration of NK cell activity. The host defense system may be crippled effectively by reducing CTL activity through Nef downregulation of HLA-A and -B, along with curtailment of NK activity by not affecting the expression of HLA-C. Evidence for downregulation of class I by human papilloma virus (HPV) has also been reported. We have developed a molecular typing technique for the KIR genes in order to study potential effects of these genes on autoimmune (psoriatic arthritis [PSA], ankylosing spondylitis and multiple sclerosis) and infectious diseases (those associated with HIV-1, hepatitis C virus and hepatitis B virus). Haplotypes of the KIR genes complex vary in the number of KIR genes present and some of the genes are slightly polymorphic. Our initial approach has been to determine presence or absence of each KIR gene, but we have also begun to develop means for typing alleles at each locus. Our protocol involves polymerase chain reaction (PCR) amplification performed with primers specific for each locus (PCR-SSP). We use the same amplification conditions for all loci, greatly enhancing the efficiency of the assay. Internal control primers for a 796-bp fragment of the third intron of DRB1 are also included in each PCR reaction. In order to confirm the presence or absence of a particular locus, two sets of primers have been designed for each locus. The entire typing protocol can be performed in a 96-well format, thereby providing a potential means for semi-automation. Recognition of HLA-C molecules by several of the KIR gene products led us to speculate that synergistic interactions between HLA and KIR genes might be most obvious in data sets obtained from diseases associated with HLA-C. HLA associations with autoimmune diseases appear to be less complex than those involving infectious diseases. Thus, we have typed a group of individuals with (PSA), a disease that has been shown to be associated with HLA-Cw*06. Frequencies of the KIR genes among individuals in the PSA group who are Cw*06 will also be will determined and compared to a control data set. This data is being analysed presently. We have also begun to type these genes using samples from a group of patients with ankylosing spondylitis and a group of HIV-1-infected individuals. Role of Killer Inhibitory Receptor Genes in AIDS - Natural killer cells, Killer inhibitory receptors, HLA, - Human Tissues, Fluids, Cells, etc.