Role of Killer Inhibitory Receptor Genes in Autoimmune and Infectious Diseases

自然杀伤（NK）细胞是一组独特的淋巴细胞，其通过涉及NK细胞表面上极其多样化的受体组识别HLA分子的机制参与监视和杀死外来或感染的细胞。杀伤抑制受体基因（KIR）与其他相关基因一起定位于染色体19 q13.4沿着。 这些基因中的一些编码识别HLA-C配体的分子，而另一些则结合HLA-A和-B分子。与由I类呈递的肽的细胞毒性T淋巴细胞（CTL）识别相反，NK细胞破坏缺乏I类表达的靶标，并且它们被细胞表面上的I类识别抑制。 NK细胞在防御抑制I类分子表达的病毒中起重要作用，从而避免被CTL识别。 例如，HIV-1下调HLA-A和-B分子（但不下调-C）的细胞表面表达，并且解释具有某些HLA类型的个体快速进展为AIDS的一种机制可能涉及NK细胞活性的改变。 Nef通过下调HLA-A和-B的表达，降低CTL活性，沿着NK活性的降低，而不影响HLA-C的表达，从而有效地削弱宿主的防御系统。 还报道了人乳头瘤病毒（HPV）下调I类的证据。我们已经开发了一种KIR基因的分子分型技术，以研究这些基因对自身免疫性疾病（银屑病关节炎[PsA]，强直性脊柱炎和多发性硬化症）和感染性疾病（与HIV-1，丙型肝炎病毒和B型肝炎病毒相关的疾病）的潜在影响。 KIR基因复合体的单倍型在存在的KIR基因的数量上变化，并且一些基因是多态的。 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分型等位基因的方法。 很明显，确定单倍型将是必要的，严格的疾病相关性研究与这个位点。 因此，我们已经开始分型59 CEPH家庭的KIR基因和初步数据表明极端的单倍型复杂的基因座，大概是由于一些基因重复，重组和基因间重排的组合。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与HLA-C相关的疾病获得的数据集中最明显。 HLA与自身免疫性疾病的关联似乎没有感染性疾病复杂。 因此，我们对一组300多名银屑病关节炎（PsA）患者进行了分型，这种疾病已被证明与HLA-Cw*06相关，我们的数据证实了这种关联。 此外，分析表明PsA与KIR基因2DS 1有很强的关联，该基因向自然杀伤细胞发送激活信号。对数据进行建模，以确定非连锁HLA和KIR基因座之间的上位相互作用是否正在进行中。 来自患有另一种相关自身免疫性疾病，强直性脊柱炎的个体的样本也正在分型。 最后，这些基因正在265名已清除HCV的个体和486名持续感染HCV的匹配个体中进行分型。后一项研究应该特别感兴趣，因为NK细胞在肝脏中的频率很高，并且已知在病毒感染的肝脏中诱导肝细胞凋亡。

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 gene complex vary in the number of KIR genes present and some of the genes are 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. It has become clear that defining the haplotypes will be necessary for rigorous disease association studies with this locus. Thus, we have begun typing 59 CEPH families for the KIR genes and preliminary data indicate extreme haplotypic complexity at the locus, presumably due to some combination of gene duplication, recombination, and intergenic rearrangements. 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 over 300 individuals with psoriatic arthritis (PsA), a disease that has been shown to be associated with HLA-Cw*06 and this association is confirmed by our data. Further, the analysis indicates a strong association of PsA with the KIR gene 2DS1, which sends an activating signal to natural killer cells. Modelling the data to determine whether epistatic interactions between the unlinked HLA and KIR loci is in progress. Samples from individuals with another related autoimmune dissease, ankylosing spondylitis are also being typed. Finally, these genes are being typed in 265 individuals who have cleared HCV and 486 matched individuals who are persistently infected with HCV. This latter study should be of particular interest since NK cells are found in high frequency in the the liver and are known to induce apoptosis of hepatocytes in virally infected livers.