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，有些基因是多态的。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上分型等位基因的方法。很明显，确定单倍型对于与该基因座进行严格的疾病关联研究是必要的。因此，我们已经开始对59个CEPH家族的KIR基因进行分型，初步数据表明，该位点存在极端的单倍型复杂性，可能是由于基因复制、重组和基因间重排的某种组合。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2DS1密切相关，KIR基因2DS1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位点之间的上位性相互作用是否正在进行中。来自另一种相关自身免疫性疾病强直性脊柱炎患者的样本也正在进行分型。最后，在265名清除HCV的个体和486名持续感染HCV的匹配个体中对这些基因进行了分型。后一项研究应该特别有趣，因为NK细胞在肝脏中发现频率很高，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.