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，通过NK细胞表面一组极其不同的受体识别HLA分子的机制，参与对外来细胞或感染细胞的监视和杀伤。杀伤细胞抑制受体基因(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人类白细胞抗原-C配体的分子，而另一些基因则结合人类白细胞抗原-A和-B分子。与第I类细胞毒性T淋巴细胞(CTL)对肽的识别不同，NK细胞破坏缺乏第I类表达的靶点，它们被细胞表面第I类识别所抑制。NK细胞在防御病毒方面发挥着重要作用，病毒抑制I类分子的表达，从而避免CTL的识别。例如，HIV-1下调了细胞表面的HLA-A和-B分子(而不是-C)的表达，而解释某些HLA型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。Nef通过下调HLAA和HLAB来降低CTL活性，同时通过不影响HLAC的表达来降低NK活性，从而有效地削弱宿主防御系统。也有证据表明人类乳头瘤病毒(HPV)下调了I类基因的表达。我们开发了KIR基因的分子分型技术，以研究这些基因在自身免疫(银屑病关节炎、强直性脊柱炎和多发性硬化症)和感染性疾病(与HIV-1、丙型肝炎病毒和乙肝病毒相关的疾病)中的潜在作用。KIR基因复合体的单倍型因存在的KIR基因的数量而不同，其中一些基因是多态的。我们最初的方法是确定每个KIR基因的存在或不存在，但我们也开始开发每个基因座的等位基因分型方法。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家系的KIR基因进行分型，初步数据表明该基因座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，在从与HLA-C相关的疾病获得的数据集中，人类白细胞抗原和KIR基因之间的协同作用可能是最明显的。人类白细胞抗原与自身免疫性疾病的关系似乎没有感染性疾病那么复杂。因此，我们对300多名患有银屑病关节炎(PSA)的患者进行了分型，这种疾病已被证明与人类白细胞抗原-CW*06有关，这种联系已被我们的数据证实。此外，分析表明PSA与KIR基因2DS1有很强的关联，KIR基因2DS1向自然杀伤细胞发送激活信号。对数据进行建模，以确定未连接的人类白细胞抗原和KIR基因座之间的上位性相互作用是否正在进行。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，正在对265名已清除丙型肝炎病毒的人和486名匹配的持续感染丙型肝炎病毒的人进行这些基因的分型。后一项研究应该特别引起人们的兴趣，因为NK细胞在肝脏中被发现的频率很高，并且已知在病毒感染的肝脏中可以诱导肝细胞的凋亡。

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.