Role of Killer Inhibitory Receptor Genes in Autoimmune a

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。杀伤免疫球蛋白样受体基因（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细胞在防御病毒感染的细胞和肿瘤细胞中起重要作用，所述病毒感染的细胞和肿瘤细胞下调I类分子表达，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，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（见项目编号Z 01 BC 10269-05 LGD）。还报道了人乳头瘤病毒（HPV）下调I类的证据。 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。我们已经开发了一种分子分型技术，确定是否存在15个KIR基因中的每一个，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，乙型肝炎B病毒和HPV相关的疾病）的潜在影响。确定KIR单倍型将是必要的，严格的疾病相关性研究与此位点。因此，我们已经开始了一项研究，以确定KIR单倍型和他们的频率使用分离分析。到目前为止，我们已经对59个CEPH家族进行了KIR基因存在或不存在的分型，这代表了近1，400种KIR单倍型（约370条独立染色体和1，000次减数分裂）。一些KIR基因在几乎所有的KIR单倍型上都有发现，所以当一个父母有两个基因拷贝（每个染色体上一个），另一个父母有一个或两个，所有的后代都对该基因呈阳性，并且不可能确定是否有一个染色体可能缺失该基因位点。在某些情况下，通过对该基因中的多态性位点进行分型可以解决这个问题。因此，我们已经设计了一个基于序列的分型系统的两个共同的KIR基因，KIR 2DL 4和KIR 3DL 1，和测序的家庭已经开始。从我们迄今收集的数据中可以清楚地看出，KIR单倍型是极其复杂的，单倍型变异的最明显机制似乎是不等交换。然而，家族数据并不表明KIR基因复合物内的重组热点。这些单倍型的分型和分析正在进行中。 NK细胞的细胞毒性由一系列复杂的激活和抑制信号控制，这些信号部分地通过NK细胞表面上的KIR与它们各自的HLA I类配体之间的相互作用而发生。鉴于这些分子的功能关系（它们都由基因组的高度多态性、非连锁区域编码），受某些HLA等位基因影响的疾病也可能受到编码相应KIR分子的基因的影响。HLA-Cw*0602先前已被证明与银屑病关节炎相关，我们在大样本的银屑病患者中证实了这一点（OR=1.97）。数据还显示了与包含KIR 2DS 1的KIR单倍型的独立疾病关联（OR=1.56）。KIR 2DS 1编码与NK细胞杀伤表达N77 K80基序的靶细胞相关的受体，该基序存在于Cw*0602中。还观察到B*27与疾病表型的特别强的关联（OR=3.56），并且当B*27和KIR 3DS 1都存在时，关联的强度甚至更大（OR=4.57）。然而，没有观察到KIR 3 DS 1对PsA的独立于B*27的主导作用，这表明KIR 3 DS 1可能加剧了B*27的易感性效应。这些数据表明，银屑病关节炎的易感性涉及编码已知调节NK细胞功能的受体-配体对的基因。因此，很可能HLA I类对这种疾病的影响是复杂的，并且HLA-KIR相互作用占总HLA对银屑病关节炎发病机制的影响的一部分。我们最近又收到了110例病例和对照（使病例和对照的总数分别达到367和330），为这些位点对疾病的影响提供了额外的力量和进一步的澄清。

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 immunoglobulin-like 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 virally infected cells and tumor cells that down regulate class I molecule expression, thereby avoiding 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 (see Project number Z01 BC 10269-05 LGD). Evidence for downregulation of class I by human papilloma virus (HPV) has also been reported. Haplotypes of the KIR gene complex vary in the number of KIR genes present and some of the genes are polymorphic. We have developed a molecular typing technique determining the presence or absence of each of the 15 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, hepatitis B virus, and HPV). Defining KIR haplotypes will be necessary for rigorous disease association studies with this locus. Thus, we have embarked on a study to define KIR haplotypes and their frequencies using segregation analysis. To date, we have typed 59 CEPH families for presence or absence of the KIR genes, which represents nearly 1,400 KIR haplotypes (about 370 independent chromosomes and 1,000 meioses). Some KIR genes are found on almost all KIR haplotypes, so when one parent has two copies of a gene (one on each chromosome) and the other parent has one or two, all offspring are positive for the gene and it is not possible to determine whether one chromosome may be missing that gene locus. In some cases, it may be possible to resolve this problem by typing polymorphic loci in that gene. Thus, we have designed a sequence-based typing system for two of the common KIR genes, KIR2DL4 and KIR3DL1, and sequencing in the families has begun. It is clear from the data we have collected thus far that KIR haplotypes are extremely complex, and the most obvious mechanism for haplotypic variation appears to be unequal crossing over. However, the family data do not indicate a hotspot for recombination within the KIR gene complex. Ongoing typing and analyses of these haplotypes are underway. NK cell cytotoxicity is controlled by a complex array of activating and inhibitory signals occurring in part through the interaction between KIR on the NK cell surface and their respective HLA class I ligands. Given the functional relationship of these molecules, which are both encoded by highly polymorphic, unlinked regions of the genome, it is possible that diseases influenced by certain HLA alleles may also be affected by the genes encoding the corresponding KIR molecules. HLA-Cw*0602 has previously been shown to associate with psoriatic arthritis, which we confirm in a large sample of individuals with the disease (OR=1.97). The data also show an independent disease association with KIR haplotypes that contain KIR2DS1 (OR=1.56). KIR2DS1 encodes a receptor correlated with NK cell killing of target cells expressing the N77K80 motif, which is present in Cw*0602. A particularly strong B*27 association with disease phenotype was also observed (OR=3.56) and the strength of the association was even greater when both B*27 and KIR3DS1 were present (OR=4.57). However, a dominant effect of KIR3DS1 on PsA independent of B*27 was not observed, suggesting that KIR3DS1 may exacerbate the susceptibility effect of B*27. The data indicate that predisposition to psoriatic arthritis involves genes encoding a receptor-ligand pair known to regulate NK cell function. Thus, it is likely that the HLA class I effects on this disease are complex, and that HLA-KIR interactions account for part of the total HLA influence on pathogenesis of psoriatic arthritis. We have recently received 110 additional cases and controls (bringing the totals to 367 and 330 for cases and controls, respectively), providing added power and further clarification of the effects these loci have on the disease.