Genetic effects of the MHC and KIR locus on autoimmune d

鼻咽癌（NPC）发生于鼻咽上皮细胞，与EB巴尔病毒（EBV）密切相关。虽然它在大多数人群中是一种相对罕见的恶性肿瘤，但它是中国南方癌症发病率的重要来源。NPC发生在患者的家庭成员中，疾病风险与人类白细胞抗原（HLA）有关，尽管HLA相关性因种族而异。我们正在研究这些基因的影响，在一个病例对照研究的鼻咽癌涉及618人来自台湾。这些个体先前已被分型为HLA-A和HLA-B基因座。我们现在已经完成了分型HLA-C和杀手免疫球蛋白样受体（KIR）基因座在这些人和数据进行了分析。已经提交了一份手稿，并已暂时接受出版。我们现在正在对该队列中的KIR 3DL 2进行分型。以前的数据表明，HLA-A*11作为KIR 3DL 2的配体，可能对NPC具有保护作用。在完成KIR 3DL 2亚型分型后，我们将分析数据以确定A*11和KIR 3DL 2的特定等位基因之间是否存在上位相互作用，这可能解释观察到的HLA-A* 11的保护作用。我们最近开始与Maria Tere Landi博士合作，研究来自意大利的地中海人群中KIR和HLA与黑色素瘤风险的关联。在一项病例对照研究中，约有180例病例和180例对照，64个一级亲属中至少有2例受影响的黑色素瘤病例的家庭已入组。这些家庭来自病例对照研究受试者的确切地区，并由同一家医院的同一皮肤科医生进行检查，具有相似的流行病学数据。我们最初的分析集中在KIR 2DS 4上，因为最近的一份报告表明黑色素瘤细胞系似乎表达KIR 2DS 4的配体。令人惊讶的是，初步结果表明，与具有全长等位基因的受试者相比，携带截短的KIR 2DS 4等位基因（其可能是非功能性的）的受试者被保护免受黑素瘤的风险。这在病例对照研究和家庭研究中都很明显。这些结果有些令人困惑，因此为了进一步探索我们的发现，我们已经开始研究与该等位基因连锁不平衡的其他KIR基因。基于我们在CEPH家族中的研究，我们已经确定KIR 2DL 4的某些等位基因与截短的KIR 2DS 4等位基因处于强连锁不平衡。我们正在对KIR 2DL 4进行分型，以确定观察到的效应是否是由于KIR 2DL 4。一些研究表明，KIR 2DL 4的配体是HLA-G，其通常主要在滋养层细胞上表达，但也可以由黑素瘤细胞表达。已知KIR 2DL 4与HLA-G的结合诱导细胞因子产生，包括干扰素-γ。我们已经提出，存在的活化KIR表达的自然杀伤（NK）细胞可能会加剧自身免疫和炎症的发病机制，诱导NK细胞介导的细胞因子分泌和细胞溶解。来自我们实验室的数据支持这一假设，观察到一组患者银屑病关节炎（PsA）参加多伦多大学银屑病关节炎诊所的照顾下，博士Dafna Gladman。最近，我们从密歇根大学的合作者James Elder和Rajan Nair博士那里收到了2000多份样本，以进行一项研究，确定HLA和KIR在银屑病自然史中的作用。已开始对这些样本进行基因分型，将在完成基因分型后进行数据分析。慢性炎症性肠病（IBD）克罗恩病和溃疡性结肠炎是胃肠道的特发性炎性疾病，被认为是由粘膜免疫系统的不适当和持续激活引起的。

Nasopharyngeal carcinoma (NPC), which arises in the epithelial cells of the nasopharynx, exhibits a strong association with Epstein Barr virus (EBV). Although it is a relatively rare malignancy in most populations, it is a substantial source of cancer morbidity in Southern China. NPC occurs among family members of patients and disease risk has been linked with human leukocyte antigens (HLA), although the HLA associations differ by ethnic group. We are studying the effects of these genes in a case-control study of NPC involving 618 individuals from Taiwan. These individuals have been typed previously for the HLA-A and HLA-B loci. We have now completed typing HLA-C and the killer immunoglobulin-like receptor (KIR) locus in these individuals and the data have been analysed. A manuscript has been submitted and has been provisionally accepted for publication. We are now in the process of subtyping KIR3DL2 in this cohort. Previous data suggests that HLA-A*11, which serves as a ligand for KIR3DL2, may be protective against NPC. Upon completion of KIR3DL2 subtyping we will analyze the data to determine if there is an epistatic interaction between A*11 and specific alleles of KIR3DL2 that might explain the protective effect observed for HLA-A*11.We have recently begun a collaboration with Dr. Maria Tere Landi to study the association of KIR and HLA with melanoma risk in a Mediterranean population from Italy. Approximately 180 cases and 180 controls in a case-control study and 64 families with at least 2 affected melanoma cases in first degree relatives have been enrolled. The families are from the exact area of the subjects enrolled in the case-control study, and were examined by the same dermatologist in the same hospital, with similar epidemiological data. Our initial analysis has focused on KIR2DS4, since a recent report indicated that melanoma cell lines appear to express a ligand for KIR2DS4. Surprisingly, preliminary results indicate that subjects carrying a truncated KIR2DS4 allele (which might be nonfunctional), were protected against the risk of melanoma when compared with subjects with the full length allele. This was evident in both the case-control and family studies. These results are somewhat puzzling, so to further explore our findings we have begun to study other KIR genes that are in linkage disequilibrium with this allele. Based on our studies in the CEPH families, we have determined that certain alleles of KIR2DL4 are in strong linkage disequilibrium with the truncated KIR2DS4 allele. We are in the process of subtyping KIR2DL4 to determine if the observed effects are due to KIR2DL4. A few studies have shown that the ligand for KIR2DL4 is HLA-G, which is normally expressed primarily on trophoblastic cells, but may also be expressed by melanoma cells. Binding of KIR2DL4 with HLA-G is known to induce cytokine production, including interferon-gamma. We have proposed that the presence of activating KIR expressed on natural killer (NK) cells may aggravate autoimmune and inflammatory pathogenesis by inducing NK cell-mediated cytokine secretion and cytolysis. Data from our lab that supports this hypothesis was observed in a group of patients with psoriatic arthritis (PsA) attending the University of Toronto Psoriatic Arthritis Clinic under the care of Dr. Dafna Gladman. More recently, we have received over 2000 samples from our collaborators Drs. James Elder and Rajan Nair at the University of Michigan to carry out a study to determine the role of HLA and KIR in the natural history of psoriasis. Genotyping of these samples has begun, and data analysis will be performed after completion of genotyping. The chronic inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis, are idiopathic, inflammatory disorders of the gastrointestinal tract that are thought to result from inappropriate and ongoing activation of the mucosal immune system.