Genetic effects of the MHC and KIR locus on autoimmune d

MHC 和 KIR 位点对自身免疫性疾病的遗传影响

• 批准号: 7291691
• 负责人: Mary N. Carrington
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7291691
• 关键词: Genetic; effects; MHC; KIR; locus

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.

鼻咽癌(NPC)发生于鼻咽上皮细胞，与EB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，但它是南方中国癌症发病率的重要来源。鼻咽癌发生在患者的家庭成员中，疾病风险与人类白细胞抗原(人类白细胞抗原)有关，尽管不同种族之间的关联有所不同。我们正在研究这些基因在鼻咽癌病例对照研究中的作用，该研究涉及618名来自台湾的人。这些个体之前已经被分型为人类白细胞抗原A和B基因座。我们现在已经完成了这些人的人类白细胞抗原-C和杀伤免疫球蛋白样受体(KIR)基因座的分型，并对数据进行了分析。已经提交了一份手稿，并已暂时接受出版。我们现在正在对这个队列中的KIR3DL2亚型进行分型。已有研究表明，作为KIR3DL2配体的人类白细胞抗原-A*11可能对鼻咽癌具有保护作用。在完成KIR3DL2亚型后，我们将分析数据，以确定A*11和KIR3DL2的特定等位基因之间是否存在上位性相互作用，这可能解释观察到的人类白细胞抗原-A*11的保护作用。我们最近开始与玛丽亚·泰尔·兰迪博士合作，在来自意大利的地中海人群中研究KIR和HLA与黑色素瘤风险的关联。在一项病例对照研究中，大约180例患者和180名对照被纳入家系，其中至少有2例黑色素瘤患者的一级亲属中有黑色素瘤病例。这些家庭来自病例对照研究中登记的受试者所在的确切地区，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。我们的初步分析集中在KIR2DS4上，因为最近的一份报告表明，黑色素瘤细胞株似乎表达KIR2DS4的配体。令人惊讶的是，初步结果表明，与携带全长等位基因的受试者相比，携带截短的KIR2DS4等位基因(可能是无功能的)的受试者避免了患黑色素瘤的风险。这一点在病例对照和家庭研究中都很明显。这些结果有些令人费解，所以为了进一步探索我们的发现，我们已经开始研究其他与该等位基因连锁不平衡的KIR基因。基于我们对CEPH家系的研究，我们已经确定KIR2DL4的某些等位基因与截短的KIR2DS4等位基因存在强烈的连锁不平衡。我们正在对KIR2DL4进行亚型分型，以确定观察到的影响是否源于KIR2DL4。一些研究表明KIR2DL4的配体是人类白细胞抗原G，通常主要在滋养层细胞表达，但也可能在黑色素瘤细胞表达。已知KIR2DL4与人类白细胞抗原G的结合可诱导细胞因子的产生，包括干扰素-γ。我们认为，自然杀伤(NK)细胞上表达的活化KIR可能通过诱导NK细胞介导的细胞因子分泌和细胞溶解而加重自身免疫和炎症的发病。来自我们实验室的数据支持这一假设，在多伦多大学牛皮癣关节炎诊所的一组牛皮癣关节炎(PSA)患者中观察到，该诊所由Dafna Gladman博士护理。最近，我们从我们的合作者密歇根大学的James Elder博士和Rajan Nair博士那里收到了2000多个样本，以开展一项研究，以确定人类白细胞抗原和KIR在牛皮癣自然历史中的作用。这些样本的基因分型工作已经开始，基因分型工作完成后将进行数据分析。慢性炎症性肠病(IBD)，克罗恩病和溃疡性结肠炎，是一种特发性的胃肠道炎症性疾病，被认为是由于粘膜免疫系统的不适当和持续激活造成的。