Genetic effects of the MHC and KIR locus on autoimmune d

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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.