Variation of the Killer Cell Immunoglobulin-Like Receptors andHLA-CGenes in Nasopharyngeal Carcinoma

Abstract

Nasopharyngeal carcinoma (NPC) is an Epstein-Barrvirus (EBV)-associated malignancy. Previous studies have shown that NPC is associated with specific human leukocyte antigen (HLA) alleles which function in adaptive immunity to present viral and other antigens to the immune system. The role of innate immunity in NPC development is unknown. To determine whether innate immunity is associated with NPC, a case-control study was conducted among 295 Taiwanese NPC cases (99% EBV seropositive) and 252 community controls (29% EBV seropositive). Using high-resolution genotyping, we evaluated the variation of HLA class I alleles and killer cell immunoglobulin-like receptor (KIR) alleles. Located on the surface of natural killer (NK) cells and a subset of T cells, inhibitory KIRs diminish NK cytolysis of target cells upon binding to their HLA class I ligands and activating KIRs are thought to stimulate NK destruction of target cells. Our results suggest that an increasing number of activating KIRs may be associated with increasing NPC risk, particularly in individuals seropositive for anti-EBV antibodies known to be linked to NPC susceptibility (P trend = 0.07). Among EBVseropositive individuals, carriers of z5 activating KIRs had a 3.4-fold increased risk of disease (95% confidence interval, 0.74-15.7) compared with individuals with no functional activating KIRs. In contrast, there was no clear evidence of risk associated with increasing numbers of inhibitory KIRs. When evaluating HLA-Cw alleles, we observed that carriers of HLA-Cw*0401 alleles were at a significantly reduced NPC risk (odds ratio, 0.46; 95% confidence intervals, 0.23-0.92), an effect that could not be explained by linkage disequilibrium with other NPCassociated HLA alleles. Our results suggest that KIRmediated activation may be associated with NPC risk. As this finding is consistent with a recent report examining cervical cancer, a malignancy caused by human papillomavirus, the data raises the possibility that KIRs, and more generally innate immunity, may be involved in the pathogenesis of viral-associated cancers. (Cancer Epidemiol Biomarkers Prev 2005;14(11):2673 -7)

Distinct KIR/HLA compound genotypes affect the kinetics of human antiviral natural killer cell responses

“…Given that the affinities of KIR2DL1 and KIR2DL3 for their respective ligands are very similar (24,25,26), the basis for weaker inhibition by KIR2DL3 could be differences in negative signaling controlled by the cytoplasmic tails (26). Thus, our data provide a functional correlate for previous epidemiological observations (5,18,19,21,45).…”

“…A distinction between the effect of the compound genotypes HLA-C2/KIR2DL1 and HLA-C1/KIR2DL3 on the outcome of various diseases has been previously reported and attributed to differential activation of NK cells (5,18,19,21,45). To address the functional basis for this finding, we studied the frequency, phenotype, and function of NK cells from healthy subjects who had both KIR2DL3 and KIR2DL1 (and not KIR2DL2), but were homozygous for either HLA group C1 or group C2 alleles.…”

“…In contrast, HLA-C2 alleles are associated with protection against cervical neoplasia (18) and, to some extent, nasopharyngeal carcinoma (19). Thus, KIR/HLA-C compound genotypes contribute to susceptibility or resistance to a variety of infectious diseases and cancer (20).…”

Several Regions in the Major Histocompatibility Complex Confer Risk for Anti-CCP-Antibody Positive Rheumatoid Arthritis, Independent of the DRB1 Locus

“…Interestingly, one report has suggested that certain combinatorial relationships at these loci may predispose to rheumatoid vasculitis (36), although others have not observed such a relationship for RA in general (37). Nevertheless, complex interactions have been described for psoriatic arthritis (38), outcome of HIV infection (39), nasopharyngeal carcinoma (40), and the maternal fetal relationships underlying preeclampsia (41). The HLA-C allele found on the 8.1 haplotype is HLA-C*0701, a member of the "C-group 1" alleles that are characterized by an asparagine residue at position 80 (35).…”

Genes Involved in DNA Repair and Nitrosamine Metabolism and Those Located on Chromosome 14q32 Are Dysregulated in Nasopharyngeal Carcinoma

“…Among others, HLA-A*0207, HLA-A*1101, HLA-B*4601, and HLA-B*5801 are associated with NPC risk. In addition to HLA gene polymorphisms that might affect the adaptive immune response, recent studies have begun to evaluate the role of innate immune responses in NPC pathogenesis through the evaluation of KIR genes and their HLA ligands (10).…”