[show abstract][hide abstract] ABSTRACT: The polymorphic killer cell immunoglobulin-like receptors (KIR) control natural killer (NK) cell response against viral infection and tumor transformation. Here we investigated if select KIR genes are associated with recurrent respiratory papillomatosis (RRP), a rare disease of the larynx and upper airway caused by human papillomaviruses (HPV)-6/11. DNA from 66 RRP patients and 195 healthy controls were characterized for KIR and HLA gene polymorphism. Patients lacking activating KIR genes 3DS1 and 2DS1 were more common in severe RRP compared with mild-moderate RRP (78.8% vs 48.5%, p = 0.019). Further, patients carrying any of the known susceptible HLA-DRB1/DQB1 alleles were more frequently negative for KIR3DS1 (p = 0.006), KIR2DS1 (p = 0.003) or KIR2DS5 (p = 0.004) compared with controls carrying any of these HLA allotypes. Nearly 80% of the patients with severe disease were missing the protective HLA-DQB1*0602 allele as well as both KIR3DS1 and KIR2DS1 genes. Phenotyping of papilloma-infiltrating mononuclear-cells revealed an elevated numbers of NK cells and CD57(+)CD4(+) T cells in KIR3DS1(-)KIR2DS1(-) patients compared with patients carrying either one or both of these KIRs. Our data suggest that NK cells expressing activating receptors KIR3DS1 and KIR2DS1 may be necessary to trigger an effective early immune response against HPV-infected targets to establish resistance to RRP development.
Human immunology 10/2009; 71(2):212-9. · 2.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Vogt-Koyanagi-Harada (VKH) disease is a putative autoimmune ocular inflammatory disease and is known to be associated with HLA-DR4 and -DR1 in Mestizos. We examined the genes encoding KIR receptors and human leukocyte antigen (HLA) class I ligands in patients with VKH disease and compared to published controls. We found trends toward more group B KIR haplogroups (p=0.059), with more activating KIR genes, in patients compared to controls. All putative activating KIR-HLA combinations were more common in patients, and some inhibitory KIR-HLA combinations were more common in controls, although the differences were not statistically significant. The trends observed in this study are consistent with those reported for other autoimmune diseases.
Human Immunology 07/2008; 69(6):349-53. · 2.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: By interacting with polymorphic HLA class I molecules, the killer cell immunoglobulin-like receptors (KIR) influence the innate and adaptive immune response to infection. The KIR family varies in gene content and sequence polymorphism, thereby, distinguishing individuals and populations. To investigate KIR diversity in the earliest settlers of India, we have characterized the KIR gene content in three Dravidian-speaking populations (Mollukurumba, Kanikar, and Paravar) from the state of Tamil Nadu, southern India. The activating KIR genes and putative group-B KIR haplotypes were frequent in Paravar and Kanikar, a scenario analogous to those seen previously in other populations of Indian origin, indicating that predominance of group-B KIR haplotypes is the characteristic feature of Indian populations. In contrast, the KIR gene profile of Mollukurumba was more related to Caucasian type. It is not clear whether a local-specific selection or a recent admixture from Iran is responsible for such discrete profile in Mollukurumba. Each southern Indian population had distinct KIR genotype profile. Comparative analyses with world populations revealed that group-B KIR haplotypes were frequent in the natives of India, Australia, and America, the populations associated with those involved in extensive prehistoric human migrations. Whether or not natural selection has acted to enrich group-B KIR haplotypes in these migratory descendants is an issue that requires objective testing.
[show abstract][hide abstract] ABSTRACT: Killer cell Ig-like receptors (KIR) control the immune response of NK cells and some T cells to infections and tumors. KIR genes evolve rapidly and are variable between individuals in their number, type and sequence. Here, we determined the nature of KIR2DL5 gene polymorphism in four ethnic groups using direct DNA sequencing method. Nine new sequences were discovered. Within the panel of 248 KIR2DL5-positive individuals, 14 KIR2DL5-sequences differing in coding regions were observed. They differed at only seven amino acid positions, and such limited polymorphism is consistent with its conserved nature throughout the hominoid lineage. Ethnic deviation was seen in the distribution of KIR2DL5A, KIR2DL5B and their alleles. African Americans had more KIR2DL5 alleles than other populations indicating that more polymorphisms are yet to be discovered in Africans. Linkage between KIR2DL5-alleles and certain activating-KIR genes were observed, but frequency of these linked clusters differed substantially between populations. Consequently, KIR2DL5 alleles can be used as markers to predict the activating-KIR gene content. Typing system distinguishing A*001 and B*002 alleles can serve as a powerful screening test to assess the content of most variable activating-KIR genes that have been implicated in human disease and in the outcome of hematopoietic stem cell transplantation.
Genes and immunity 06/2008; 9(5):470-80. · 4.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: Birdshot chorioretinopathy (BCR), a chronic ocular inflammatory disease with characteristic choroidal lymphocytic infiltrates, has been strongly associated with human leukocyte antigen (HLA)-A29. Although HLA-A29 occurs frequently in all populations, BCR affects only a small percentage of HLA-A29-positive Caucasians, indicating additional susceptibility factors for BCR. Discovery of HLA class I-specific killer cell immunoglobulin-like receptors (KIR) led to a series of epidemiological studies implicating KIR-HLA gene combinations in disease. Here, we characterized KIR-HLA pairs in BCR patients and controls carrying HLA-A*29 as well as controls lacking HLA-A*29. KIR-HLA pairs implicated for weak inhibition (KIR2DL2/3+HLA-C1 and KIR3DL1+HLA-Bw4(T80)) in combination with activating KIR genes associated with autoimmunity (KIR2DS2, 2DS3 and 2DS4) augment the risk of developing BCR in HLA-A*29-positive individuals. The reciprocal association of strong inhibitory pairs (KIR3DL1+HLA-Bw4(I80) and KIR2DL1+HLA-C2) in combination with those implicated in protection from infection (KIR3DS1+HLA-Bw4(I80) and KIR2DS1+HLA-C2) was observed in HLA-A*29-negative controls. These results suggest that a profound effect of KIR2DS2/S3/S4 in the absence of strong inhibition may enhance the activation of natural killer cells and T-cell subsets against intraocular self-antigens, thereby contributing to pathogenesis of BCR.
Genes and immunity 05/2008; 9(3):249-58. · 4.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine the nucleotide polymorphism of activating killer-cell immunoglobulin-like receptors (aKIR) 3DS1 and 2DS3, we developed a novel direct-sequencing method and analyzed DNA samples of 175 KIR3DS1(+) individuals and 72 KIR2DS3(+) individuals from the white population. The putative ligand-binding extracellular immunoglobulin (Ig)-like domains of these aKIR receptors are highly conserved, a scenario contrary to inhibitory KIRs that recognize polymorphic human leukocyte antigen (HLA) class I molecules. Null alleles 3DS1*049N and 2DS3*003N that do not express cell-surface receptors were discovered, and they occur commonly in whites (3DS1*049N = 2%; 2DS3*003N = 0.8%). Sequence-specific polymerase chain reaction (PCR) detecting these null alleles is negative with DNA from nonwhite subjects, suggesting that these null alleles are specific to whites and probably originated after the colonization of modern humans in Europe.
[show abstract][hide abstract] ABSTRACT: Interactions between inhibitory killer cell immunoglobulin-like receptors (iKIR) and human leukocyte antigen (HLA) class I molecules regulate natural killer (NK) cell responses to eliminate infected and transformed cells while maintaining tolerance to healthy cells. Unlinked polymorphic gene families encode KIR receptors and HLA class I ligands and their independent segregation results in a variable number and type of iKIR + HLA pairs inherited in individuals. The diversity in the co-inheritance of iKIR + HLA pairs and activating KIR (aKIR) genes in 759 unrelated individuals from four ethnic populations was analyzed. Every individual studied inherited a minimum of one iKIR + HLA pair; suggesting that major histocompatibility complex class I-dependent inhibitory KIR signaling is essential for human NK cell function. In contrast, 13.4% of the study group lacked all aKIR genes. Twenty percent of the study group carried only one of the four iKIR + HLA pairs. Interestingly, 3% of the study group carrying only KIR2DL3 + HLA-C1 as an iKIR + HLA pair lacked aKIR genes. These data suggest that a single iKIR can constitute the minimal KIR repertoire for human NK cells. Genotypes carrying an equal number of iKIR + HLA pairs and aKIR genes represented 20% of the study group. The remaining individuals had either a dominant inhibitory KIR genotype (iKIR + HLA > aKIR) or a dominant activating KIR genotype (iKIR + HLA < aKIR). Genotypes encoding these imbalanced inhibitory and activating interactions may contribute to susceptibility or resistance to human diseases.
[show abstract][hide abstract] ABSTRACT: A major milestone in transplantation would be the use of biomarkers to monitor rejection. We examined the association between perforin and granzyme-B gene expression detected in the peripheral blood of renal allograft recipients with cellular and antibody-mediated rejection. Furthermore, we judged the appropriateness of assigning negative rejection statuses to persons without a biopsy whose grafts were functioning well clinically. Of the 46 patients who completed the study, recipients with cellular rejection had higher perforin and granzyme-B levels compared with nonrejectors (p = 0.006). Interestingly, recipients with antibody-mediated rejection also had higher perforin and granzyme-B levels compared with nonrejectors (p = 0.04). Patients with high levels of granzyme B had a probability of rejecting that was 26.7 times greater than those patients with low levels of granzyme B. Perforin and granzyme B had sensitivities of 50% and specificities of 95% in predicting rejection (cutoff value = 140). Assigning negative rejection statuses to recipients without a biopsy whose grafts were functioning well did not have a major effect on the direction or significance of covariate values. This study suggests that perforin and granzyme-B gene expressions in peripheral blood are accurate in detecting both cellular and antibody-mediated rejection.
Human Immunology 11/2006; 67(10):777-86. · 2.30 Impact Factor