Report from the killer immunoglobulin-like receptor (KIR) anthropology component of the 15th International Histocompatibility Workshop: worldwide variation in the KIR loci and further evidence for the co-evolution of KIR and HLA.

The killer immunoglobulin-like receptor (KIR) anthropology component of the 15th International Histocompatibility Workshop (IHIWS) sought to explore worldwide population variation in the KIR loci, and to examine the relationship between KIR genes and their human leukocyte antigen (HLA) ligands. Fifteen laboratories submitted KIR genotype and HLA ligand data in 27 populations from six broad ethnic groups. Data were analyzed for correlations between the frequencies of KIR and their known HLA ligands. In addition, allelic typing was performed for KIR2DL2 and 3DL1 in a subset of populations. Strong and significant correlations were observed between KIR2DL2, 2DL3 genotype frequencies and the frequency of their ligand, HLA-C1. In contrast, only weak associations were seen for 3DL1, 3DS1 and the HLA-Bw4 ligand. Although some aspects of the correlations observed here differ from those reported in other populations, these data provide additional evidence of linked evolutionary histories for some KIR and HLA loci. Investigation of allele-level variation for the B haplotype locus KIR 2DL2 showed that two alleles, *001 and *003, predominate in all populations in this study. Much more allelic variation was observed for the A haplotype locus 3DL1, with several alleles observed at moderate frequencies and extensive variation observed between populations.

Killer immunoglobulin-like receptors (KIR2DL2 and/or KIR2DS2) in presence of their ligand (HLA-C1 group) protect against chronic myeloid leukaemia.

We have analysed the frequency of killer immunoglobulin-like receptors (KIR) in cohorts of patients from Turkey with acute lymphocyte leukaemia (n = 52), acute myeloid leukaemia (n = 54) and chronic myeloid leukaemia (CML) (n = 52) and compared the results with 154 controls. We also examined the frequencies of human leucocyte antigen (HLA)-C groups, -Bw4, -Bw6 and where appropriate the combination of the KIR gene and its ligand. We found several statistically significant results between the patients and the controls. We proposed a model in CML of protection via KIR2DL2 and/or KIR2DS2 with the presence of the ligand HLA-C1 group and susceptibility via HLA-Bw4 homozygosity (i.e. absence of HLA-Bw6).

Reassessing the impact of donor HLA-C genotype on long-term liver transplant survival.

HLA-C is the major inhibitory ligand for killer immunoglobulin-like receptors (KIRs) that are expressed on natural killer (NK) cells. Based on their KIR specificity, HLA-C alleles can be divided into two groups, termed HLA-C1 and HLA-C2. Donor HLA-C group has recently been identified by Hanvesakul et al. (Am J Transplant 2008) as a critical determinant of clinical outcome following liver transplantation: Possession of at least one HLA-C group 2 allele by the donor was associated with significantly improved long-term graft and patient survival, presumably due to an inhibition of host NK cell function. To verify this study, we performed genotyping of 913 deceased liver donors for the relevant KIR epitopes of HLA-C and correlated the presence or absence of donor HLA-C2 genotype with graft and patient survival. In our study, donor HLA-C2 genotype had no impact on 10-year graft or patient survival. We cannot confirm a major role of donor HLA-C2 genotype on long-term allograft survival after liver transplantation.

Analysis of killer immunoglobulin-like receptor genes in ankylosing spondylitis.

OBJECTIVES: To assess the possible association of killer immunoglobulin-like receptor (KIR) genes, specifically KIR3DL1, KIR3DS1 and KIR3DL2, with ankylosing spondylitis (AS). METHODS: 14 KIR genes were genotyped in 200 UK patients with AS and 405 healthy controls using multiplex polymerase chain reaction. Sequence-specific oligonucleotide probes were used to subtype 368 cases with AS and 366 controls for 12 KIR3DL2 alleles. Differences in KIR genotypes and KIR3DL2 allele frequencies were assessed using the chi(2) test. RESULTS: KIR3DL1 and KIR3DS1 gene frequencies were very similar in cases with AS and controls (odds ratio = 1.5, 95% confidence interval 0.8 to 3.0, and odds ratio = 1.02, 95% confidence interval 0.2 to 5.3, respectively). KIR3DL2 allele frequencies were not significantly different between cases with AS and controls. CONCLUSIONS: Neither the KIR gene content of particular KIR haplotypes nor KIR3DL2 polymorphisms contribute to AS.

Investigation of killer cell immunoglobulin-like receptor gene diversity, KIR2DL1 and KIR2DS1.

Polymorphism in the alleles of the killer cell immunoglobulin-like receptor 2DL1 and 2DS1 genes has been investigated by the development of polymerase chain reaction-sequence-specific oligonucleotide probing systems. The methods have been applied to 77 Northern Irish families, establishing allele frequencies from the unrelated parents. Additionally, cell line DNA from individuals and CEPH families of the 13th International Histocompatibility Workshop panel were investigated. Eight of the reported KIR2DL1 alleles and only the KIR2DS1*002 allele were identified in the groups studied. Two individuals were positive for three alleles of KIR2DL1, and a putative variant of KIR2DL1*001 was observed. Results also indicated an inherited KIR2DL1/2DS1 splice variant present in a haplotype with several core loci absent, in two families.

Investigation of killer cell immunoglobulin-like receptor (KIR) gene diversity: KIR2DL2, KIR2DL5 and KIR2DS5.

Human killer cell immunoglobulin-like receptor (KIR) genes are important for restraining natural killer cytotoxicity toward cells with autologous human leukocyte antigen (HLA) while targeting cells lacking or expressing low levels of self-HLA molecules. KIR gene content and alleles vary across individual genomes and populations, requiring specialized laboratory tools for their characterization. Here, we detail methods based on sequence-specific polymerase chain reaction amplification and oligonucleotide probe hybridization to identify alleles of KIR2DL2, KIR2DL5A, KIR2DL5B and KIR2DS5. Allele frequencies for a Northern Irish population of 354 individuals typed with this system are given, along with results from 132 cell lines from the International Histocompatibility Workshop that cover many world populations. This information complements published reports by our laboratory for allele-level typing of other KIR members, totaling 12 of the 17 known genes. These methods are allowing us to characterize KIR haplotypes in our population.

No association of KIR genes with Behcet's disease.

Behcet's disease (BD) is thought to be caused by multiple genetic, environmental and immunological factors, one of the most prominent being the strong association with human leucocyte antigen (HLA)-Bw51, an HLA-Bw4-associated allele. We examined the presence/absence of 14 killer cell immunoglobulin-like receptors (KIRs) and their ligands in 134 Turkish individuals with BD and compared the results with those of 154 ethnically matched controls. Although KIR3DL1 with its ligand (HLA-Bw4) was significantly increased in the patients with BD (P = 0.0003), this no longer applied when the patients and controls were categorised by HLA-Bw51 status. Thus, no association was identified between presence or absence of any of the 14 KIR genes studied and BD. In addition, we did not find any associations of KIR with various manifestations of the disease nor with gender or age of onset.

Ketamine disrupts frontal and hippocampal contribution to encoding and retrieval of episodic memory: an fMRI study.

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine produces episodic memory deficits. We used functional magnetic resonance imaging to characterize the effects of ketamine on frontal and hippocampal responses to memory encoding and retrieval in healthy volunteers using a double-blind, placebo-controlled, randomized, within-subjects comparison of two doses of intravenous ketamine. Dissociation of the effects of ketamine on encoding and retrieval processes was achieved using two study-test cycles: in the first, items were encoded prior to drug infusion and retrieval tested, during scanning, on drug; in the second, encoding was scanned on drug, and retrieval tested once ketamine plasma levels had declined. We additionally determined the interaction of ketamine with the depth of processing that occurred at encoding. A number of effects upon task-dependent activations were seen. Overall, our results suggest that left frontal activation is augmented by ketamine when elaborative semantic processing is required at encoding. In addition, successful encoding on ketamine is supplemented by additional non-verbal processing that is incidental to task demands. The effects of ketamine at retrieval are consistent with impaired access to accompanying contextual features of studied items. Our findings show that, even when overt behaviour is unimpaired, ketamine has an impact upon the recruitment of key regions in episodic memory task performance.

Investigation of killer cell immunoglobulin-like receptor gene diversity V. KIR3DL2.

Allelic definition within the killer cell immunoglobulin-like receptor gene, KIR3DL2, has been achieved through a sequence-specific oligonucleotide probe methodology, designed around the specific amplification of the D0 and D1 domains and a section of the cytoplasmic tail of this gene. The system has been applied to a healthy Northern Irish control group, establishing frequencies for this Caucasian population. Additionally, the KIR3DL2 allele status of cell line DNA and Centre d'Etude du Polymorphisme Humain (CEPH) families, both from the 13th International Histocompatibility Workshop, has been established. A high level of KIR3DL2 allelic polymorphism has been identified.

Investigation of killer cell immunoglobulin-like receptor gene diversity III. KIR2DL3.

The allelic variation of one of the chromosome 19 KIR genes, KIR2DL3, has been investigated using a polymerase chain reaction sequence-specific oligonucleotide probe-based methodology. The procedure has been applied to a healthy Northern Irish control group in order to establish phenotype and genotype frequencies in this Caucasian population. In addition, cell line DNA and Centre d'Etude du Humaine (CEPH) families, both from the 13th International Histocompatibility Workshop have been investigated, establishing control data for this gene.

Pre-transplantation immunological monitoring and graft survival in recipients of renal allografts.

Various immunological parameters were measured pre-transplantation in 82 renal transplant recipients. The results were compared with the clinical course of the recipient post-transplantation and with the results of 40 controls. Only one test C3 inactivation products (C3i) was associated with transplant outcome in that 0/30 patients with no rejection episodes had C3i whereas 9/38 patients with rejection episodes, including 3/12 patients whose graft failed, had C3i.