KIR/HLA Interactions and Pathogen Immunity

Abstract

The innate immune system is the first line of defence in response to pathogen infection. Natural killer (NK) cells perform a vital role in this response with the ability to directly kill infected cells, produce cytokines, and cross-talk with the adaptive immune system. These effector functions are dependent on activation of NK cells which is determined by surface receptor interactions with ligands on target cells. Of these receptors, the polymorphic killer immunoglobulin-like receptors (KIRs), which interact with MHC class 1 (also highly polymorphic), are largely inhibitory, and exhibit substantial genetic diversity. The result is a significant variation of NK cell repertoire between individuals and also between populations, with a multitude of possible KIR:HLA combinations. As each KIR:ligand interaction may have differential effects on NK cell activation and inhibition, this diversity has important potential influences on the host response to infections. Genetic studies have demonstrated associations between specific KIR:ligand combinations and the outcome of viral (and other) infections, in particular hepatitis C and HIV infection. Detailed functional studies are not required to define the mechanisms underpinning these disease associations.

Characterization of human killer immunoglobulin-like receptors (KIRs) among healthy Saudis

“…Full-length sequencing of KIR haplotypes showed that the framework regions divide the KIR locus into two parts: centromeric (C) and telomeric (T) segments that differ in their gene contents [5,9,10]. The centromeric part of the A haplotype contains KIR2DL3, -2DL1 and -2DP1, in addition to 3DL3 and -3DP1,while the telomeric part contains the KIR3DL1 and -2DS4 genes, in addition to KIR2DL4 and -3DL1.…”

“…The centromeric part of the A haplotype contains KIR2DL3, -2DL1 and -2DP1, in addition to 3DL3 and -3DP1,while the telomeric part contains the KIR3DL1 and -2DS4 genes, in addition to KIR2DL4 and -3DL1. Unlike the A haplotype, which is fixed, uniform and conserved, the B haplotype is polymorphic and exhibits a variable centromeric end that includes the KIR2DS2, -2DL2, -2DL5B, -2DS3 and -2DS5 genes, in addition to KIR3DL3 and -3DP1, while the telomeric part of the B haplotype contains the KIR3DS1 and -2DS1 genes, in addition to KIR2DL4 and -3DL1 [10,11]. Therefore, diversity is generated in the KIR locus by the content of group A and group B haplotype genes and the allelic variation that occurs within both the centromeric and telomeric regions [12].…”

“…KIR allelic products have been shown to differ in their specificity and affinity regarding ligand binding [13], and these allelic differences may contribute to disease susceptibility and progression [14]. The frequencies of KIR genes and haplotypes show great variation among different populations, and the crucial function of KIRs in immunity may have an impact on susceptibility to infection, autoimmune diseases and transplantation outcomes among different ethnic groups [10,15,16].…”

Immune Abnormalities in Patients Meeting New Diagnostic Criteria for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

“…Specifically, in the ICC group profound increases were observed in KIR2DL1, KIR3DL1 and NKG2D in contrast to the 1994 CDC group. KIR2DL1 and KIR3DL1 are inhibitory receptors while NKG2D is an activating receptor, these receptors inhibit and activate NK cytotoxic activity respectively [22][23][24][25]. An increase in inhibitory receptors in the ICC group may account for the reduced cytotoxic activity.…”

Association of Killer Cell Immunoglobulin-Like Receptor Genes with Pandemic Influenza A (H1N1)pdm09 Infection in Critically Ill Macedonian Patients

“…To date, these studies have mainly targeted viral infections such as human immunodeficiency virus infection, hepatitis C, but also cancer, autoimmune, and inflammatory disorders [29][30][31][32]. In general, activating genotypes generally appear to be beneficial during viral infections, whereas they increase the risk for susceptibility to autoimmunity [33].…”