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Killer Cell Immunoglobulin-Like Receptor (KIR) Genes
and Association with Human Viral Infections
Mirko Spiroski, MD, PhD
Institute of Immunobiology and Human Genetics, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje, Republic of Macedonia
http://www.iibhg.ukim.edu.mk/e-mail: [email protected]
FB: mirko.spiroski
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At a glance ...
• Natural killer cells• Leukocyte Receptor Complex• KIR genes• KIR genes diversity• Determination of KIR genes• Diversity of KIR genes• Association of KIR genes with viruses
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A model for natural T cells' role within the immune system
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Natural killer (NK) cells and cytotoxic T cells (CTL) are professional killer cells and share several common features
but differ by their HLA class I-specific receptors that are used to distinguish unhealthy targets from the healthy host cells
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The extended Leukocyte Receptor Complex
(19q13.4) and a KIR haplotype
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KIR gene organisation
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KIR protein structures
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Approximate KIR protein domain and region lengths
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KIR Gene Names Gene
Symbol Protein Symbol
Description Aliases
KIR2DL1 KIR2DL1 killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 1 47.11, CD158a,cl-42, nkat1, p58.1
KIR2DL2 KIR2DL2 killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 2 CD158b1, cl-43, nkat6
KIR2DL3 KIR2DL3 killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 3 CD158b2, cl-6, nkat2, nkat2a, nkat2b, p58
KIR2DL4 KIR2DL4 killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 4 15.212, 103AS, CD158d
KIR2DL5A KIR2DL5A killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 5A CD158f, KIR2DL5.1
KIR2DL5B KIR2DL5B killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 5B KIR2DL5.2, KIR2DL5.3, KIR2DL5.4
KIR2DS1 KIR2DS1 killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 1 CD158h, EB6Actl, EB6Actll
KIR2DS2 KIR2DS2 killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 2 183Actl, CD158j, cl-49, nkat5
KIR2DS3 KIR2DS3 killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 3 nkat7
KIR2DS4 KIR2DS4 killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 4 CD158i, cl-39, KKA3, nkat8
KIR2DS5 KIR2DS5 killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 5 CD158g, nkat9
KIR2DP1 KIR2DP1 killer cell immunoglobulin-like receptor, two domains, pseudogene 1 KIR2DL6, KIR15, KIRY, KIRZ
KIR3DL1 KIR3DL1 killer cell immunoglobulin-like receptor, three domains, long cytoplasmic tail, 1 AMB11, CD158e1, cl-2, cl-11, KIR, nkat3, NKB1, NKB1B
KIR3DL2 KIR3DL2 killer cell immunoglobulin-like receptor, three domains, long cytoplasmic tail, 2 CD158k, cl-5, nkat4, nkat4a, nkat4b
KIR3DL3 KIR3DL3 killer cell immunoglobulin-like receptor, three domains, long cytoplasmic tail, 3 CD158z, KIR3DL7, KIR44, KIRC1
KIR3DS1 KIR3DS1 killer cell immunoglobulin-like receptor, three domains, short cytoplasmic tail, 1 CD158e2, nkat10
KIR3DP1 KIR3DP1 killer cell immunoglobulin-like receptor, three domains, pseudogene, 1 CD158c, KIR2DS6, KIR3DS2P, KIR48, KIRX
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KIR Allele Nomenclature
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Determination of KIR genes by single strand polymorphism (SSP)
method
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Identification of KIR genes by SSP method
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KIR gene frequencies in Macedonian population
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KIR genotypes in Macedonian population (n =
214)
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France
Argentina
IrelandNorthern
Italy
BelgiumKIRPop
Lebanon
Reunion
SwedenVasterbotten
Macedonia
SpainGranada
MexicoVeraCruzMestizos
EnglandWestMidlandsCaucasian
EnglandWestMidlandsIndianAsian
Basque
Africans
EnglandWestMidlandsAfroCaribbean
Guadeloupe
Senegal
Koreans
Japanese
Finland
Mestizo
Tarahumara
Huichol
Purepecha
IndiaNorthHindus
SouthAsians
PakistanKarachi
BrazilSouthEastCaucasian
0.0000.0050.0100.0150.020
KIR genetic three of 29
world populations
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Interaction between KIR genes and their ligand (HLA)
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Killer cell immunoglobulin-like receptor (KIR) diversity can impact natural killer
(NK) cells at different levels
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Natural killer (NK) cells are diverse at the level of receptors, ligands and
signalling adaptors
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Diversity of KIR genes and their ligands heredited in offspring from the parents with
different KIR and HLA genotypes ...
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... Diversity of KIR genes and their ligands heredited in offspring from the parents with
different KIR and HLA genotypes ...
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KIR3DL1/S1, like HLA-A,
B, C and HLA-DRB1, is one of the most highly polymorphic
human genes
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Association of KIR with viruses
• HIV-1• HCV• HBV• (H1N1)pdm90• West Nile Virus
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Model for the engagement of NK cells to mediate HIV inhibition
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NK cell-mediated recognition of HIV-1 infected cells
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KIR3DL1 polymorphism affects specificity for HLA class I
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KIR gene frequencies in control and patients with chronic hepatitis C viral infection
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Combined effect HLA-C1C1/Bw4-80/(KIR2DS4/1D) on
hepatocellular carcinoma (HCC) occurrence in HBV-infected patients
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Comparison of KIR3DL1/S1 allele frequencies between (H1N1)pdm09 ICU
patients and analogous world populations
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Percentages of carriers of inhibitory, activating, and pseudogene KIR genes in a control Gabonese
population and in contacts (IgG+), survivors, and fatalities of Ebola virus infection
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Comparison of the observed and estimated KIR gene frequencies for critically ill Macedonian patients
with pandemic influenza A (H1N1)pdm09 infection (N = 63) and healthy Macedonians (N=214)
N, number of individuals; F, observed frequency was obtained by direct counting; GF, gene frequencies were calculated using the formula GF=1-√(1-F); p, statistical significance; &, cannot be calculated because expected <5, χ2 test; OR, Odds ratio; CI,confidence interval.
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KIR locus haplogroups, genotypes ID and genotype frequency of critically ill Macedonian patients with pandemic influenza A (H1N1)pdm09 infection (N =
63) and corresponding frequencies in healthy Macedonians (n=214)
KIR Genotype [1=Positive, 0=negative]
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Comparison of the observed and estimated KIR gene frequencies for Macedonian patients with
West Nile Virus (WNV) infection (N = 4) and healthy Macedonians (N=214)
N, number of individuals; F, observed frequency was obtained by direct counting; GF, gene frequencies were calculated using the formula GF=1-(1-F); p, statistical significance; &, cannot be calculated because expected <5, 2 test; OR, Odds ratio; CI, confidence interval.
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KIR genotype frequencies in Macedonian patients with West Nile Virus (WNV) infection (N = 4) and healthy Macedonians (N=214)
N, number of individuals displaying certain Bx KIR genotype; F, frequency of KIR genotype; CI, confidence interval. &, cannot be calculated.
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Conclusions
• Associations of KIR genes, alleles, genotypes and haplotypes are found with some viral infections (HIV-1, HCV, HBV, (H1N1)pdm09, Ebola, and WNV).
• We expect intensive investigations about the susceptibility and/or resistance to viral infections connected with KIR genes and their ligands.
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Acknowledgement
Associate Professor Dr. Dejan TrajkovAssistant Dr. Aleksandar PetlichkovskiAssistant Dr. Slavica HristomanovaAssistant Dr. Meri KirijasAssistant Dr. Aleksandar SenevBiotechnologist Olivija Efinska-MladenovskaMolecular biolog Olgica SibinovskaLaboratory technician Elena Cvetkovska