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: mspiroski@yahoo.com

FB: mirko.spiroski

2

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

3

A model for natural T cells' role within the immune system

4

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

5

The extended Leukocyte Receptor Complex

(19q13.4) and a KIR haplotype

6

KIR gene organisation

7

KIR protein structures

8

Approximate KIR protein domain and region lengths

9

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

10

KIR Allele Nomenclature

11

Determination of KIR genes by single strand polymorphism (SSP)

method

12

Identification of KIR genes by SSP method

13

KIR gene frequencies in Macedonian population

14

KIR genotypes in Macedonian population (n =

214)

15

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

16

Interaction between KIR genes and their ligand (HLA)

17

Killer cell immunoglobulin-like receptor (KIR) diversity can impact natural killer

(NK) cells at different levels

18

Natural killer (NK) cells are diverse at the level of receptors, ligands and

signalling adaptors

19

Diversity of KIR genes and their ligands heredited in offspring from the parents with

different KIR and HLA genotypes ...

20

... Diversity of KIR genes and their ligands heredited in offspring from the parents with

different KIR and HLA genotypes ...

21

KIR3DL1/S1, like HLA-A,

B, C and HLA-DRB1, is one of the most highly polymorphic

human genes

22

Association of KIR with viruses

• HIV-1• HCV• HBV• (H1N1)pdm90• West Nile Virus

23

Model for the engagement of NK cells to mediate HIV inhibition

24

NK cell-mediated recognition of HIV-1 infected cells

25

KIR3DL1 polymorphism affects specificity for HLA class I

26

KIR gene frequencies in control and patients with chronic hepatitis C viral infection

27

Combined effect HLA-C1C1/Bw4-80/(KIR2DS4/1D) on

hepatocellular carcinoma (HCC) occurrence in HBV-infected patients

28

Comparison of KIR3DL1/S1 allele frequencies between (H1N1)pdm09 ICU

patients and analogous world populations

29

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

30

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.

31

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]

32

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.

33

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.

34

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.

35

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