The Killer-cell Immunoglobulin-like Receptors (KIR) constitute a group of proteins which are
present on the cell surface of Natural Killer (NK) cells and in some T cells (Parham 2005a). The main task of these receptors is to participate in the regulation of the killing function against infections and malignancy by interacting with MHC Class I molecules (Kumar & McNerney 2005; Parham 2005b).
1.5.1 Genes and alleles in the KIR family
The KIR family consists of fifteen genes and two pseudogenes9 clustered on the
Leukocyte Receptor Complex (LRC) residing on the long arm of chromosome 19 at position
19q13.4 (Wende et al. 1999). These receptors may be activating (KIR2DS1, KIR2DS2,
KIR2DS3, KIR2DS4, KIR2DS5 and KIR3DS1) or inhibitory (KIR2DL1, KIR2DL2,
KIR2DL3, KIR2DL5A, KIR2DL5B, KIR3DL1, KIR3DL2 and KIR3DL3) based on the
activating role on the function of the NK cell, except KIR2DL4 which appear to have both functions (Middleton, Curran & Maxwell 2002).
KIR genes are also inherited as blocks of genes. According to recent studies, each individual may carry from seven to eleven different genes (Middleton, Meenagh & Gourraud 2007; Shilling et al. 2002; Uhrberg, Parham & Wernet 2002). Because of the high variability in the gene content and the allelic polymorphism found in this genomic region, individuals rarely present identical KIR genotypes (presence or absence of the KIR genes in an individual).
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The KIR family also presents a high level of polymorphism derived from presence or absence of genes, although not at the same level as the HLA region. A total of 601 KIR alleles have been reported as of release 2.4.0 April 2011 in the IPD-KIR database (Robinson et al. 2005). KIR3DL1, KIR3DL2 and KIR3DL3 are the most polymorphic genes with 70, 84 and 101 alleles respectively (Table 1.3).
Table 1.3: Genes and number of alleles in the KIR family
KIR locus Alleles KIR locus Alleles
KIR2DL1 43 KIR2DS1 15 KIR2DL2 27 KIR2DS2 22 KIR2DL3 32 KIR2DS3 13 KIR2DL4 47 KIR2DS4 30 KIR2DL5A 15 KIR2DS5 16 KIR2DL5B 25 KIR3DS1 16 KIR3DL1 70 KIR2DP1 22 KIR3DL2 84 KIR3DP1 23 KIR3DL3 101
Number of KIR alleles as of April 2011 from release 2.4.0 available in the IPD-KIR Database (Robinson et al. 2005).
1.5.2 Organisation of the KIR genes
In the last decade, many studies have been performed to analyse the organisation of the KIR genes. Researchers have classified genes in two main groups „A‟ and „B‟ according to the haplotype content, originally based on the presence or absence of a 24kb HindIII restriction enzyme fragment (Uhrberg et al. 1997). The basis of each haplotype group consists of four genes KIR3DL3 and KIR3DP1 located at the centromeric10 side and
KIR2DL4 and KIR3DL2 at the telomeric11 side, which are considered to be framework
genes and always present (Figure 1.6). Group A consists of the presence of KIR3DL1,
KIR2DL1, KIR2DL3 and KIR2DS4 genes whereas group B is composed of the presence
of one or more of the following genes: KIR2DL2, KIR2DL5, KIR3DS1, KIR2DS1,
10 Centromere is the region of DNA situated near the middle of the chromosome and which is involved in cell division.
11 Telomere is the region of DNA located at the end of the chromosome and which protects from deterioration or fusion with other chromosomes.
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KIR2DS2, KIR2DS3 and KIR2DS5 [For KIR haplotypes see review in (Middleton &
Gonzalez 2010)].
According to the A and B haplotype classification, the resulting haplotype groups can be categorised as AA or Bx (in which x can be either A or B) as defined by McQueen and colleagues due to the difficulty of distinguishing the other A or B haplotype without familial data (McQueen et al. 2007). The terms AA and Bx will be used throughout this thesis for referencing KIR haplotype groups.
Figure 1.6: Organisation of the KIR genes.
In this figure, KIR genes are classified by centromeric and telomeric side. Two examples of haplotypes are shown in the figure. Framework genes are shown in brown. Genes specific to B haplotypes are shown in blue. Genes that are
present in both groups are shown in yellow (Parham 2005b).
Based on the number of genes in each group (as shown in Figure 1.6), the number of haplotype combinations containing B genes is expected to be greater than A subsets (Hsu et al. 2002a). In recent studies, more than twenty different haplotypes have been identified by family studies. With these haplotypes, a high number of genotypes can be generated by haplotype permutations (Hsu et al. 2002b).
1.5.3 KIR nomenclature
The KIR nomenclature guidelines are defined by the Human Genome Organisation (HUGO) via the Genome Nomenclature Committee (Marsh et al. 2003). Following a similar notation as used for HLA allele designations, the KIR nomenclature is
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composed of two main components: (i) the gene name and (ii) the code for the allele variant which are separated by an asterisk (*) (Figure 1.7).
Figure 1.7: Structure of the nomenclature for KIR alleles. (Reprinted with permission of S.G.E. Marsh)
Source: http://www.ebi.ac.uk/ipd/kir/alleles.html
The gene name is formed by the acronym of the polymorphic region (KIR) and the name of the corresponding gene (e.g. 2DL1, 2DL2, etc.). The name of the gene is composed of four to five alphanumeric characters which define the characteristics of the gene. The first character represents the number of immunoglobulin-like domains (2 or 3 domains), the second denotes the prefix of the word domain (D), the third character indicates whether the gene has a long (L) or short (S) cytoplasmic tail, or if it is a pseudogene (P). Long tail codes are commonly associated with inhibitory genes and short tail codes with activating genes, except KIR2DL4 which appear to have both functions as mentioned in Section 1.5.1. The fourth character describes the number of the gene in consecutive numerical order which is assigned by the GenBank database (Benson et al. 2008) and a suffix „A‟ or „B‟ is added to distinguish genes that present similar structures and sequences, e.g. 2DL5A and 2DL5B (Marsh et al. 2003).
Finally, the KIR allele variant is composed of three to seven digits. The first three digits represent the sequence that encodes a specific protein (e.g. KIR2DL1*003), the next two digits are used to distinguished differences (synonymous nucleotide substitutions) within the coding region (e.g. KIR2DL1*00302), and the last two digits are used to denote differences which are located in the non-coding region (e.g. KIR2DL1*0030202).
Differs from other KIR2DL1*00302 alleles by a DNA substitution within a non-coding region.
KIR2DL1*0030202
First 2DL protein describedLong cytoplasmic tail
Two lg-like domains
Acronym
Separator
Member of the third series of KIR2DL1 proteins Differs from other KIR2DL1*003 proteins by a synonymous DNA substitution within the coding region.
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1.5.4 KIR and HLA ligands
The products of certain HLA Class I loci (principally HLA-B and -C) and the products of some KIR genes present specific interactions and have been studied by immunologists in recent years.
The epitope Bw4 in the HLA-B locus is believed to function as a ligand with the
KIR3DL1 gene (Trowsdale 2001). In the case of the HLA-C locus, the subsets are
divided into C1 and C2 epitopes whose differences are found at positions 77-80 in the amino acid sequence. KIR2DL1 interacts with the C2 epitope (covering alleles under the C*02, *04, *05, *06 allele families) and KIR2DL2/3 with the C1 epitope (for C*01, *03, *07, *08 allele families) (Trowsdale 2001).
These interactions are suggested to influence resistance to infections, susceptibility to autoimmune diseases, pregnancy and success in haematopoietic stem cell transplantation (Parham 2005b).
1.5.5 Applications of the KIR family
The investigation of the genes of this genomic region and their organisation has assisted scientists in the understanding of the functioning of these genes and their interaction with other molecules such as the HLA system.
From these studies a number of important topics have been under investigation by researchers. For example, the presence of activating KIR genes in individuals is believed to protect against infections, but has also been linked to the susceptibility to certain autoimmune diseases (Single et al. 2007a). In contrast, the presence of inhibitory KIR genes is believed to protect against inflammatory diseases (Single et al. 2007a).
In population genetics, the diversity present in the genes of the KIR family has been studied by anthropologists to understand theories of human migration (Rajalingam et al. 2008). The analysis of KIR gene/allele frequencies and the correlation of KIR and HLA ligands in different populations have provided evidence for coevolution of these
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genomic regions (Norman et al. 2007; Single et al. 2007a). The number of different analyses has also been extended to include a range of populations among regions and continents (Middleton et al. 2008).