**4. Killer cell immunoglobulin-like receptors (KIRs)**

#### **4.1. Natural killer cells**

In exon 5, there is a short tandem repeat sequence (STR) at position 304 consisting of GCT nucleotide breaks, which encode the amino acid alanine in the transmembrane region (TM). STR is absent in *MICB*. Based on the number of GCT, the alleles are named as A4, A5, A5.1, A6, A7, A8, A9 and A10. A5.1 differs from A5 by the insertion of a guanine nucleotide in the GCT (GGCT) [62], leading to a change in the reading matrix causing a terminus premature codon within the exon that encodes the transmembrane domain [33, 63, 64]. Thus, A5.1 is a 35–40 kDa truncated glycoprotein that eventually reaches the cell surface, but not at its physiological site. This is another characteristic of the *MICA* polymorphism: several alleles have identical extracellular domains but differ in the TM region. The identification of the polymor-

The expression of the *MICA* gene was recognized in gastrointestinal and thymic epithelial cells in isolated endothelial cells, fibroblasts and keratinocytes. MICA molecules are ligands of the NKG2D receptors and Tγδ cell receptors (TCRγδ). The recognition of the MICA molecules by Tγδ Vδ1 cells through the interaction with the α1 and α2 domains was confirmed

Tγδ cells constitute a small population of T cells expressing antigenic receptor proteins that resemble those of CD4+ and CD8+ T cells, but are not identical. Tγδ cells recognize many different types of antigens, including some proteins and lipids, as well as small phosphorylated molecules and alkyl amines. These antigens are not presented by MHC molecules [25]. It is not known whether there is a need for a particular cell type or distinct antigen presentation system for the presentation of antigens to these cells. MICA molecules are also recognized by their NKG2D receptors present on the surfaces of NK cells, associated with DAP10 molecule. This NKG2D-MICA complex activates phosphorylation of the tyrosine residues of the DAP10 molecule, triggering a cascade of cell signaling that enhances the cytotoxicity of NK cells. This complex also enhances the production of IFN-γ by NK cells, participating as a co-stimulator

Therefore, MICA is a stress-induced MHC class I molecule that binds to NKG2D receptors, primarily NK cells, stimulating NK cells, T CD8+ cells and some Tγδ cells [68]. Previous studies have suggested that HLA-B *loci* alleles were associated with some diseases caused by pathogens and, as there is strong linkage disequilibrium between the two genes due to the

Some infectious and noninfectious diseases such Behçet's disease, ankylosing spondylitis, Reiter's syndrome, Kawasaki disease, psoriasis vulgaris and Chagas disease have been associated to *MICA* genes. These studies suggest that allelic variants of *MICA* may be directly related to NKG2D receptor binding of Tγδ and NK cells affecting the effects of cells activation [35, 69–74]. In the first study of association between the *MICA* gene and leprosy, the *MICA*\*A5 allele was found associated with protection against MB form in Chinese patients [19]. In India, the *MICA\*5A5.1, MICB\*CA16* and *MICB\*CA19* alleles were associated with susceptibility to leprosy *per se* and *MICB\*CA21* allele with protection [48]. Recently, in a study in Brazil, the *MICA\*010* and *MICA\*027* alleles were associated with protection against the MB form and

phism in the TM region is essential to avoid ambiguities [65].

factor in the immune response against *Mycobacterium* [67].

**3.2. Association of** *MICA* **and** *MICB* **genes with leprosy**

*MICA\*027* was associated with protection to leprosy *per se* [16].

proximity of *MICA*, this could indirectly contribute to this response.

later in another study [66].

126 Hansen's Disease - The Forgotten and Neglected Disease

Natural killer (NK) cells make up about 10–15% of the lymphocytes in human peripheral blood, with an important participation on the innate immune response. In addition, they are sources of type I cytokines, IFN-γ, as well as TNF-α, granulocyte macrophage colony-stimulating factor (GM-CSF) and other cytokines and chemokines [75]. In their original lineage, repertoire of receptors and effector functions, the NK cells appear to be a transitional cell type, which would be a bridge between the innate and adaptive immune system. The name is derived from two aspects: (*i*) NK cells are able to mediate their effector function (lysis of target cells) spontaneously in the absence of prior sensitization and are then called "killer" and "natural" and (*ii*) another aspect is that they perform their function with a very limited repertoire of receptors encoded in progenitor lines that do not undergo somatic recombination. The absence of previous sensitization and the absence of gene rearrangement for the formation of receptors for target cells indicate that NK cells are part of the innate immune system [76]. The major surface markers associated with NK cells are CD16 and CD56, while the T cell receptor (TCR) is absent [77].

The function of NK cells is to remove abnormal cells from the host, as infected cells or tumor cells, by exocytosis of lytic proteins (perforin/granzyme pathway) and by FasL or TRAIL (factor-apoptosis inducing linker of tumor necrosis) expression. Chemokines secreted by NK cells, such as IFN-γ and TNF-α, can mediate cytotoxic effects, activate dendritic and T cells, and influence the individual's immune response [78].

NK cells perform their task using two sets of receptors: activators and inhibitors present on their surface that interact with binding molecules on the surface of the target cell. The balance of these interactions determines whether or not the NK cell will be activated [9]. The major activation receptors expressed on NK cells include FcγRIIIA (CD16), DNAM-1 (CD226), NKG2C (KLRC2: killer cell lectin-like C2 receptor), NKG2E (KLRC3: killer cell lectin-like C3 receptor), NKG2D (KLRK1: killer cell lectin-like receptor K1), KIR-activating forms (KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5 and KIR3DS1), natural cytotoxicity receptors (NCRs) called NKp30 (natural cytotoxicity triggering receptor 3), NKp46 (NCR1: natural cytotoxicity triggering receptor 1), NKp65 (KLRF2: killer cell lectin-like F2 receptor) and NKp80 (KLRF1: killer cell lectin-like F1 receptor). The inhibitory receptors are KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5, KIR3DL1, KIR3DL2, KIR3DL3, NKG2A (KLRC1: killer cell lectin-like C1 receptor), LILRB1 (leukocyte immunoglobulin-like B1 receptor), KLRG1 (NKR2B4: natural killer cell receptor 2B4), NKp44 (NCR2: natural cytotoxicity triggering receptor 2) and KIR2DL4 (NKR2B4: natural killer cell receptor 2B4) [75].

#### **4.2. KIR molecules**

KIRs are members of a group of regulatory molecules found on the surface of NK cells and T cell subpopulations. They were first identified for their ability to confer some specificity in cytolysis mediated by NK cells [79, 80]. This specificity occurs through the interaction of isotypes of KIR with HLA class I molecules, protecting unaltered cells from the destruction caused by NK cells. Different types of KIRs can be expressed on the surface of NK cells, which may be activators or inhibitors [79], with a combinatorial selection of receptors to be expressed by the cell.

Thus, in an individual, NK cells can randomly express a different set of activating and inhibitory receptors, and not all NK cells in an individual have the same receptors. This differential expression between NK cells and certain KIR/HLA interactions may contribute to heterogeneity in NK cell activation levels, observed both among different individuals and among distinct NK cell subpopulations of the same individual [81].

NK cells become responsible for tolerance when their inhibitory KIRs identify class I HLA surface molecules as self-antigens, and trigger inhibitory signaling through the tyrosine kinase phosphorylation of intracytoplasmic inhibition motifs based on tyrosine immunosorbent (ITIM) [82]. Even with the presence of activating receptors, the inhibitory signal is translated into tolerance, absence of cytotoxicity and cytokine production by NK cells when the target cell is normal. When the cell is infected with a virus or transformed into a tumor cell, this tolerance environment is altered, especially by the low or no expression of HLA class I molecules, which is known as part of the escape mechanism of tumor cells to the adaptive immunity [83].

NK cells are activated to produce cytotoxicity and cytokines, precisely due to the escape mechanism of altered ITIM cells; but alternatively there are positively charged transmembrane residues, which facilitate the physical association with DAP12 accessory proteins, releasing the activating signal via immunoreceptor tyrosine-based activation motifs (ITAM) [75].

#### **4.3.** *KIR* **genes**

The *KIR* genes are located on chromosome 19 (19q13.4) in a 1 Mb gene complex called the leukocyte receptor complex (LRC) which is shown in **Figure 8**. There are several gene families in the LRC region, among them leukocyte Ig-like receptors (LILRs); Ig-like transcripts (ILTs); killer cell Ig-like receptors (KIRs); platelet collagen receptor glycoprotein VI (GPVI); Fc IgA receptors, FcGammaR; natural cytotoxicity triggering receptor 1 (NRC1); leukocyte-associated Ig-like receptors (LAIRs); sialic acid-binding immunoglobulin-like lectins (SIGLECs); members of the CD66 family, such as the carcinoembryonic antigen (CEA) genes and the genes encoding the transmembrane adapter molecules DAP10 and DAP12 [84, 85].

They are classified based on two characteristics: number of extracellular Ig domains (2D or 3D) and characteristics of the cytoplasmic tail of the KIR protein, being S for short tail and L for long tail [88]. KIR3D is formed by the domains D0, D1 and D2, while KIR2DL1, KIR2DL2, KIR2DL3 and all KIR2DS have the D1 and D2 (Type I) domains; and KIR2DL4 and KIR2DL5 have the domains D0 and D2 (Type II) [89]. The long cytoplasmic tail (L) is associated with ITIM motifs that release a signal of inhibition to the cell. This signal of inhibition is due to the phosphorylation of a tyrosine residue that promotes the recruitment of (SHP-1 and SHP-2), which promote the dephosphorylation of protein substrates of tyrosine kinases related to the activation of NK cells. On the other hand, short tail (S) activation receptors have ITAM motifs in their transmembrane domain that associate with the adapter molecule DAP-12. The interaction of these receptors with their ligands results in the recruitment of SyK and ZAP-70 tyrosine kinases by ITAMs, resulting in the reorganization of the cytoskeleton to release granules and also in the transcription of cytokine and chemokine genes [90]. The structural characteristics of KIR that

**Figure 8.** Diagram showing the cluster genes of the extended leukocyte receptor complex located (LRC) on chromosome 19 with highlight to *KIR* A haplotype at position 19q13.4 (in red). Among the molecules encoded by the extended LRC set of genes are the DAP adaptor proteins, CD66 antigens, SIGLEC, FcGRT, LILR, LAIR, FcAlphaR and NCR1 receptors. Within the *KIR* A haplotype are the framework genes (blue boxes), pseudogenes (purple box), inhibitory *KIR* (red boxes) and activating *KIR* genes (green box). *KIR2DL4* can be an inhibitory or an activating gene and *KIR3DP1* is also

Immunogenetics of *MHC* and *KIR* in the Leprosy http://dx.doi.org/10.5772/intechopen.75253 129

The *KIR* pseudogenes are identified by the letter "P" just after the digit corresponding to the

*KIR* genes follow a basic organization structure with 4–9 exons. Exons 1 and 2 encode the protein leader sequence; exons 3, 4 and 5 encode extracellular domains (D0, D1 and D2, respectively);

define their nomenclature are represented in **Figure 9**.

considered as framework gene [86].

domain type, as in the pseudogenes: *KIR2DP* and *KIR3DP*.

The *KIR* gene family has 15 genes (*KIR2DL1, KIR2DL3, KIR2DL4, KIR2DL5A, KIR2DL5B, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2D5, KIR3DL1, KIR3DL2, KIR3DL3* and *KIR3DS1*) and 2 pseudogenes (*KIR2DP1* and *KIR3DP1*). They are divided into two functional groups: inhibitors that prevent lysis of the target cell and the activators that cause lysis of the target cell. The inhibitory group has eight genes that are *KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5A, KIR2DL5B, KIR3DL1, KIR3DL2* and *KIR3DL3;* the activator group has genes such as *KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5* and *KIR3DS1*; while *KIR2DL4* may be an activator or inhibitor. Between them, there are four *KIR* genes that are called structural (framework) genes, since they are present in almost all individuals: *KIR3DL3, KIR3DP1, KIR2DL4* and *KIR3DL2* [85, 86].

#### **4.4. Structure and nomenclature of KIR**

The naming of *KIR* genes is responsibility of the HUGO Genome Nomenclature Committee (HGNC) [87]. The designation of the *KIR* gene system considers the structure of the KIR protein.

which may be activators or inhibitors [79], with a combinatorial selection of receptors to be

Thus, in an individual, NK cells can randomly express a different set of activating and inhibitory receptors, and not all NK cells in an individual have the same receptors. This differential expression between NK cells and certain KIR/HLA interactions may contribute to heterogeneity in NK cell activation levels, observed both among different individuals and among distinct

NK cells become responsible for tolerance when their inhibitory KIRs identify class I HLA surface molecules as self-antigens, and trigger inhibitory signaling through the tyrosine kinase phosphorylation of intracytoplasmic inhibition motifs based on tyrosine immunosorbent (ITIM) [82]. Even with the presence of activating receptors, the inhibitory signal is translated into tolerance, absence of cytotoxicity and cytokine production by NK cells when the target cell is normal. When the cell is infected with a virus or transformed into a tumor cell, this tolerance environment is altered, especially by the low or no expression of HLA class I molecules, which is known as part of the escape mechanism of tumor cells to the adaptive immunity [83]. NK cells are activated to produce cytotoxicity and cytokines, precisely due to the escape mechanism of altered ITIM cells; but alternatively there are positively charged transmembrane residues, which facilitate the physical association with DAP12 accessory proteins, releasing the activating signal via immunoreceptor tyrosine-based activation motifs (ITAM) [75].

The *KIR* genes are located on chromosome 19 (19q13.4) in a 1 Mb gene complex called the leukocyte receptor complex (LRC) which is shown in **Figure 8**. There are several gene families in the LRC region, among them leukocyte Ig-like receptors (LILRs); Ig-like transcripts (ILTs); killer cell Ig-like receptors (KIRs); platelet collagen receptor glycoprotein VI (GPVI); Fc IgA receptors, FcGammaR; natural cytotoxicity triggering receptor 1 (NRC1); leukocyte-associated Ig-like receptors (LAIRs); sialic acid-binding immunoglobulin-like lectins (SIGLECs); members of the CD66 family, such as the carcinoembryonic antigen (CEA) genes and the

The *KIR* gene family has 15 genes (*KIR2DL1, KIR2DL3, KIR2DL4, KIR2DL5A, KIR2DL5B, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2D5, KIR3DL1, KIR3DL2, KIR3DL3* and *KIR3DS1*) and 2 pseudogenes (*KIR2DP1* and *KIR3DP1*). They are divided into two functional groups: inhibitors that prevent lysis of the target cell and the activators that cause lysis of the target cell. The inhibitory group has eight genes that are *KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5A, KIR2DL5B, KIR3DL1, KIR3DL2* and *KIR3DL3;* the activator group has genes such as *KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5* and *KIR3DS1*; while *KIR2DL4* may be an activator or inhibitor. Between them, there are four *KIR* genes that are called structural (framework) genes, since they are present in almost all individuals: *KIR3DL3, KIR3DP1, KIR2DL4* and

The naming of *KIR* genes is responsibility of the HUGO Genome Nomenclature Committee (HGNC) [87]. The designation of the *KIR* gene system considers the structure of the KIR protein.

genes encoding the transmembrane adapter molecules DAP10 and DAP12 [84, 85].

expressed by the cell.

128 Hansen's Disease - The Forgotten and Neglected Disease

**4.3.** *KIR* **genes**

*KIR3DL2* [85, 86].

**4.4. Structure and nomenclature of KIR**

NK cell subpopulations of the same individual [81].

**Figure 8.** Diagram showing the cluster genes of the extended leukocyte receptor complex located (LRC) on chromosome 19 with highlight to *KIR* A haplotype at position 19q13.4 (in red). Among the molecules encoded by the extended LRC set of genes are the DAP adaptor proteins, CD66 antigens, SIGLEC, FcGRT, LILR, LAIR, FcAlphaR and NCR1 receptors. Within the *KIR* A haplotype are the framework genes (blue boxes), pseudogenes (purple box), inhibitory *KIR* (red boxes) and activating *KIR* genes (green box). *KIR2DL4* can be an inhibitory or an activating gene and *KIR3DP1* is also considered as framework gene [86].

They are classified based on two characteristics: number of extracellular Ig domains (2D or 3D) and characteristics of the cytoplasmic tail of the KIR protein, being S for short tail and L for long tail [88]. KIR3D is formed by the domains D0, D1 and D2, while KIR2DL1, KIR2DL2, KIR2DL3 and all KIR2DS have the D1 and D2 (Type I) domains; and KIR2DL4 and KIR2DL5 have the domains D0 and D2 (Type II) [89]. The long cytoplasmic tail (L) is associated with ITIM motifs that release a signal of inhibition to the cell. This signal of inhibition is due to the phosphorylation of a tyrosine residue that promotes the recruitment of (SHP-1 and SHP-2), which promote the dephosphorylation of protein substrates of tyrosine kinases related to the activation of NK cells. On the other hand, short tail (S) activation receptors have ITAM motifs in their transmembrane domain that associate with the adapter molecule DAP-12. The interaction of these receptors with their ligands results in the recruitment of SyK and ZAP-70 tyrosine kinases by ITAMs, resulting in the reorganization of the cytoskeleton to release granules and also in the transcription of cytokine and chemokine genes [90]. The structural characteristics of KIR that define their nomenclature are represented in **Figure 9**.

The *KIR* pseudogenes are identified by the letter "P" just after the digit corresponding to the domain type, as in the pseudogenes: *KIR2DP* and *KIR3DP*.

*KIR* genes follow a basic organization structure with 4–9 exons. Exons 1 and 2 encode the protein leader sequence; exons 3, 4 and 5 encode extracellular domains (D0, D1 and D2, respectively);

one activator gene, *KIR2DS4*. The B haplotype has a greater diversity of genes: *KIR2DL5, KIR2DL2, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5* and *KIR3DS1*, with the activation signals

Immunogenetics of *MHC* and *KIR* in the Leprosy http://dx.doi.org/10.5772/intechopen.75253 131

The KIR Nomenclature Committee considered that the distinction between A and B haplotypes is useful in biological and clinical terms, and thus developed a consistent and logical set of criteria to distinguish them. Therefore, a haplotype can, for example, be called KH-001A or KH-022B [86]. The haplotypic diversity of *KIR* genes varies in different populations, suggesting that there may be variable effects of the receptors on several diseases, offering protection

NK cells perform the recognition of foreign cells in the body through the interaction of KIRs on own cell surface with ligands on target cells surface: classical class I HLA-specific molecules (HLA-A, HLA-B and HLA-C) and non-classical (HLA-E and HLA-G) [94]. The activity of NK cells requires the interaction between a given class I HLA antigen expressed on the

HLA-C molecules are the major ligands of KIR and can be distinguished in two groups of ligands (C1 and C2). All HLA-C carry a valine (V) at position 76 and a dimorphism in the position 80, which may be asparagine (N) or lysine (K). The alleles that have asparagine at position 80 are called C1 group (codifying by *C\*01, C\*03, C\*07, C\*08, C\*12, C\*13, C\*14, C\*16:01, C\*16:03* and *C\*16:04*) and are the ligands of KIR2DL2/KIR2DL3 and KIR2DS2. On the other hand, the molecules that possess lysine at position 80 (K80) belong to the C2 group (codifying by *C\*02, C\*04, C\*05, C\*06, C\*15, C\*16:02, C\*17* and *C\*18* genes) and bind to KIR2DL1 and

Some HLA-B molecules express Bw4 epitopes that are also present in some HLA-A molecules encoded by HLA-A\*09, HLA-A\*23, HLA-A\*24, HLA-A\*24:03, HLA-A\*25 and HLA-A\*32. The KIR3DL1 and the KIR3DS1 interact with HLA-Bw4, which differs from Bw6 due to a polymorphism at position 77 and 80. Bw4 molecules may have multiple amino acids at the position 77, either asparagine or aspartic acid or serine, and a dimorphism at the position 80, which may be isoleucine or threonine. The allotypes containing Bw4 with Isoleucine (Bw4-80I) generally exhibit strong inhibition, while Bw4 alleles with Threonine (Bw4-80 T), such as those encoded by HLA-B\*13, HLA-B\*27, HLA-B\*37:01 and HLA-B\*44, appear to be better ligands for certain KIR3DL1 subtypes. Other KIRs have less defined specificities, such as KIR3DL2, which recognizes HLA-A variants (A3 and A11), KIR2DL4 recognizing HLA-G and KIR2DS4 recognizing C\*04. The ligands for KIR2DL5, KIR2DS3, KIR2DS5, KIR3DS1 and

Although KIR activators exhibit a ligand recognition structure very similar to inhibitory receptors, as in the 2DL1/2DS1-C2 group pair and the triad of 2DL2/2DL3/2DS2-C1 group, the binding affinity of the activating variants is strongly reduced in comparison to the inhibitory variants. Therefore, when there are binding of inhibitory and activating receptors at the

predominating. A and B haplotypes have the frameworks genes [86, 93].

against one particular pathology or predisposition to the other.

surface of the cells and a specific KIR, inhibitor or activator.

KIR3DL3 have not been identified to date [95, 96].

same time, it is believed that the inhibitory signal prevails [96].

**4.6. KIR ligands**

KIR2DS1 [95].

**Figure 9.** Domain structure of the KIR molecules. The structural characteristics of two and three Ig-like domain KIR proteins are shown. The association of activating KIR to adaptor molecules is shown in green, whereas the ITIM of inhibitory KIR are shown as red boxes. KIR2DL4 contains signature sequences of both activating and inhibitory receptors [86].

exon 6 encodes the tail, which lies between the extracellular domain and the membrane; exon 7, the transmembrane portion; and exons 8 and 9 encode the cytoplasmic tail [91].

#### **4.5.** *KIR* **haplotypes**

The *KIR* genes in the LRC form haplotypes on the same chromosome passed in blocks from generation to generation. There are two groups of *KIR* haplotypes: A and B, differentiated mainly by the number of activator *KIR* genes [92].

The A haplotype has seven *KIR* genes, predominantly the genes that encode the inhibitor receptors, such as *KIR2DL1, KIR2DL3, KIR2DL4, KIR3DL1, KIR3DL2* and *KIR3DL3*, with only one activator gene, *KIR2DS4*. The B haplotype has a greater diversity of genes: *KIR2DL5, KIR2DL2, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5* and *KIR3DS1*, with the activation signals predominating. A and B haplotypes have the frameworks genes [86, 93].

The KIR Nomenclature Committee considered that the distinction between A and B haplotypes is useful in biological and clinical terms, and thus developed a consistent and logical set of criteria to distinguish them. Therefore, a haplotype can, for example, be called KH-001A or KH-022B [86]. The haplotypic diversity of *KIR* genes varies in different populations, suggesting that there may be variable effects of the receptors on several diseases, offering protection against one particular pathology or predisposition to the other.

#### **4.6. KIR ligands**

exon 6 encodes the tail, which lies between the extracellular domain and the membrane; exon 7,

**Figure 9.** Domain structure of the KIR molecules. The structural characteristics of two and three Ig-like domain KIR proteins are shown. The association of activating KIR to adaptor molecules is shown in green, whereas the ITIM of inhibitory KIR are shown as red boxes. KIR2DL4 contains signature sequences of both activating and inhibitory

The *KIR* genes in the LRC form haplotypes on the same chromosome passed in blocks from generation to generation. There are two groups of *KIR* haplotypes: A and B, differentiated

The A haplotype has seven *KIR* genes, predominantly the genes that encode the inhibitor receptors, such as *KIR2DL1, KIR2DL3, KIR2DL4, KIR3DL1, KIR3DL2* and *KIR3DL3*, with only

the transmembrane portion; and exons 8 and 9 encode the cytoplasmic tail [91].

**4.5.** *KIR* **haplotypes**

receptors [86].

mainly by the number of activator *KIR* genes [92].

130 Hansen's Disease - The Forgotten and Neglected Disease

NK cells perform the recognition of foreign cells in the body through the interaction of KIRs on own cell surface with ligands on target cells surface: classical class I HLA-specific molecules (HLA-A, HLA-B and HLA-C) and non-classical (HLA-E and HLA-G) [94]. The activity of NK cells requires the interaction between a given class I HLA antigen expressed on the surface of the cells and a specific KIR, inhibitor or activator.

HLA-C molecules are the major ligands of KIR and can be distinguished in two groups of ligands (C1 and C2). All HLA-C carry a valine (V) at position 76 and a dimorphism in the position 80, which may be asparagine (N) or lysine (K). The alleles that have asparagine at position 80 are called C1 group (codifying by *C\*01, C\*03, C\*07, C\*08, C\*12, C\*13, C\*14, C\*16:01, C\*16:03* and *C\*16:04*) and are the ligands of KIR2DL2/KIR2DL3 and KIR2DS2. On the other hand, the molecules that possess lysine at position 80 (K80) belong to the C2 group (codifying by *C\*02, C\*04, C\*05, C\*06, C\*15, C\*16:02, C\*17* and *C\*18* genes) and bind to KIR2DL1 and KIR2DS1 [95].

Some HLA-B molecules express Bw4 epitopes that are also present in some HLA-A molecules encoded by HLA-A\*09, HLA-A\*23, HLA-A\*24, HLA-A\*24:03, HLA-A\*25 and HLA-A\*32. The KIR3DL1 and the KIR3DS1 interact with HLA-Bw4, which differs from Bw6 due to a polymorphism at position 77 and 80. Bw4 molecules may have multiple amino acids at the position 77, either asparagine or aspartic acid or serine, and a dimorphism at the position 80, which may be isoleucine or threonine. The allotypes containing Bw4 with Isoleucine (Bw4-80I) generally exhibit strong inhibition, while Bw4 alleles with Threonine (Bw4-80 T), such as those encoded by HLA-B\*13, HLA-B\*27, HLA-B\*37:01 and HLA-B\*44, appear to be better ligands for certain KIR3DL1 subtypes. Other KIRs have less defined specificities, such as KIR3DL2, which recognizes HLA-A variants (A3 and A11), KIR2DL4 recognizing HLA-G and KIR2DS4 recognizing C\*04. The ligands for KIR2DL5, KIR2DS3, KIR2DS5, KIR3DS1 and KIR3DL3 have not been identified to date [95, 96].

Although KIR activators exhibit a ligand recognition structure very similar to inhibitory receptors, as in the 2DL1/2DS1-C2 group pair and the triad of 2DL2/2DL3/2DS2-C1 group, the binding affinity of the activating variants is strongly reduced in comparison to the inhibitory variants. Therefore, when there are binding of inhibitory and activating receptors at the same time, it is believed that the inhibitory signal prevails [96].

#### **4.7. Influence of** *KIR* **genes and ligands on leprosy**

It is known that the interaction of KIRs and their HLA ligands can result in activation or inhibition of NK cells and the occurrence of different immunological and clinical responses to various types of diseases, such as infectious diseases (AIDS, malaria, tuberculosis, Chagas disease, dengue fever and leprosy) [97–101], autoimmune and inflammatory diseases (psoriasis, rheumatoid vasculitis and Crohn's disease) [102–104] in different populations and ethnicities.

affecting the susceptibility to leprosy, resulting in different clinical manifestations or reactions. Hence, for a complete understanding of the genetic mechanisms of leprosy susceptibility, it will be necessary to join efforts to present a pattern of genes that would in fact be

This study was supported by Laboratory of Immunogenetics – UEM (Proc. No. 00639/99-DEG-UEM), Fundação Araucária (State of Parana Research Foundation), CNPq (National Council for Scientific and Technological Development) and CAPES Foundation (Coordination for the Improvement of Higher Education Personnel). The authors are grateful to Prof Steven GE Marsh, Anthony Nolan Research Institute, London, UK for permission to reproduce this

, Ana Maria Sell<sup>1</sup>

1 Post-Graduation Program of Biosciences and Physiopathology, Department of Clinical

[1] Eichelmann K, González González SE, Salas-Alanis JC, Ocampo-Candiani J. Leprosy. An update: Definition, pathogenesis, classification, diagnosis, and treatment. Actas Dermo-

[2] Klioze AM, Ramos-Caro FA. Visceral leprosy. International Journal of Dermatology. Sep

[3] World Health Organization. Global leprosy update, 2016: Accelerating reduction of dis-

[4] Moraes MO, Cardoso CC, Vanderborght PR, Pacheco AG. Genetics of host response in

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[5] Britton WJ, Lockwood DNJ. Leprosy. Lancet. Apr 10, 2004;**363**(9416):1209-1219

Analysis and Biomedicine, Maringa State University, Maringá, Parana, Brazil

2 Immunogenetics Laboratory – Basic Health Sciences Department, Maringa State

and

Immunogenetics of *MHC* and *KIR* in the Leprosy http://dx.doi.org/10.5772/intechopen.75253 133

important to predict a clinical form or more severe reaction of the disease.

, Bruna Tiaki Tiyo1

\*Address all correspondence to: jelvisentainer@gmail.com

**Acknowledgements**

graph authors.

**Author details**

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Jeane Eliete Laguila Visentainer1,2\*

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The pioneering studies of *KIR* genes in leprosy were carried out in Brazil. The first study was performed in the southern region of Brazil, where the *KIR2DL1* inhibitor gene with its C2 group ligand was shown to be protective for BB and its homozygous ligand (*KIR2DL1*-C2/C2) was associated with the clinical form TT. Another inhibitory gene and its ligands (*KIR3DL2*-A\*03/A\*11) were associated with susceptibility to borderline leprosy. The activating genes *KIR2DS2* and *KIR2DS3* were shown to be a risk factor for TT form, compared to the more widespread form LL. Thus, TT patients with both activating genes (*KIR2DS2* and *KIR2DS3*) may develop better activation of NK cells and a competent cellular immune response with a more localized manifestation of the disease. The inhibitory *KIR2DL3*-C1 and *KIR2DL3*-C1/C1 were associated to protection against TT form, when compared to the control group and other clinical forms [105].

The second study of *KIR* genes with leprosy was performed in a hyperendemic region of Brazil, and the *KIR2DL1* inhibitory gene was a protective factor for leprosy *per se* and its BB form. The frequency of the homozygous *KIR2DL2* gene in the presence of the C1 group (*KIR2DL2*/*KIR2DL2*-C1) was higher in leprosy patients *per se* and in clinical forms TT and LL, when compared to the control group. The *KIR2DL2*/*KIR2DL3* haplotype with its homozygous C1 ligand (C1/C1) was associated with protection for leprosy *per se* and TT and LL forms [17].

The inhibitory effect of *KIR2DL2*/*2DL2*-C1 may contribute to the development of leprosy, mainly to a worse prognosis in *M. leprae* infections. The activating *KIR2DS2* gene with its C1 ligand was a risk factor for leprosy *per se* and the clinical form TT. In this same study, it was observed that higher frequency of inhibitory genes may favor the susceptibility of the development of the disease [17]. Thus, this study confirmed the influence of *KIR* genes and their HLA ligands on the immunopathology of leprosy.

Activating and inhibitory *KIR* genes in the presence of their HLA ligands may have an impact on the development of leprosy and its clinical forms. The balance between these genes may interfere with the progression of the disease to a more localized (TT) or disseminated (LL), or to maintain an intermediate pattern between the two poles (BB), thus highlighting the role of NK cells and the production of cytokines.

## **5. Conclusions**

This chapter outlined the contribution of the innate and adaptive immune genes to leprosy pathogenesis, highlighting the *HLA*, *KIR* and *MIC* polymorphism genes contribution for clinical forms and reactions of leprosy. Immune responses against the *M. leprae* vary considerably between populations, which can be partly attributed to the genetic variation of the immune response to ensure the survival of populations. HLA and non-HLA genes should act together affecting the susceptibility to leprosy, resulting in different clinical manifestations or reactions. Hence, for a complete understanding of the genetic mechanisms of leprosy susceptibility, it will be necessary to join efforts to present a pattern of genes that would in fact be important to predict a clinical form or more severe reaction of the disease.
