**3.** *MIC* **genes**

The findings of new immune response genes are occurring in order to clarify their possible participation in the occurrence or severity of a disease. Among them, we can highlight *MIC* (MHC class I chain-related genes) that were discovered during a search for new coding sequences, located near the *HLA-B* gene [55].

*MIC* constitutes a second lineage of non-classical *MHC* class I genes and correspond to the *MICA, MICB, MICC, MICD, MICE, MICF* and *MICG loci* (**Figure 6**). *MICA* genes are located on the short arm of chromosome 6 (6p21.3), about 46.5 kb from HLA-B toward the centromere. Only *MICA* and *MICB* are expressed in proteins that belong to the immunoglobulin superfamily (IgSF) [56–58].

Like classical HLA genes, *MICA* also shows a high polymorphism in humans, whereas *MICB* appears to be less polymorphic, although it has been little explored. Since the discovery and characterization of NKG2D as its corresponding receptor in NK cells and in subsets of T cells, these genes have received increasing attention in the context of organs and stem cell

Immunogenetics of *MHC* and *KIR* in the Leprosy http://dx.doi.org/10.5772/intechopen.75253 125

**Figure 6.** Genes and pseudogenes of the *MIC* family on region class I of the human MHC. Functional genes are represented in blue and the pseudogenes in yellow.

transplantation. *MICA* and *MICB* encode glycoproteins, which are stress induced and can be recognized by receptors such as NKG2D (C-type lectin-like activating immunoreceptor). They are capable of inducing immune responses involving Tγδ cells and NK cells, independently of the processing of conventional class I MHC antigens [57, 59, 60].

#### **3.1. Structure of the MIC molecule**

**3.** *MIC* **genes**

*DRB1\*15:01- DRB5\*01:01- DQA1\*01:02- DQB1\*05:02*

family (IgSF) [56–58].

sequences, located near the *HLA-B* gene [55].

**Table 3.** Associations between *HLA* class II and leprosy.

The findings of new immune response genes are occurring in order to clarify their possible participation in the occurrence or severity of a disease. Among them, we can highlight *MIC* (MHC class I chain-related genes) that were discovered during a search for new coding

MB: multibacillary, PB: paucibacillary; B: borderline leprosy, BB: borderline borderline, BL: borderline lepromatous, BT: borderline tuberculoide, LL: lepromatous leprosy; TT: tuberculoid leprosy, *per se*: Leprosy independent of specific clinical manifestations, ENL: type 2 reactions or erythema nodosum leprosum, RR: type 1 or reversal reaction.

**Allele, haplotype Population Population size Phenotype Association**

BL/LL Susceptibility [52]

LL Susceptibility [39]

TT Susceptibility [39]

TT Susceptibility [53]

TT Susceptibility [54]

LL Susceptibility [20]

BL Susceptibility [46]

LL Susceptibility [39]

TT Protection [53]

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

Indian 85 leprosy patients and 104 healthy individuals

*DRB1\*15:02* Southern Indian 230 leprosy-affected sib-pair TT Susceptibility [48]

*DRB1\*15:01* North Indian 113 leprosy patients and 111

124 Hansen's Disease - The Forgotten and Neglected Disease

*DRB1\*15:01* Indian 93 leprosy patients and 47

*DRB1\*15:02* Indian 93 leprosy patients and 47

*DRB1\*15:02* Indian 85 leprosy patients and 104

*DRB1\*15:02* Asian Indian 27 leprosy patients and 19

*DRB1\*16* Brazilian 85 leprosy patients and 85

*DRB1\*16:01* Brazilian 169 leprosy patients and 217

*DRB5\*01:01* Indian 93 leprosy patients and 47

*MIC* constitutes a second lineage of non-classical *MHC* class I genes and correspond to the *MICA, MICB, MICC, MICD, MICE, MICF* and *MICG loci* (**Figure 6**). *MICA* genes are located on the short arm of chromosome 6 (6p21.3), about 46.5 kb from HLA-B toward the centromere. Only *MICA* and *MICB* are expressed in proteins that belong to the immunoglobulin super-

Like classical HLA genes, *MICA* also shows a high polymorphism in humans, whereas *MICB* appears to be less polymorphic, although it has been little explored. Since the discovery and characterization of NKG2D as its corresponding receptor in NK cells and in subsets of T cells, these genes have received increasing attention in the context of organs and stem cell MICA molecules are codominantly expressed and are polypeptides of 383–389 amino acids with a size of 43 kDa in length [56, 57] and the MICB molecules are also polypeptides with a similarity of 83% amino acids with MICA. The structure of the MICA molecule is similar to HLA class I antigens, with three extracellular domains (α1, α2 and α3), a transmembrane domain and a cytoplasmic tail. MICA molecules have an extremely flexible rod connected to the platform formed by the α1/α2 domains and the α3 domain. Four α-helices are arranged under eight pleated β-strands forming a reduced slit that it would not be possible to attach a peptide composed of more than three or four amino acid residues (**Figure 7**) [61].

**Figure 7.** The structure of the *MICA*. Exon 2 encodes a leader peptide, exons 2–4 encode three extracellular domains, exon 5 a transmembrane domain and exon 6 a cytoplasmic tail [61].

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

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

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

Immunogenetics of *MHC* and *KIR* in the Leprosy http://dx.doi.org/10.5772/intechopen.75253 127

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,

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

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,

**4.1. Natural killer cells**

the T cell receptor (TCR) is absent [77].

and influence the individual's immune response [78].

(NKR2B4: natural killer cell receptor 2B4) [75].

**4.2. KIR molecules**

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 later in another study [66].

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

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

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

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