**2.4. HLA classical**

#### *2.4.1. HLA class I*

There are three classical *loci* belonging to MHC class I: *HLA-A*, *HLA-B* and *HLA-C*. They encode molecules that have the same name as their respective genes. HLA class I molecules are expressed in all nucleated cells and platelets, as these molecules present the antigenic peptides for CD8+ T lymphocytes, which kill infected cells or with tumor antigens. The *HLA-E*, *HLA-F* and *HLA-G loci* also belong to *HLA* class I, but are considered non-classical (**Figure 3**) [32]. They are expressed at low levels when compared to classical *HLA* class I as well as do not have as many polymorphisms, and their functions in the immune system are limited [29, 30].

### *2.4.2. HLA class II*

HLA class II molecules are expressed in dendritic cells, B lymphocytes, macrophages and other cell types, and present the antigenic peptides to the virulent CD4+ helper T lymphocytes, which recognize the antigens in the secondary lymphoid organs. Differentiated CD4+ helper T cells activate other cells, together with B lymphocytes, so that the extracellular microorganisms are eliminated. The three *HLA* class II *loci* are called *HLA-DP*, *HLA-DQ* and *HLA-DR*. The two chains of each molecule of class II are encoded by two different MHC genes. Thus, the extracellular parts of α and β chains are subdivided into two segments, A1 and A2, or B1 and B2, both of which are polymorphic chains, that is, each of the DP, DQ and DR *loci* contain separate genes designated as A or B, which encode α and β chains, respectively, in each copy of chromosome 6. Each individual has one HLA-DRA (DRA1), one to three DRB (DRB1 and DRB3, 4 and/or 5), one DQA (DQA1), one DQB (DQB1), one DPA (DPA1) and one DPB (DPB1) [25, 29, 30].

**2.6. HLA polymorphism**

**Figure 4.** Schematic map of the human *MHC* gene [32].

The immune system has the complex task of responding to different types of pathogens that come in contact with the human organism. Adaptation that ensures antigen protection and increased immune system efficiency can occur through life-long genetic recombination, such as antibody formation, or the different HLA molecules in the population. HLA molecules are responsible for presenting a fraction of the antigenic peptide (epitope) for T cells; however, the choice to determine which epitope will be presented according to the *HLA* genes and their alleles in each individual. Thus, the regions responsible for the antigenic presentation in the HLA molecules present high polymorphism rates. This means that with the advancement of diagnostic methodologies, the discovery of allelic variations of HLA has increased exponentially (**Figure 5**) [27, 29]. The evolutionary success in the amplification of the HLA repertoire may explain why it is difficult to associate a specific HLA phenotype with the susceptibility or protection against a particular disease, since the change of a single amino acid in the sequence of the HLA molecule can affect the adaptive immune response of the individual [32]. Despite this difficulty, studies have shown associations among several HLA and autoimmune and infectious diseases [27, 29].

Immunogenetics of *MHC* and *KIR* in the Leprosy http://dx.doi.org/10.5772/intechopen.75253 119

#### **2.5.** *MICA* **and** *MICB* **genes**

The human MHC class I chain-related genes (*MICA* and *MICB*) are located in the *HLA* class I region in chromosome 6, but are not part of the classical *HLA* (**Figure 4**). These genes show about 30% of homology to HLA class I, but the transcribed molecules do not present antigenic peptides on the cell surface. These genes are mainly transcribed into fibroblasts and epithelial cells. The MIC molecules bind to NKG2 receptors, activating NK cells and also modulate the function of CD8+ T cells. Studies have related associations of polymorphisms in *MICA* and *MICB* genes with several diseases (ankylosing spondylitis, psoriasis, dengue and tuberculosis) [32–36], one of them being leprosy, which will be discussed in a next topic in this chapter.

**Figure 4.** Schematic map of the human *MHC* gene [32].

#### **2.6. HLA polymorphism**

**2.4. HLA classical**

118 Hansen's Disease - The Forgotten and Neglected Disease

*2.4.1. HLA class I*

*2.4.2. HLA class II*

**2.5.** *MICA* **and** *MICB* **genes**

There are three classical *loci* belonging to MHC class I: *HLA-A*, *HLA-B* and *HLA-C*. They encode molecules that have the same name as their respective genes. HLA class I molecules are expressed in all nucleated cells and platelets, as these molecules present the antigenic peptides for CD8+ T lymphocytes, which kill infected cells or with tumor antigens. The *HLA-E*, *HLA-F* and *HLA-G loci* also belong to *HLA* class I, but are considered non-classical (**Figure 3**) [32]. They are expressed at low levels when compared to classical *HLA* class I as well as do not have as many polymorphisms, and their functions in the immune system are limited [29, 30].

**Figure 3.** Schematic example of the meanings for each code in the HLA nomenclature [31].

HLA class II molecules are expressed in dendritic cells, B lymphocytes, macrophages and other cell types, and present the antigenic peptides to the virulent CD4+ helper T lymphocytes, which recognize the antigens in the secondary lymphoid organs. Differentiated CD4+ helper T cells activate other cells, together with B lymphocytes, so that the extracellular microorganisms are eliminated. The three *HLA* class II *loci* are called *HLA-DP*, *HLA-DQ* and *HLA-DR*. The two chains of each molecule of class II are encoded by two different MHC genes. Thus, the extracellular parts of α and β chains are subdivided into two segments, A1 and A2, or B1 and B2, both of which are polymorphic chains, that is, each of the DP, DQ and DR *loci* contain separate genes designated as A or B, which encode α and β chains, respectively, in each copy of chromosome 6. Each individual has one HLA-DRA (DRA1), one to three DRB (DRB1 and DRB3, 4 and/or 5), one DQA (DQA1), one DQB (DQB1), one DPA (DPA1) and one DPB (DPB1) [25, 29, 30].

The human MHC class I chain-related genes (*MICA* and *MICB*) are located in the *HLA* class I region in chromosome 6, but are not part of the classical *HLA* (**Figure 4**). These genes show about 30% of homology to HLA class I, but the transcribed molecules do not present antigenic peptides on the cell surface. These genes are mainly transcribed into fibroblasts and epithelial cells. The MIC molecules bind to NKG2 receptors, activating NK cells and also modulate the function of CD8+ T cells. Studies have related associations of polymorphisms in *MICA* and *MICB* genes with several diseases (ankylosing spondylitis, psoriasis, dengue and tuberculosis) [32–36], one of them being leprosy, which will be discussed in a next topic in this chapter.

The immune system has the complex task of responding to different types of pathogens that come in contact with the human organism. Adaptation that ensures antigen protection and increased immune system efficiency can occur through life-long genetic recombination, such as antibody formation, or the different HLA molecules in the population. HLA molecules are responsible for presenting a fraction of the antigenic peptide (epitope) for T cells; however, the choice to determine which epitope will be presented according to the *HLA* genes and their alleles in each individual. Thus, the regions responsible for the antigenic presentation in the HLA molecules present high polymorphism rates. This means that with the advancement of diagnostic methodologies, the discovery of allelic variations of HLA has increased exponentially (**Figure 5**) [27, 29].

The evolutionary success in the amplification of the HLA repertoire may explain why it is difficult to associate a specific HLA phenotype with the susceptibility or protection against a particular disease, since the change of a single amino acid in the sequence of the HLA molecule can affect the adaptive immune response of the individual [32]. Despite this difficulty, studies have shown associations among several HLA and autoimmune and infectious diseases [27, 29].

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

Leprosy *per se* Susceptibility [37]

Immunogenetics of *MHC* and *KIR* in the Leprosy http://dx.doi.org/10.5772/intechopen.75253 121

Leprosy *per se* Susceptibility [38]

Leprosy *per se* Susceptibility [37]

MB Susceptibility [14]

Leprosy *per se* Susceptibility [37]

MB Susceptibility [14]

MB Protection [14]

Leprosy *per se* Protection [37]

B Protection [22]

Leprosy *per se* Susceptibility [38]

Leprosy *per se* Susceptibility [37]

MB Susceptibility [14]

Leprosy *per se* Susceptibility [38]

Leprosy *per se* Susceptibility [15]

ML Susceptibility [14]

Leprosy *per se* Protection [38]

LL Protection [38]

LL Protection [38]

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

*C\*15:05* Vietnamese 198 families Leprosy *per se* Susceptibility [15] *C\*15:05* Vietnamese 292 families Leprosy *per se* Susceptibility [15]

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 I or reversal reaction.

*B\*18:01* Southern Indian 32 leprosy patients and 67

*B\*35* Brazilian 225 leprosy patients and 450

*B\*38* Brazilian 225 leprosy patients and 450

*B\*51:10* Southern Indian 32 leprosy patients and 67

*B\*51:10* Mumbai/Indian 103 leprosy patients and 101

*C\*04* Brazilian 225 leprosy patients and 450

*C\*04:07* Southern Indian 32 leprosy patients and 67

*C\*04:07* Mumbai/Indian 103 leprosy patients and 101

*C\*04:11* Mumbai/Indian 103 leprosy patients and 101

*C\*04:11* Southern Indian 32 leprosy patients and 67

*C\*05* Brazilian 202 leprosy patients and 478

*C\*07* Brazilian 225 leprosy patients and 450

*C\*07:03* Southern Indian 32 leprosy patients and 67

*C\*07:03* Mumbai/Indian 103 leprosy patients and 101

*C\*12* Brazilian 225 leprosy patients and 450

*C\*16* Brazilian 225 leprosy patients and 450

*C\*15:05* Indian 364 leprosy patients and 371

*A\*11-B\*40* Mumbai/Indian 103 leprosy patients and 101

**Table 2.** Associations between *HLA* class I and leprosy.

**Figure 5.** Advances in the findings of allelic variations in *HLA* class I and II *loci* over the past 30 years. Class I *HLA* alleles are represented in green and class II *HLA* alleles in black [32].

#### **2.7. Influence of HLA on leprosy**

The role of HLA molecules in leprosy is to present epitopes of the bacillus to T lymphocytes. However, polymorphisms in *HLA* genes or incorrect presentation of the antigenic peptide may interfere or contribute to the success of the response of the host against the pathogen. In view of this, several studies have indicated genes associated with susceptibility or protection against leprosy in different populations (**Tables 2** and **3**).



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 I or reversal reaction.

**Table 2.** Associations between *HLA* class I and leprosy.

**2.7. Influence of HLA on leprosy**

120 Hansen's Disease - The Forgotten and Neglected Disease

**Allele, haplotype**

are represented in green and class II *HLA* alleles in black [32].

against leprosy in different populations (**Tables 2** and **3**).

*A\*02:06* Southern Indian 32 leprosy patients and 67

*A\*02:06* Mumbai/Indian 103 leprosy patients and 101

*A\*11* Brazilian 225 leprosy patients and 450

*A\*11:02* Southern Indian 32 leprosy patients and 67

*A\*11:02* Mumbai/Indian 103 leprosy patients and 101

*B\*15* Brazilian 202 leprosy patients and 478

*B\*18:01* Mumbai/Indian 103 leprosy patients and 101

The role of HLA molecules in leprosy is to present epitopes of the bacillus to T lymphocytes. However, polymorphisms in *HLA* genes or incorrect presentation of the antigenic peptide may interfere or contribute to the success of the response of the host against the pathogen. In view of this, several studies have indicated genes associated with susceptibility or protection

**Population Population size Phenotype Association**

Leprosy *per se* Susceptibility [37]

Leprosy *per se* Susceptibility [14]

Leprosy *per se* Susceptibility [38]

Leprosy *per se* Susceptibility [37]

Leprosy *per se* Susceptibility [14]

RR Susceptibility [22]

Leprosy *per se* Susceptibility [14]

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

**Figure 5.** Advances in the findings of allelic variations in *HLA* class I and II *loci* over the past 30 years. Class I *HLA* alleles


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

Leprosy *per se* Protection [44]

Immunogenetics of *MHC* and *KIR* in the Leprosy http://dx.doi.org/10.5772/intechopen.75253 123

B Protection [22]

LL Susceptibility [39]

LL Susceptibility [46]

Leprosy *per se* Protection [47]

Leprosy *per se* Protection [49]

Leprosy *per se* Susceptibility [44]

Leprosy *per se* Susceptibility [44]

LL Protection [50]

Leprosy *per se* Protection [47]

Leprosy *per se* Protection [44]

Leprosy *per se* Protection [43]

TT Susceptibility [20]

Leprosy *per se* Susceptibility [47]

Leprosy *per se* Susceptibility [47]

Leprosy *per se* Susceptibility [44]

Leprosy *per se* Susceptibility [44]

Leprosy *per se* Susceptibility [49]

TT Susceptibility [39]

LL Susceptibility [39]

TT Susceptibility [51]

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

*DRB1\*10* Vietnam 194 single-case families Leprosy *per se* Susceptibility [44]

*DRB1\*09* Southern Indian 230 leprosy-affected sib-pair TT Protection [48]

*DRB1\*07* Brazilian 578 leprosy patients and 691

*DRB1\*07* Brazilian 202 leprosy patients and 478

*DRB1\*07:01* Indian 93 leprosy patients and 47

*DRB1\*08* Brazilian 169 leprosy patients and 217

*DRB1\*08:08* Argentinean 71 leprosy patients and 81

*DRB1\*09* Chinese 305 leprosy patients and 527

*DRB1\*10* Brazilian 578 leprosy patients and 691

*DRB1\*10* Afro-Brazilian 578 leprosy patients and 691

*DRB1\*11* Brazilian 70 leprosy patients and 77

*DRB1\*11:03* Argentinean 71 leprosy patients and 81

*DRB1\*12* Brazilian 578 leprosy patients and 691

*DRB1\*12* Japanese 79 leprosy patients and 50

*DRB1\*14* Brazilian 85 leprosy patients and 85

*DRB1\*14:01* Argentinean 71 leprosy patients and 81

*DRB1\*14:06* Argentinean 71 leprosy patients and 81

*DRB1\*15* Afro-Brazilian 578 leprosy patients and 691

*DRB1\*15* Brazilian 578 leprosy patients and 691

*DRB1\*15* Chinese 305 leprosy patients and 527

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

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

*DRB1\*15* Indian 54 leprosy patients and 44


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

LL Susceptibility [39]

LL Susceptibility [39]

LL Susceptibility [39]

Leprosy *per se* Protection [40]

B Protection [22]

LL Protection [42]

LL Protection [42]

LL Protection [42]

Leprosy *per se* Protection [40]

TT Protection [39]

TT Susceptibility [39]

LL Susceptibility [39]

BL/LL Susceptibility [43]

Leprosy *per se* Protection [44]

Leprosy *per se* Protection [44]

TT Protection [42]

Leprosy *per se* Protection [40]

MB Protection [45]

Leprosy *per se* Protection [44]

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

healthy individuals

*DRB1\*07* Brazilian 76 families (1166 individuals) Leprosy *per se* Protection [41]

*DRB1\*04* Vietnam 194 single-case families Leprosy *per se* Protection [44]

*DQB1\*05:01* Brazilian 76 families (1166 individuals) TT Susceptibility [41] *DQB1\*05:01* Brazilian 76 families (1166 individuals) Leprosy *per se* Susceptibility [41]

*DQB1\*02:01* Brazilian 76 families (1166 individuals) TT Protection [41] *DQB1\*02:01* Brazilian 76 families (1166 individuals) Leprosy *per se* Protection [41]

*DQA1\*01:02* Indian 93 leprosy patients and 47

122 Hansen's Disease - The Forgotten and Neglected Disease

*DQA1\*01:03* Indian 93 leprosy patients and 47

*DQA1\*02:01* Indian 93 leprosy patients and 47

*DQA1\*03* Japanese 93 leprosy patients and 114

*DQB1\*02* Brazilian 202 leprosy patients and 478

*DQB1\*02:01* Argentinean 89 leprosy patients and 112

*DQB1\*02:02* Argentinean 89 leprosy patients and 112

*DQB1\*02:03* Argentinean 89 leprosy patients and 112

*DQB1\*04:01* Japanese 93 leprosy patients and 114

*DQB1\*05:03* Indian 93 leprosy patients and 47

*DQB1\*06:01* Indian 93 leprosy patients and 47

*DQB1\*06:01* Indian 93 leprosy patients and 47

*DRB1\*02* Japanese 79 leprosy patients and 50

*DRB1\*04* Brazilian 578 leprosy patients and 691

*DRB1\*04* Euro-Brazilian 578 leprosy patients and 691

*DRB1\*04* Argentinean 89 leprosy patients and 112

*DRB1\*04:05* Japanese 93 leprosy patients and 114

*DRB1\*04:05* Taiwanese 65 leprosy patients and 190

*DRB1\*07* Euro-Brazilian 578 leprosy patients and 691


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, indepen-

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

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

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

**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].

dently of the processing of conventional class I MHC antigens [57, 59, 60].

peptide composed of more than three or four amino acid residues (**Figure 7**) [61].

**3.1. Structure of the MIC molecule**

represented in blue and the pseudogenes in yellow.

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.

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