**2. Major histocompatibility complex**

#### **2.1. Introduction**

The major histocompatibility complex (MHC) is composed of several genes, some of which are capable of encoding molecules that will display antigenic peptides on the cell surface for recognition by T cells. Other genes encode heat shock proteins, some cytokines and complement factors and approximately 40% of them have some function in the immune system [25, 26].

In relation to antigen presentation on the cell surface, the antigenic peptides originate from several sources, such as intracellular bacteria and viruses, products of cellular metabolism or proteins and lipids own or foreign to the organism [26].

In humans, a MHC sub region, called human leukocyte antigen (HLA), is located on the short arm of chromosome 6 and gives rise to HLA class I and II molecules. The HLA is polymorphic and each locus has many alleles contributing to human diversity as well as meeting the need for presentation of a wide range of antigens. The set of *HLA* alleles present on each chromosome is called haplotype, so all heterozygous individuals have two codominant *HLA* haplotypes [25, 27].

Understanding the mechanism of the presentation of antigens is of great importance for immunology, since it is able to explain events such as transplant rejection, autoimmune diseases, tumor immunity and response to infection, such as leprosy [28].

#### **2.2. Structural characteristics**

These genes are generally those that participate in the immune response in leprosy, such as cytokine genes, *HLA* (human leukocyte antigen) genes, *MICA* (major histocompatibility complex class I chain-related protein A) and *KIR* (killer cell immunoglobulin-like genes receptors),

The two types of studies with molecular genetic markers are those of binding and association. The binding studies are related to the genetic mapping that allows the tracking of chromosomal regions linked to the disease. Gene-susceptibility/disease resistance studies are based on the comparison of the allelic frequencies of a genetic marker in populations (affected and

Recently, a new approach to identify genes involved in human diseases is being carried out; it is the so-called genome-wide association study (GWAS). This is an association study of the entire genome in which many single nucleotide polymorphisms (SNPs) are tested in healthy controls and patients, allowing the analysis of hundreds or thousands of these polymorphisms at the same time. Genetic markers are considered to be associated with disease phenotypes when there is a significant difference in the frequencies observed between these two groups [24]. These works with genetic markers are performed aiming to contribute to the early diagnosis, prognosis, understanding of pathophysiology and improvement in the treatment of the disease. Thus, the proposal of this chapter is to evidence the participation of some innate immune response genes, specifically, *HLA*, *MIC* and *KIR* genes, on overall leprosy and on evolution to

The major histocompatibility complex (MHC) is composed of several genes, some of which are capable of encoding molecules that will display antigenic peptides on the cell surface for recognition by T cells. Other genes encode heat shock proteins, some cytokines and complement factors and approximately 40% of them have some function in the immune system [25, 26].

In relation to antigen presentation on the cell surface, the antigenic peptides originate from several sources, such as intracellular bacteria and viruses, products of cellular metabolism or

In humans, a MHC sub region, called human leukocyte antigen (HLA), is located on the short arm of chromosome 6 and gives rise to HLA class I and II molecules. The HLA is polymorphic and each locus has many alleles contributing to human diversity as well as meeting the need for presentation of a wide range of antigens. The set of *HLA* alleles present on each chromosome is called haplotype, so all heterozygous individuals have two codominant *HLA*

Understanding the mechanism of the presentation of antigens is of great importance for immunology, since it is able to explain events such as transplant rejection, autoimmune dis-

eases, tumor immunity and response to infection, such as leprosy [28].

among others.

unaffected individuals) [23].

116 Hansen's Disease - The Forgotten and Neglected Disease

the various clinic forms of disease.

**2.1. Introduction**

haplotypes [25, 27].

**2. Major histocompatibility complex**

proteins and lipids own or foreign to the organism [26].

Each HLA molecule consists of a peptide-binding cleft, immunoglobulin (Ig)-like domains and transmembrane and cytoplasmic domains. Class I HLA has the α-chain encoded by MHC genes and the β2-microglobulin chain encoded by a non-MHC region. Class II HLA has both the α- and β-chain encoded in the MHC (**Figure 2**). The cleavage site is the site where the peptides are established during their presentation to the T lymphocytes. In addition, cleft are the polymorphic residues, that the amino acids responsible for differentiating the HLA from each other, as well as making the presentations more antigenic specific. The Ig domains are nonpolymorphic and are responsible for binding between HLA and T cell: class I HLA molecules bind to CD8+ T cells and HLA class II molecules bind to the helper T cells CD4+ T cells [29, 30].

#### **2.3. Nomenclature**

The convention for the use of a four-digit code to name *HLA* alleles and distinguish them from the nomenclature given to coded proteins was introduced by the Nomenclature Report 1987. Currently, an allele name can be composed of four, six or eight digits, depending on its sequence. The first two digits describe the allele family. The third and fourth digits refer to the way in which DNA sequences were discovered.

Alleles that are different in the initial four digits have differences in nucleotide substitutions, which alter in protein coding. The fifth and sixth digits are used to distinguish alleles that differ by the synonymous substitutions of nucleotides in the coded sequence. The seventh and eighth digits are used when the alleles differ by sequence polymorphisms in introns or in 5′ and 3′ untranslated regions.

Each HLA allele name has a unique number, corresponding to up to four sets of digits, separated by a colon. The first two sets of digits are assigned to all alleles and the other two only for longer names and when needed (**Figure 3**) [31].

**Figure 2.** Structure of the class I and II MHC molecules.

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