Correlation between the classifications of Madrid [8], Ridley and Jopling [9] and WHO [10, 11] adopted for leprosy.
Abstract
Several genetic polymorphisms in immune response genes have been associated to leprosy. This fact converges on the main hypothesis that genetic factors are involved in the disease susceptibility in two distinct steps: leprosy per se and their clinical forms. These genes play an important role in the recognition process, in the activation of the main metabolic pathway of the immune response and in the evolution of the disease. The scope of this project was to highlight the role of the immune response genes in the context of leprosy, emphasizing the participation of some of them in the signaling and targeting processes in response to bacillus infection and on disease evolution, such as HLA, KIR and MIC genes. Some environmental and genetic factors are important when the exposure to the bacillus occurs, leading to cure or not. Factors that favor a cellular or humoral immune response may influence the clinical manifestations after the infection inducting to one of extreme poles. Furthermore, some genetic factors were associated to the type of reaction that some individuals present during the disease development. Thus, it is very important to highlight the participation of some genetic factors in the immunopathogenesis of leprosy.
Keywords
- leprosy
- HLA genes
- MICA genes
- KIR genes
- genetic predisposition
- genetic polymorphism
1. Introduction
Leprosy is a chronic infectious granulomatous disease caused by the obligate intracellular bacillus
Leprosy is an important endemic disease, considered as a serious public health and social problem worldwide, as it leads to neural impairment or physical disability. Thus, special attention is needed, due to the consequences in the socioeconomic life of the patients or even their possible sequels in those who are cured. Worldwide, leprosy cases spread across more than 140 countries, with 22 countries accounting for 95% of global leprosy. These countries such as India, Brazil, Indonesia, Democratic Republic of Congo, Ethiopia, Nepal, Bangladesh and others have a high detection rate [3].
Bacillus has a high infectivity and low pathogenicity, that is, it infects many people, but only few become ill [1]. Leprosy is influenced by host genetic and mycobacterial factors, and environmental factors such as nutritional status and rate of exposure to bacillus. The immune response is of fundamental importance for the body’s defense against exposure to the bacillus, but in some individuals, leprosy can lead to changes in the immune response and to the development of distinct clinical forms. Among those who fall ill, the degree of immunity varies by determining the clinical form and course of the disease [4].
The immune response to the
The predominance of cellular or humoral immune response may influence the evolution of the leprosy and the clinical characteristics observed in the tuberculoid (TT) and lepromatous (LL) clinical forms. The patients with the TT form have a strong cellular immune response, with a predominance of Th1 cells, activation of macrophages and Th1 cytokines secretion, such as interleukin (IL)-2, IL-6, IL-12, IL-15, IL-18, tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), limiting the disease to few localized lesions of the skin and peripheral nerves. Patients with the LL form present a humoral response and lack of cellular response, with a predominance of CD8+ suppressor T cells and Th2 standard cytokines, such as IL-4, IL-5, IL-10 and IL-13, which inhibit the activation of macrophages. Here there is a proliferation of bacillus and presence of many lesions in the skin and peripheral nerves [5–7].
The disease can be classified into three forms: (i) Madrid (1953) classification, based on clinical and bacteriological criteria [8]; (ii) Classification of Ridley and Jopling (1966) that emphasizes clinical, bacteriological, immunological and histological aspects [9] and (iii) World Health Organization (WHO) (1982) operational classification with therapeutic purpose, based on the bacilloscopic index, which is related to the clinical forms [10]. In 1988, this operational classification was updated and clinical criteria were also established, considering paucibacillary (PB) patients such as those with less than five cutaneous lesions and/or one affected nerve trunk and multibacillary (MB) such as those with more than six lesions and/or more than one affected nerve trunk. It is still considered MB when the bacilloscopy is positive, regardless the number of lesions [11]. The classifications adopted for clinical forms of leprosy such as Madrid, Ridley and Jopling and WHO are summarized and listed in Table 1.
WHO | Paucibacillary (PB) | Multibacillary (MB) | ||
---|---|---|---|---|
MADRID | Indetermined (I) | Tuberculoid (T) | Dimorph (D) | Virchowian (V) |
Ridley and Jopling | TT | BT BB BL | LL |
At present, it is known that there are several factors influencing the control and appearance of the disease, such as immune response, time of exposure to bacillus, virulence of the pathogen, environmental factors, genetic variation of the bacillus and, mainly, the immunogenetic variability of the host leading to susceptibility or resistance to leprosy
The selection of candidate genes in disease pathogenesis is usually based on two criteria: functional genes with a critical role in the pathogenesis of the disease and the location in the genomic region that may be involved in disease control; and yet a combination of the both. These genes are generally those that participate in the immune response in leprosy, such as cytokine genes,
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 unaffected individuals) [23].
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,
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
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
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 non-polymorphic 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
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].
2.4. HLA classical
2.4.1. HLA class I
There are three classical
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
2.5. MICA and MICB genes
The human MHC class I chain-related genes (
2.6. HLA polymorphism
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
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].
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
Allele, haplotype | Population | Population size | Phenotype | Association |
---|---|---|---|---|
Southern Indian | 32 leprosy patients and 67 healthy individuals | Leprosy | Susceptibility [37] | |
Mumbai/Indian | 103 leprosy patients and 101 healthy individuals | Leprosy | Susceptibility [14] | |
Brazilian | 225 leprosy patients and 450 healthy individuals | Leprosy | Susceptibility [38] | |
Southern Indian | 32 leprosy patients and 67 healthy individuals | Leprosy | Susceptibility [37] | |
Mumbai/Indian | 103 leprosy patients and 101 healthy individuals | Leprosy | Susceptibility [14] | |
Brazilian | 202 leprosy patients and 478 healthy individuals | RR | Susceptibility [22] | |
Mumbai/Indian | 103 leprosy patients and 101 healthy individuals | Leprosy | Susceptibility [14] | |
Southern Indian | 32 leprosy patients and 67 healthy individuals | Leprosy | Susceptibility [37] | |
Brazilian | 225 leprosy patients and 450 healthy individuals | LL | Protection [38] | |
Brazilian | 225 leprosy patients and 450 healthy individuals | Leprosy | Susceptibility [38] | |
Southern Indian | 32 leprosy patients and 67 healthy individuals | Leprosy | Susceptibility [37] | |
Mumbai/Indian | 103 leprosy patients and 101 healthy individuals | MB | Susceptibility [14] | |
Brazilian | 225 leprosy patients and 450 healthy individuals | LL | Protection [38] | |
Southern Indian | 32 leprosy patients and 67 healthy individuals | Leprosy | Susceptibility [37] | |
Mumbai/Indian | 103 leprosy patients and 101 healthy individuals | MB | Susceptibility [14] | |
Mumbai/Indian | 103 leprosy patients and 101 healthy individuals | MB | Protection [14] | |
Southern Indian | 32 leprosy patients and 67 healthy individuals | Leprosy | Protection [37] | |
Brazilian | 202 leprosy patients and 478 healthy individuals | B | Protection [22] | |
Brazilian | 225 leprosy patients and 450 healthy individuals | Leprosy | Susceptibility [38] | |
Southern Indian | 32 leprosy patients and 67 healthy individuals | Leprosy | Susceptibility [37] | |
Mumbai/Indian | 103 leprosy patients and 101 healthy individuals | MB | Susceptibility [14] | |
Brazilian | 225 leprosy patients and 450 healthy individuals | Leprosy | Susceptibility [38] | |
Brazilian | 225 leprosy patients and 450 healthy individuals | Leprosy | Protection [38] | |
Indian | 364 leprosy patients and 371 healthy individuals | Leprosy | Susceptibility [15] | |
Vietnamese | 198 families | Leprosy | Susceptibility [15] | |
Vietnamese | 292 families | Leprosy | Susceptibility [15] | |
Mumbai/Indian | 103 leprosy patients and 101 healthy individuals | ML | Susceptibility [14] |
Allele, haplotype | Population | Population size | Phenotype | Association |
---|---|---|---|---|
Indian | 93 leprosy patients and 47 healthy individuals | LL | Susceptibility [39] | |
Indian | 93 leprosy patients and 47 healthy individuals | LL | Susceptibility [39] | |
Indian | 93 leprosy patients and 47 healthy individuals | LL | Susceptibility [39] | |
Japanese | 93 leprosy patients and 114 healthy individuals | Leprosy | Protection [40] | |
Brazilian | 202 leprosy patients and 478 healthy individuals | B | Protection [22] | |
Brazilian | 76 families (1166 individuals) | TT | Protection [41] | |
Brazilian | 76 families (1166 individuals) | Leprosy | Protection [41] | |
Argentinean | 89 leprosy patients and 112 healthy individuals | LL | Protection [42] | |
Argentinean | 89 leprosy patients and 112 healthy individuals | LL | Protection [42] | |
Argentinean | 89 leprosy patients and 112 healthy individuals | LL | Protection [42] | |
Japanese | 93 leprosy patients and 114 healthy individuals | Leprosy | Protection [40] | |
Brazilian | 76 families (1166 individuals) | TT | Susceptibility [41] | |
Brazilian | 76 families (1166 individuals) | Leprosy | Susceptibility [41] | |
Indian | 93 leprosy patients and 47 healthy individuals | TT | Protection [39] | |
Indian | 93 leprosy patients and 47 healthy individuals | TT | Susceptibility [39] | |
Indian | 93 leprosy patients and 47 healthy individuals | LL | Susceptibility [39] | |
Japanese | 79 leprosy patients and 50 healthy individuals | BL/LL | Susceptibility [43] | |
Brazilian | 578 leprosy patients and 691 healthy individuals | Leprosy | Protection [44] | |
Euro-Brazilian | 578 leprosy patients and 691 healthy individuals | Leprosy | Protection [44] | |
Vietnam | 194 single-case families | Leprosy | Protection [44] | |
Argentinean | 89 leprosy patients and 112 healthy individuals | TT | Protection [42] | |
Japanese | 93 leprosy patients and 114 healthy individuals | Leprosy | Protection [40] | |
Taiwanese | 65 leprosy patients and 190 healthy individuals | MB | Protection [45] | |
Brazilian | 76 families (1166 individuals) | Leprosy | Protection [41] | |
Euro-Brazilian | 578 leprosy patients and 691 healthy individuals | Leprosy | Protection [44] | |
Brazilian | 578 leprosy patients and 691 healthy individuals | Leprosy | Protection [44] | |
Brazilian | 202 leprosy patients and 478 healthy individuals | B | Protection [22] | |
Indian | 93 leprosy patients and 47 healthy individuals | LL | Susceptibility [39] | |
Brazilian | 169 leprosy patients and 217 healthy individuals | LL | Susceptibility [46] | |
Argentinean | 71 leprosy patients and 81 healthy individuals | Leprosy | Protection [47] | |
Southern Indian | 230 leprosy-affected sib-pair | TT | Protection [48] | |
Chinese | 305 leprosy patients and 527 healthy individuals | Leprosy | Protection [49] | |
Brazilian | 578 leprosy patients and 691 healthy individuals | Leprosy | Susceptibility [44] | |
Afro-Brazilian | 578 leprosy patients and 691 healthy individuals | Leprosy | Susceptibility [44] | |
Vietnam | 194 single-case families | Leprosy | Susceptibility [44] | |
Brazilian | 70 leprosy patients and 77 healthy individuals | LL | Protection [50] | |
Argentinean | 71 leprosy patients and 81 healthy individuals | Leprosy | Protection [47] | |
Brazilian | 578 leprosy patients and 691 healthy individuals | Leprosy | Protection [44] | |
Japanese | 79 leprosy patients and 50 healthy individuals | Leprosy | Protection [43] | |
Brazilian | 85 leprosy patients and 85 healthy individuals | TT | Susceptibility [20] | |
Argentinean | 71 leprosy patients and 81 healthy individuals | Leprosy | Susceptibility [47] | |
Argentinean | 71 leprosy patients and 81 healthy individuals | Leprosy | Susceptibility [47] | |
Afro-Brazilian | 578 leprosy patients and 691 healthy individuals | Leprosy | Susceptibility [44] | |
Brazilian | 578 leprosy patients and 691 healthy individuals | Leprosy | Susceptibility [44] | |
Chinese | 305 leprosy patients and 527 healthy individuals | Leprosy | Susceptibility [49] | |
Indian | 93 leprosy patients and 47 healthy individuals | TT | Susceptibility [39] | |
Indian | 93 leprosy patients and 47 healthy individuals | LL | Susceptibility [39] | |
Indian | 54 leprosy patients and 44 healthy individuals | TT | Susceptibility [51] | |
North Indian | 113 leprosy patients and 111 healthy individuals | BL/LL | Susceptibility [52] | |
Indian | 93 leprosy patients and 47 healthy individuals | LL | Susceptibility [39] | |
Southern Indian | 230 leprosy-affected sib-pair | TT | Susceptibility [48] | |
Indian | 93 leprosy patients and 47 healthy individuals | TT | Susceptibility [39] | |
Indian | 85 leprosy patients and 104 healthy individuals | TT | Susceptibility [53] | |
Asian Indian | 27 leprosy patients and 19 healthy individuals | TT | Susceptibility [54] | |
Brazilian | 85 leprosy patients and 85 healthy individuals | LL | Susceptibility [20] | |
Brazilian | 169 leprosy patients and 217 healthy individuals | BL | Susceptibility [46] | |
Indian | 93 leprosy patients and 47 healthy individuals | LL | Susceptibility [39] | |
Indian | 85 leprosy patients and 104 healthy individuals | TT | Protection [53] |
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
Like classical HLA genes,
3.1. Structure of the MIC molecule
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].
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
The expression of the
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
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
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
In the first study of association between the
4. Killer cell immunoglobulin-like receptors (KIRs)
4.1. Natural killer cells
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: (
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
The
4.4. Structure and nomenclature of KIR
The naming of
The
4.5. KIR haplotypes
The
The A haplotype has seven
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
4.6. KIR ligands
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
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.
The pioneering studies of
The second study of
The inhibitory effect of
Activating and inhibitory
5. Conclusions
This chapter outlined the contribution of the innate and adaptive immune genes to leprosy pathogenesis, highlighting the
Acknowledgments
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 graph authors.
References
- 1.
Eichelmann K, González González SE, Salas-Alanis JC, Ocampo-Candiani J. Leprosy. An update: Definition, pathogenesis, classification, diagnosis, and treatment. Actas Dermo-Sifiliográficas. Sep 2013; 104 (7):554-563 - 2.
Klioze AM, Ramos-Caro FA. Visceral leprosy. International Journal of Dermatology. Sep 2000; 39 (9):641-658 - 3.
World Health Organization. Global leprosy update, 2016: Accelerating reduction of disease burden. Releve Epidemiologique Hebdomadaire. 2017; 92 (35):501-520 - 4.
Moraes MO, Cardoso CC, Vanderborght PR, Pacheco AG. Genetics of host response in leprosy. Leprosy Review. 2006; 77 (3):189-202 - 5.
Britton WJ, Lockwood DNJ. Leprosy. Lancet. Apr 10, 2004; 363 (9416):1209-1219 - 6.
Mendonça VA, Costa RD, de Melo GEBA, Antunes CM, Teixeira AL. Immunology of leprosy. Anais Brasileiros de Dermatologia. 2008; 83 (4):343-350 - 7.
Ottenhoff TH. Immunology of leprosy: Lessons from and for leprosy. International Journal of Leprosy and other Mycobacterial Diseases: Official Organ of the International Leprosy Association. 1994; 62 (1):108-121 - 8.
Wade HW, Prieto JG, Vegas M, Basombrio G, Cochrane RG, Khanolhar VR, et al. The technical resolution on classification at the 6th international congress of leprosy, Madrid, 1953. International Journal of Leprosy. 1953; 21 :504-516 - 9.
Ridley DS, Jopling WH. Classification of leprosy according to immunity. A five-group system. International Journal of Leprosy and Other Mycobacterial Diseases. 1966; 34 (3):255-273 - 10.
Chemotherapy of leprosy for control programmes. World Health Organization Technical Report Series. 1982; 675 :1-33 - 11.
WHO Expert Committee on Leprosy. World Health Organization Technical Report Series. 1988; 768 :1-51 - 12.
Kim SJ, Choi IH, Dahlberg S, Nisperos B, Kim JD, Hansen JA. HLA and leprosy in Koreans. Tissue Antigens. Mar 1987; 29 (3):146-153 - 13.
Koçak M, Balcı M, Pençe B, Kundakçı N. Associations between human leukocyte antigens and leprosy in the Turkish population. Clinical and Experimental Dermatology. 2002; 27 (3):235-239 - 14.
Shankarkumar U. HLA associations in leprosy patients from Mumbai, India. Leprosy Review. 2004 Mar; 75 (1):79-85 - 15.
Alter A, Huong NT, Singh M, Orlova M, Van Thuc N, Katoch K, et al. Human leukocyte antigen class I region single-nucleotide polymorphisms are associated with leprosy susceptibility in Vietnam and India. The Journal of Infectious Diseases. May 2011; 203 (9):1274-1281 - 16.
do Sacramento WS, Mazini PS, Franceschi DAS, de Melo FC, Braga MA, Sell AM, et al. Frequencies of MICA alleles in patients from southern Brazil with multibacillary and paucibacillary leprosy. International Journal of Immunogenetics. Jun 2012; 39 (3):210-215 - 17.
Jarduli LR, Alves HV, de Souza-Santana FC, Marcos EVC, Pereira AC, Dias-Baptista IMF, et al. Influence of KIR genes and their HLA ligands in the pathogenesis of leprosy in a hyperendemic population of Rondonópolis, Southern Brazil. BMC Infectious Diseases. 2014; 14 (1):438 - 18.
Rani R, Zaheer SA, Mukherjee R. Do human leukocyte antigens have a role to play in differential manifestation of multibacillary leprosy: A study on multibacillary leprosy patients from North India. Tissue Antigens. Sep 1992; 40 (3):124-127 - 19.
Wang LM, Kimura A, Satoh M, Mineshita S. HLA Linked with leprosy in southern China: HLA-linked resistance alleles to leprosy. International Journal of Leprosy and Other Mycobacterial Diseases. 1999; 67 (4):403-408 - 20.
Corrêa R d GCF, de Aquino DMC, Caldas A d JM, Serra H d O, Silva FF, Ferreira M d JC, et al. Association analysis of human leukocyte antigen class II (DRB1) alleles with leprosy in individuals from São Luís, state of Maranhão, Brazil. Memórias do Instituto Oswaldo Cruz. 2012; 107 :150-155 - 21.
Agrewala JN, Ghei SK, Sudhakar KS, Girdhar BK, Sengupta U. HLA antigens and erythema nodosum leprosum (ENL). HLA Journal. 1989; 33 (4):486-487 - 22.
de Souza-Santana FC, Marcos EVC, Nogueira MES, Ura S, Tomimori J. Human leukocyte antigen class I and class II alleles are associated with susceptibility and resistance in borderline leprosy patients from Southeast Brazil. BMC Infectious Diseases. 2015; 15 :22 - 23.
Prevedello FC, Mira MT. Hanseniase una doenca genetica? Leprosy: A genetic disease. Anais Brasileiros de Dermatologia. 2007; 82 (5):451-459 - 24.
Khoury MJ, Yang Q. The future of genetic studies of complex human diseases: An epidemiologic perspective. Epidemiology. 1998; 9 (3):350-354 - 25.
Abbas AK, Lichtman AHH, Pillai S. Imunologia Celular e Molecular. Brasil: Elsevier; 2015 - 26.
Goldberg AC, Rizzo LV. MHC structure and function–antigen presentation. Part 1. Einstein (Sao Paulo). 2015; 13 (1):153-156 - 27.
Jin P, Wang E. Polymorphism in clinical immunology – From HLA typing to immunogenetic profiling. Journal of Translational Medicine. 2003; 1 (1):8 - 28.
Mazini PS, Alves HV, Reis PG, Lopes AP, Sell AM, Santos-Rosa M, et al. Gene association with leprosy: A review of published data. Frontiers in Immunology. 2015; 6 :658 - 29.
Williams TM. Human leukocyte antigen gene polymorphism and the histocompatibility laboratory. Journal of Molecular Diagnostics. 2001; 3 (3):98-104 - 30.
Magalhães PSC, Böhlke M, Neubarth F. Complexo Principal de Histocompatibilidade (MHC): codificação genética, bases estruturais e implicações clínicas. Revue Médicale UCPEL. 2004; 2 (5):59 - 31.
Marsh SGE, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, et al. Nomenclature for factors of the HLA system, 2010. Tissue Antigens. Apr 2010; 75 (4):291-455 - 32.
Robinson J, Halliwell JA, Hayhurst JD, Flicek P, Parham P, Marsh SGE. The IPD and IMGT/HLA database: Allele variant databases. Nucleic Acids Research. 2015 Jan; 43 :D423-D431 - 33.
García G, del Puerto F, Pérez AB, Sierra B, Aguirre E, Kikuchi M, et al. Association of MICA and MICB alleles with symptomatic dengue infection. Human Immunology. 2011; 72 (10):904-907 - 34.
Gonzalez S, Martinez-Borra J, Torre-Alonso JC, Gonzalez-Roces S, Sanchez del Río J, Rodriguez Pérez A, et al. The MICA-A9 triplet repeat polymorphism in the transmembrane region confers additional susceptibility to the development of psoriatic arthritis and is independent of the association of Cw*0602 in psoriasis. Arthritis & Rheumatology. 1999 May; 42 (5):1010-1016 [cited Jul 25, 2017] - 35.
Souza CF, Noguti EN, Visentainer JEL, Cardoso RF, Petzl-Erler ML, Tsuneto LT. HLA and MICA genes in patients with tuberculosis in Brazil. Tissue Antigens. 2012; 79 (1):58-63 - 36.
Zhou X, Wang J, Zou H, Ward MM, Weisman MH, Espitia MG, et al. MICA, a gene contributing strong susceptibility to ankylosing spondylitis. Annals of the Rheumatic Diseases. Aug 2014; 73 (8):1552-1557 - 37.
Shankarkumar U, Ghosh K, Badakere S, Mohanty D. Novel HLA class I alleles associated with Indian leprosy patients. Journal of Biomedicine & Biotechnology. 2003; 2003 (3):208-211 - 38.
Franceschi DSA, Tsuneto LT, Mazini PS, Sacramento WS d, Reis PG, Rudnick CCC, et al. Class-I human leukocyte alleles in leprosy patients from Southern Brazil. Revista da Sociedade Brasileira de Medicina Tropical. Oct 2011; 44 (5):616-620 - 39.
Rani R, Fernandez-Vina MA, Zaheer SA, Beena KR, Stastny P. Study of HLA class II alleles by PCR oligotyping in leprosy patients from North India. Tissue Antigens. Sep 1993; 42 (3):133-137 - 40.
Joko S, Numaga J, Kawashima H, Namisato M, Maeda H. Human leukocyte antigens in forms of leprosy among Japanese patients. International Journal of Leprosy and Other Mycobacterial Diseases. Mar 2000; 68 (1):49-56 - 41.
Shaw MA, Donaldson IJ, Collins A, Peacock CS, Lins-Lainson Z, Shaw JJ, et al. Association and linkage of leprosy phenotypes with HLA class II and tumour necrosis factor genes. Genes and Immunity. Jun 2001; 2 (4):196-204 - 42.
Motta PMF, Cech N, Fontan C, Gimenez MF, Lodeiro N, Marinic K, et al. Role of HLA-DR and HLA-DQ alleles in multibacillary leprosy and paucibacillary leprosy in the province of Chaco (Argentina). Enfermedades Infecciosas y Microbiología Clínica. Dec 2007; 25 (10):627-631 - 43.
Soebono H, Giphart MJ, Schreuder GM, Klatser PR, de Vries RR. Associations between HLA-DRB1 alleles and leprosy in an Indonesian population. International Journal of Leprosy and Other Mycobacterial Diseases. 1997 Jun; 65 (2):190-196 - 44.
Vanderborght PR, Pacheco AG, Moraes ME, Antoni G, Romero M, Verville A, et al. HLA-DRB1*04 and DRB1*10 are associated with resistance and susceptibility, respectively, in Brazilian and Vietnamese leprosy patients. Genes and Immunity. 2007 Jun; 8 (4):320-324 - 45.
Hsieh N-K, Chu C-C, Lee N-S, Lee H-L, Lin M. Association of HLA-DRB1*0405 with resistance to multibacillary leprosy in Taiwanese. Human Immunology. 2010 Jul; 71 (7):712-716 - 46.
da Silva SA, Mazini PS, Reis PG, Sell AM, Tsuneto LT, Peixoto PR, et al. HLA-DR and HLA-DQ alleles in patients from the south of Brazil: Markers for leprosy susceptibility and resistance. BMC Infectious Diseases. 2009; 9 :134 - 47.
Borrás SG, Cotorruelo C, Racca L, Recarte M, Garcías C, Biondi C, et al. Association of leprosy with HLA-DRB1 in an Argentinean population. Annals of Clinical Biochemistry. 2008; 45 (1):96-98 - 48.
Tosh K, Ravikumar M, Bell JT, Meisner S, Hill AVS, Pitchappan R. Variation in MICA and MICB genes and enhanced susceptibility to paucibacillary leprosy in South India. Human Molecular Genetics. 2006; 15 (19):2880-2887 - 49.
Zhang F, Liu H, Chen S, Wang C, Zhu C, Zhang L, et al. Evidence for an association of HLA-DRB1*15 and DRB1*09 with leprosy and the impact of DRB1*09 on disease onset in a Chinese Han population. BMC Medical Genetics. 2009; 10 :133 - 50.
Lavado-Valenzuela R, Jose Bravo M, Junqueira-Kipnis AP, Ramos de Souza M, Moreno C, Alonso A, et al. Distribution of the HLA class II frequency alleles in patients with leprosy from the mid-west of Brazil. International Journal of Immunogenetics. 2011 Jun; 38 (3):255-258 - 51.
Zerva L, Cizman B, Mehra NK, Alahari SK, Murali R, Zmijewski CM, et al. Arginine at positions 13 or 70-71 in pocket 4 of HLA-DRB1 alleles is associated with susceptibility to tuberculoid leprosy. The Journal of Experimental Medicine. Mar 1996; 183 (3):829-836 - 52.
Singh M, Balamurugan A, Katoch K, Sharma SK, Mehra NK. Immunogenetics of mycobacterial infections in the North Indian population. HLA Journal. 2007; 69 (s1):228-230 - 53.
Mehra NK, Rajalingam R, Mitra DK, Taneja V, Giphart MJ. Variants of HLA-DR2/DR51 group haplotypes and susceptibility to tuberculoid leprosy and pulmonary tuberculosis in Asian Indians. International Journal of Leprosy and Other Mycobacterial Diseases. 1995; 63 :241 - 54.
Mehra NK, Verduijn W, Taneja V, Drabbels J, Singh SP, Giphart MJ. Analysis of HLA-DR2-associated polymorphisms by oligonucleotide hybridization in an Asian Indian population. Human Immunology. Dec 1991; 32 (4):246-253 - 55.
Groh V, Bahram S, Bauer S, Herman A, Beauchamp M, Spies T. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proceedings of the National Academy of Sciences of the United States of America. 1996; 93 (22):12445-12450 - 56.
Bahram S, Bresnahan M, Geraghty DE, Spies T. A second lineage of mammalian major histocompatibility complex class I genes. Proceedings of the National Academy of Sciences of the United States of America. 1994; 91 (14):6259-6263 - 57.
Bahram SMIC. Genes: From genetics to biology. Advances in Immunology. 2000; 76 :1-60 - 58.
Bahram S, Mizuki N, Inoko H, Spies T. Nucleotide sequence of the human MHC class I MICA gene. Immunogenetics. 1996; 44 (1):80-81 - 59.
Groh V, Bruhl A, El-Gabalawy H, Nelson JL, Spies T. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. Proceedings of the National Academy of Sciences of the United States of America. 2003; 100 (16):9452-9457 - 60.
Kahraman A, Fingas CD, Syn W-K, Gerken G, Canbay A. Role of stress-induced NKG2D ligands in liver diseases. Liver International. 2012; 32 (3):370-382 - 61.
Risti M, Bicalho M da G. MICA and NKG2D: Is there an impact on kidney transplant outcome? Frontiers in Immunology. 2017; 8 :179 - 62.
Collins RWM. Human MHC class I chain related (MIC) genes: Their biological function and relevance to disease and transplantation. European Journal of Immunogenetics. 2004; 31 (3):105-114 - 63.
Gambelunghe G, Brozzetti AL, Ghaderi M, Tortoioli C, Falorni A. MICA A8: A new allele within MHC class I chain-related A transmembrane region with eight GCT repeats. Human Immunology. 2006; 67 (12):1005-1007 - 64.
Pérez-Rodríguez M, Corell A, Argüello JR, Cox ST, McWhinnie A, Marsh SG, et al. A new MICA allele with ten alanine residues in the exon 5 microsatellite. Tissue Antigens. 2000; 55 (2):162-165 - 65.
Rueda B, Pascual M, López-Nevot MA, González E, Martín J. A new allele within the transmembrane region of the human MICA gene with seven GCT repeats. Tissue Antigens. 2002; 60 (6):526-528 - 66.
Sridevi K, Neena K, Chitralekha KT, Arif AK, Tomar D, Rao DN. Expression of costimulatory molecules (CD80, CD86, CD28, CD152), accessory molecules (TCR alphabeta, TCR gammadelta) and T cell lineage molecules (CD4+, CD8+) in PBMC of leprosy patients using Mycobacterium leprae antigen (MLCWA) with murabutide and T cell peptide of Trat protein. International Immunopharmacology. 2004;4 (1):1-14 - 67.
Li P, Morris DL, Willcox BE, Steinle A, Spies T, Strong RK. Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA. Nature Immunology. 2001; 2 (5):443-451 - 68.
Steinle A, Li P, Morris DL, Groh V, Lanier LL, Strong RK, et al. Interactions of human NKG2D with its ligands MICA, MICB, and homologs of the mouse RAE-1 protein family. Immunogenetics. 2001; 53 (4):279-287 - 69.
Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science. 1999; 285 (5428):727-729 - 70.
Mizuki N, Meguro A, Tohnai I, Gül A, Ohno S, Mizuki N. Association of major histocompatibility complex class i chain-related gene A and HLA-B alleles with Behçet’s disease in Turkey. Japanese Journal of Ophthalmology. 2007; 51 (6):431-436 - 71.
Tsuchiya N, Shiota M, Moriyama S, Ogawa A, Komatsu-Wakui M, Mitsui H, et al. MICA allele typing of HLA-B27 positive Japanese patients with seronegative spondylarthropathies and healthy individuals: Differential linkage disequilibrium with HLA-B27 subtypes. Arthritis and Rheumatism. 1998; 41 (1):68-73 - 72.
Hsieh Y-Y, Chang C-C, Hsu C-M, Chen S-Y, Lin W-H, Tsai F-J. Major histocompatibility complex class I chain-related gene polymorphisms: Associated with susceptibility to Kawasaki disease and coronary artery aneurysms. Genetic Testing and Molecular Biomarkers. 2011; 15 (11):755-763 - 73.
Chang YT, Tsai SF, Lee DD, Shiao YM, Huang CY, Liu HN, et al. A study of candidate genes for psoriasis near HLA-C in Chinese patients with psoriasis. The British Journal of Dermatology. 2003; 148 (3):418-423 - 74.
Ayo CM, de Oliveira AP, Camargo AV da S, de Mattos CCB, Bestetti RB, de Mattos LC. Association of the Functional MICA-129 polymorphism with the severity of chronic Chagas heart disease. Clinical Infectious Diseases. 2015; 61 (8):1310-1313 - 75.
Campbell KS, Hasegawa J. Natural killer cell biology: An update and future directions. The Journal of Allergy and Clinical Immunology. 2013; 132 (3):536-544 - 76.
O’Connor GM, Hart OM, Gardiner CM. Putting the natural killer cell in its place. Immunology [Internet]. Jan 2006; 117 (1):1-10 - 77.
Trinchieri G. Biology of natural killer cells. Advances in Immunology. 1989; 47 :187-376 - 78.
Smyth MJ, Cretney E, Kelly JM, Westwood JA, Street SEA, Yagita H, et al. Activation of NK cell cytotoxicity. Molecular Immunology. 2005; 42 (4):501-510 - 79.
Moretta A, Pende D, Locatelli F, Moretta L. Activating and inhibitory killer immunoglobulin-like receptors (KIR) in haploidentical haemopoietic stem cell transplantation to cure high-risk leukaemias. Clinical and Experimental Immunology. 2009; 157 (3):325-331 - 80.
Moretta L, Biassoni R, Bottino C, Cantoni C, Pende D, Mingari MC, et al. Human NK cells and their receptors. Microbes and Infection. 2002; 4 (15):1539-1544 - 81.
Kim S, Sunwoo JB, Yang L, Choi T, Song Y-J, French AR, et al. HLA alleles determine differences in human natural killer cell responsiveness and potency. Proceedings of the National Academy of Sciences of the United States of America. 2008; 105 (8):3053-3058 - 82.
Billadeau DD, Leibson PJ. ITAMs versus ITIMs: Striking a balance during cell regulation. The Journal of Clinical Investigation. 2002; 109 (2):161-168 - 83.
McVicar DW, Burshtyn DN. Intracellular signaling by the killer immunoglobulin-like receptors and Ly49. Science’s STKE. 2001; 2001 (75):re1 - 84.
Martin AM, Kulski JK, Witt C, Pontarotti P, Christiansen FT. Leukocyte Ig-like receptor complex (LRC) in mice and men. Trends in Immunology. 2002; 23 (2):81-88 - 85.
Trowsdale J. Genetic and functional relationships between MHC and NK receptor genes. Immunity. 2001; 15 (3):363-374 - 86.
Robinson J, Halliwell JA, McWilliam H, Lopez R, Marsh SGE. IPD – The Immuno polymorphism database. Nucleic Acids Research. 2013; 41 :D1234-D1240 - 87.
Marsh SGE, Parham P, Dupont B, Geraghty DE, Trowsdale J, Middleton D, et al. Killer-cell immunoglobulin-like receptor (KIR) nomenclature report, 2002. Tissue Antigens. 2003; 62 (1):79-86 - 88.
Bashirova AA, Martin MP, McVicar DW, Carrington M. The killer immunoglobulin-like receptor gene cluster: Tuning the genome for defense. Annual Review of Genomics and Human Genetics. 2006; 7 (1):277-300 - 89.
Vilches C, Pando MJ, Parham P. Genes encoding human killer-cell Ig-like receptors with D1 and D2 extracellular domains all contain untranslated pseudoexons encoding a third Ig-like domain. Immunogenetics. 2000; 51 (8-9):639-646 - 90.
Barrow AD, Trowsdale J. The extended human leukocyte receptor complex: Diverse ways of modulating immune responses. Immunological Reviews. 2008; 224 (1):98-123 - 91.
Wilson MJ, Torkar M, Haude A, Milne S, Jones T, Sheer D, et al. Plasticity in the organization and sequences of human KIR/ILT gene families. Proceedings of the National Academy of Sciences of the United States of America. 2000; 97 (9):4778-4783 - 92.
Uhrberg M, Parham P, Wernet P. Definition of gene content for nine common group B haplotypes of the Caucasoid population: KIR haplotypes contain between seven and eleven KIR genes. Immunogenetics. 2002; 54 (4):221-229 - 93.
Hsu KC, Chida S, Geraghty DE, Dupont B. The killer cell immunoglobulin-like receptor (KIR) genomic region: Gene-order, haplotypes and allelic polymorphism. Immunological Reviews. 2002; 190 :40-52 - 94.
Winter CC, Long EO. A single amino acid in the p58 killer cell inhibitory receptor controls the ability of natural killer cells to discriminate between the two groups of HLA-C allotypes. Journal of Immunology. 1997; 158 (9):4026-4028 - 95.
Sidney J, Peters B, Frahm N, Brander C, Sette A. HLA class I supertypes: A revised and updated classification. BMC Immunology. 2008; 9 (1):1 - 96.
Carrington M, Norman P. The KIR Gene Cluster. Bethesda (MD): National Center for Biotechnology Information (US); 2003 - 97.
Fernandes-Cardoso J, Süffert TA, Correa M d G, Jobim LFJ, Jobim M, Salim PH, et al. Association between KIR genotypes and HLA-B alleles on viral load in southern Brazilian individuals infected by HIV-1 subtypes B and C. Human Immunology. 2016; 77 (10):854-860 - 98.
Salie M, Daya M, Möller M, Hoal EG. Activating KIRs alter susceptibility to pulmonary tuberculosis in a South African population. Tuberculosis (Edinburgh, Scotland). 2015; 95 (6):817-821 - 99.
Ayo CM, Reis PG, Dalalio MM de O, Visentainer JEL, Oliveira C de F, de Araújo SM, et al. Killer cell immunoglobulin-like receptors and their HLA ligands are related with the immunopathology of Chagas disease (Rodrigues MM, editor). PLoS Neglected Tropical Diseases. 2015; 9 (5):e0003753 - 100.
Beltrame LM, Sell AM, Moliterno RA, Clementino SL, Cardozo DM, Dalalio MM, et al. Influence of KIR genes and their HLA ligands in susceptibility to dengue in a population from southern Brazil. Tissue Antigens. 2013; 82 (6):397-404 - 101.
Olaniyan SA, Amodu OK, Yindom L-M, Conway DJ, Aka P, Bakare AA, et al. Killer-cell immunoglobulin-like receptors and falciparum malaria in Southwest Nigeria. Human Immunology. 2014; 75 (8):816-821 - 102.
Jobim M, Jobim LFJ, Salim PH, Cestari TF, Toresan R, Gil BC, et al. A study of the killer cell immunoglobulin-like receptor gene KIR2DS1 in a Caucasoid Brazilian population with psoriasis vulgaris. Tissue Antigens. 2008; 72 (4):392-396 - 103.
Nishimura WE, Sachetto Z, Costallat LTL, Yazbek MA, Londe ACS, Guariento EG, et al. The role of KIR2DL3/HLA-C*0802 in Brazilian patients with rheumatoid vasculitis. Clinics. 2015; 70 (6):408-412 - 104.
Díaz-Peña R, Vidal-Castiñeira JR, Moro-García MA, Alonso-Arias R, Castro-Santos P. Significant association of the KIR2DL3/HLA-C1 genotype with susceptibility to Crohn’s disease. Human Immunology. 2016; 77 (1):104-109 - 105.
Franceschi DSA, Mazini PS, Rudnick CCC, Sell AM, Tsuneto LT, de Melo FC, et al. Association between killer-cell immunoglobulin-like receptor genotypes and leprosy in Brazil. Tissue Antigens. 2008; 72 (5):478-482