Cases vs. healthy controls Adaptated to [78].
1. Introduction
The Human Leukocyte Antigen (HLA) system is the Major Histocompatibility Complex (MHC) in humans, and all knowledge on this system is of great interest to the field of medical sciences. HLA has become an important tool for understanding the pathogenesis of various infectious diseases; the alleles or HLA haplotypes inherited by an individual can predict several risk and protective factors related to infections caused by various agents.
The list of infectious diseases associated with the HLA system is constantly increasing and the level of association is quite variable. New classification methods and frequent nomenclature updates have facilitated the understanding of the role of polymorphisms in this system and the association with various diseases.
The purpose of this chapter is to show the genetic variability of HLA genes and its influence in the immunopathogenesis of diseases caused by different classes of pathogens. The first part of the chapter encompasses aspects of the structure and function of MHC genes and the role of the molecules encoded by these genes. Subsequently, we present some infectious diseases associated with the HLA system that have been highlighted in the global overview.
2. Structure and function of the HLA
MHC is divided into three main regions and has over 200 genes, most of which have functions related to immunity, and are contained within 4.2 Mbp of DNA on the short arm of chromosome 6 at 6p21.3 [1]. In the HLA Class I region, near to the telomere, are located the HLA-A, -B and -C classic genes and -E, -F and -G non-classic genes, among other genes and pseudogenes. The HLA Class II region, near to centromere, contains HLA-DR, -DQ and –DP genes. Sub-region DR includes DRA gene which codes for the low-polymorphic alpha-chain and can combine with any beta chains codifying for DRB genes [2]. The Class III region, located between class I and II region contains the C2, C4A, C4B and B genes, that code for complement proteins and tumor necrosis factor (TNF) [1,2].
HLA molecules are polymorphic membrane glycoproteins found on the surface of nearly all cells. Multiple genetic loci within MHC encode these proteins, and one individual expresses simultaneously several polymorphic forms from a large pool of alleles in the population. The overall structure of the HLA class I and class II molecules is similar, with most of the polymorphisms located in the peptide binding groove, where there is the antigens recognized [3].
Class I molecules are composed of one heavy chain (45kD) encoded within the MHC and a light chain called β2-microglobulin (12kD) whose gene is on chromosome 15. Class II molecules consist of one α (34kD) and one β chain (30kD) both coding within MHC [1]
The class I heavy chain has three domains of which the membrane-distal first (α1) and the second (α2) are the polymorphic ones. These polymorphic domains concentrate three regions: positions 62 to 83; 92 to 121; and 135 to 157. These areas are called hypervariable regions. The two polymorphic domains are encoded by exons 2 and 3 of the class I gene. The diversity in these domains is of great importance as this is where the two domains that form the antigen binding cleft (ABC) or peptide binding groove (PBG) of MHC class I molecule are located [4,5]. The sides of the antigen-binding cleft are formed by α helices, whereas the floor of the cleft is comprised of eight anti-parallel beta sheets. The antigenic peptides of eight to ten amino acids (typically nonamers) bind to the cleft with low specificity but high stability. The α3 domain contains a conserved seven amino acid loop (positions 223 to 229), which serves as a binding site for CD8 [3,6-8].
Class II molecules comprised of two transmembrane glycoproteins: α and β chains, are restricted to the cells of the immune system (e.g. B cells, dendritic cells), but may also be induced on other cells during immune response. The PBG of class II molecules has open ends which allow the peptide to extend beyond the groove at both ends, and therefore to be longer (12-24 amino acids). The peptide is presented to CD4 T-cells [1]. Both α and β chains are usually polymorphic in class II molecules. In these chains, the α1 and β1 domains are of the PBG and therefore diversity is found mainly in these domains, which are encoded by the exon 2 of their class II A or B genes and the hypervariable regions tend to be found in the groove walls [7].
T cell activation occurs following recognition of peptide / MHC complexes on an antigen-presenting cell (APC). T cell activation can be viewed as a series of intertwined steps, ultimately resulting in the ability to secrete cytokines, replicate, and perform various effector functions. During antigen presentation, the antigen receptors of T cells (TCR) recognize both the antigen peptide and the MHC molecules, with the peptide being responsible for the fine specificity of antigen recognition and MHC residues contributes for the restriction of the T cells (CD4 and CD8). During antigen presentation, CD4 and CD8 are intimately associated with the TCR and bind to the MHC molecule [9].
3. Haplotype, linkage disequilibrium and HLA genes expression
HLA genes are transmitted for Mendel segregation and allelic variant is expressed in a codominant mode. The set of HLA alleles present in each chromosome of the pair is denominated haplotype. The probability of a sibling having the same HLA haplotype as the other is 25%, different haplotypes is 25% and 50% are share only one haplotype [2].
Moreover, there is a fact that occurs in HLA genes called linkage disequilibrium which denotes that certain alleles occur together with a greater frequency than would be expected by chance (non-random gametic association). Variations in the expected combinations of alleles in the population, more often or less often than would be expected from a random formation of haplotypes from alleles, could be related to linkage disequilibrium [1]. For example, a determined population has a gene frequency of 14% for
4. HLA and infection diseases
The frequency and the presence of HLA alleles vary among different populations. Studies suggest that the alleles that can confer resistance to certain pathogens are prevalent in areas with endemic diseases. Furthermore, genomic analysis in families has helped to map and identify the loci related to a number of diseases. Moreover, a number of diseases have been mapped and had their related loci identified thanks to the genomic analysis of families.
4.1. Bacterial diseases
4.1.1. Tuberculosis and leprosy
Leprosy and tuberculosis (TB) have afflicted humanity since time immemorial, and a number of factors converge to a timely discussion on mycobacterial disease. These factors include the re-emergence of human tuberculosis in epidemic proportions on a global scale, and the special position of leprosy among communicable diseases, the frequency of disabilities, and the social and economic consequences of these diseases.
The immunological mechanism involved in the breakdown of host resistance in these individuals remains unclear. A better understanding of the mechanisms that lead to the protective immunity of the host is fundamental in order to develop novel therapies and vaccines.
Cell-mediated immunity is thought to be the major component of host defense against mycobacterium; consequently, the induction of optimal Th1 response is protective immunity against mycobacterial infection.
Whereas exposure to and infection by
The extensive polymorphism of the class II genes and molecules results in genetically controlled interindividual differences in antigen-specific immune responsiveness, which in turn may lead to differential susceptibility to or expression of disease. The induction of cytolytic CD4+ Th1-like cells during mycobacterial infections has been extensively documented [10,11]. Thus, under inflammatory conditions it would be conceivable for T cells to access Schwann cells and recognize the HLA/peptide complexes presented by the Schwann cell.
4.1.2. HLA and leprosy
Leprosy is a chronic infection disease caused by
A global increase in both prevalence and new case detection has been observed as compared to 2011. The prevalence of leprosy in 2012 was 181,941 (0.34), compared to 189,018 (0.33) at the end of the first quarter of 2013, and approximately, 232,857 new cases reported (4.00/100,000 population), in the population were detected during the year of 2012 [14]. Currently, the major prevalence is in the Southeast Asiatic, South American, and African continents.
In 1966, Ridley and Jopling, based on clinical, histological, and immunological criteria, classified the spectra of leprosy into 5 groups: tuberculoid (TT), borderline-tuberculoid (BT), borderline-borderline (BB), borderline-lepromatous (BL) and lepromatous (LL). The Madrid classification was presented to subdivide leprosy patients into four different types (lepromatous, tuberculoid, borderline, and indeterminate), and since the year of 1998, the World Health Organization has recommended a new classification based on the number of skin lesions: paucibacillary (PB) for patients who have up to five skin lesions (lower bacterial load) and multibacillary (MB) for patients who have six or more skin lesions (higher bacterial load) [15].
The major signals of this disease are hypostatical cutaneous lesions, dilation of peripheral nerves, and the presence of acid-resistant bacillus in the skin lesions [16]. The undetermined form is an initial stage where the clinical and histopathological courses are uncertain. In the TT form, the lesions are maculates or infiltrated and can reappear or develop from undetermined macula, whereas in the LL form there are multiple lesions with numerous bacillus detected by skin biopsies [17].
Leprosy has been considered a multifactorial disease; the expression of clinical manifestations reflects the relation between the host and the parasite. The infection evolution depends on to the specific response on behalf of the host to the parasite. There is a good relationship observed
The susceptibility to
HLA has been studied in several distinctive illnesses, including infectious diseases. HLA alleles codify class I and II crucial molecules for CMI cell interaction. The HLA system participates effectively in the immune response by promoting the interaction between pathogen epitopes and the host cell T repertory. Consequently, depending on host HLA, different host responses can occur against the same antigen.
Previous investigations demonstrated different class I HLA variants associated to TT and LL forms of leprosy, in several populations. In India, the most important country in number of infected individuals with the bacillus, an important association with leprosy was reported for HLA-B40 antigen and HLA-A2-B40, HLA-A11-B40, and HLA-A24-B40 haplotypes [20]. Further studies in India replicated these findings; HLA-A11 [21] and HLA-B60 (split of B40) [22] antigens were associated to the LL form. Subsequently, with the advent of molecular genotyping, HLA class I alleles were determined in Indian multibacillary leprosy patients, resulting in a positive association with
Recent studies have shown a positive association between LD and
However, the main restriction determinants for
HLA molecules with the highest affinity to peptide produce the greatest T cell proliferation and IFN-γ response [36], and the peptide presentation by low affinity class II molecules may result in muted cell-mediated immunity [36]. Alternatively, peptide presentation by specific class II molecules may result in activation of suppressor/regulatory T-cells [37]. A protective effect against leprosy has been described for
In addition to the studies that have been performed to investigate the molecular mechanisms of mycobacterium antigens restricted to HLA, certain Class II HLA genes have been suggested, as the selection of determined groups of antigen peptides and specific T helper cells, can contribute to the development of leprosy polar [41] and also tuberculoses [42].
4.1.3. HLA and tuberculosis
Tuberculosis, or TB, is a chronic disease caused by
According to the World Health Organization [14], in 2011, there were an estimated 8.7 million new cases of TB (13% co-infected with HIV) and 1.4 million people died from TB, including almost one million deaths among HIV-negative individuals and 430,000 among people who were HIV-positive. Among the TB high-burden countries (approximately, 80% of all new TB cases arising each year), the highest rates of case detection in 2011 were estimated to be in Brazil, China, Kenya, the Russian Federation, and the United Republic of Tanzania.
A great challenge in immunology is to understand the complexities, mechanisms, and consequences of host interactions with microbial pathogens. The innate immune response to intracellular bacteria involves mainly macrophages and natural killing cells (NK). Bacteria activate NK cells directly or stimulate macrophages to produce cytokines that activate NK cells, which results in a broad and fast antimicrobial response critical to the control of pathogen dispersion. Innate immunity can limit bacterium growth for some time, but in general, it does not succeed in eradicating infections, triggering the acquired immunity mainly through cell action.
Proteins are processed by APCs that interact with surface receptors of T-lymphocytes (T CD4+) as peptides associated with class II HLA molecules. Either the phagocyted bacteria are transported from the phagosome to the cytosol or they escape the phagosome and enter the cytoplasm of infected cells, and their degraded products are expressed on the cell surface associated with the HLA molecule, whose complex interacts with the specific cytotoxic T CD8+ receptors. Thus, the T cell eradicates the target cell. The activation of the macrophage can also result in tissue lesion in the form of late hypersensibility reaction to the protein antigens. Bacteria may resist death within the phagocytes for a long period, producing macrophage and lymphocyte cell infiltration around them and giving rise to granulomes [44,45].
A number of genes are thought to be important in the pathogenesis of TB [46,47]. HLA class I molecules are involved in antigen presentation to CD8 cytotoxic T-cell response stimulation. However, the participation of these molecules is controversial in tuberculosis. A meta-analysis study reported that subjects carrying HLA-B13 had a lower risk for thoracic TB, whereas other class I antigens could not be related to tuberculosis pathogenesis [48].
Earlier studies revealed that HLA-DR2/DR3, DR2/DR4 and DR2/DR5 are the major heterozygous combinations associated with susceptibility to TB [49]. These same authors have also identified the association of HLA-DRB1 alleles and cytokine secretion in response to live
The HLA class II variant, DR2 encoded by
Hence, whether the presentation of mycobacterial epitopes by HLA molecules is beneficial or detrimental to mounting a protective response to tuberculosis and leprosy conditions has yet to be explored.
4.2. Viral diseases
4.2.1. HLA and dengue
Dengue is a resurging mosquito-borne disease that is often contracted by US travelers visiting Latin America, Asia, and the Caribbean. The clinical symptoms range from a simple febrile illness, called to Dengue Fever (DF), to hemorrhagic fever represented for Dengue Hemorrhagic Fever (DHF) or shock symptoms, called to Dengue Shock Sindrome (DSS) [56].
Nowadays, there are currently four known serotypes: DEN 1, 2, 3 and 4, which are strongly related. The viruses belong to the genus flavivirus, family
The pathophysiology of DF viral infections and factors that result in severe clinical disease are poorly understood. Cross-reactive memory T cells and antibodies have been suggested to contribute to the immunopathology by altering the cytokine profiles during secondary infection and are believed to be less effective in eliminating the newly infective virus serotype [58].
However, genetic factors appear to be important in the manifestation of DF as, even in endemic areas, only a small proportion of people develop DF or the most serious forms of the disease. During infection by DF virus, a series of genes have their regulation mechanisms modified, among them, genes linked to high production of IFN-gamma, as well as MIP-1β, RANTES, MBL2, IL-8 and IL-10 [59,60]. Host genetic polymorphisms involved in innate immune responses have been shown to be correlated with resistance to DHF, such as a variant of the FcGRIIA [61], functional polymorphisms of MBL2 [62], and the polymorphisms the CD209 promoter [63].
Similarly, studies on MHC-encoded transporters associated with antigen processing (TAP) genes have also shown associations with DHF [64, 65]. In addition, the analyses of tumor necrosis factor (TNF) and lymphotoxin alpha (LTA) genes have revealed specific combinations of TNF, LTA, and HLA class I alleles that associate with DHF and production of LTA and TNF [66].
Several aspects of T cell functionality are altered in DHF patients, including proliferation, activation status, production of cytokines, and their survival [67–70]. All these functions are influenced by specific recognition, through TCRs, of the antigen associated with HLA molecules. Thus, polymorphisms of HLA genes may also play an important role in dengue severity. Several genetic variations in HLA class I alleles have been found to correlate with dengue severity in Southeast Asian populations.
Some studies have revealed positive associations, whereas others have reported negative associations between DF and HLA classes I and II alleles. In Mexico and Cuba,
Results based on a study with 85 dengue fever cases, 29 dengue hemorrhagic fever and 110 health controls (HCs) on Western India population, revealed a significantly higher frequency of
The combined frequency of
Our group had previously found a strong association between HLA-DQ1 and classical DF, during an epidemic that occurred in a Southern Brazilian population in 1995, characterized by the presence of DF virus serotype 1, however no association between DF and HLA class I antigens was detected [74].
The statistical analysis revealed however, an association between
In addition, HLA class I and II have been associated to primary and the several forms of DF around the world [76]. The host HLA allele profile influenced the reactivity of DF-specific T cells, and may be responsible for the immunopathology of DF infection [77].
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2nd | DV-1 | DF (49) | 140 | Thai | Stephens et al., 2002 |
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2nd | DV-3 | DF (26) | 140 | Thai | Stephens et al., 2002 |
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2nd | all | DF (106) | 140 | Thai | Stephens et al., 2002 |
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2nd | DV-2 | DF (17) | 140 | Thai | Stephens et al., 2002 |
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2nd | - | DF (106) | 140 | Thai | Stephens et al., 2002 |
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- | - | DF (23) | 34 | Mexican | Falcón-Lezama et. al., 2009 |
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- | - | DF (23) | 34 | Mexican | Falcón-Lezama et. al., 2009 |
DQ1 | - | - | DF (64) | 64 | Brazilian | Polizel et. al., 2004 |
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- | - | DHF (59) | 200 | Vietnamese | Lan et. al., 2008 |
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- | - | DHF (117) | 250 | Vietnamese | Lan et. al., 2008 |
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2nd | DV-1 | DHF/DSS (32) | 140 | Thai | Stephens et al., 2002 |
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2nd | DV-2 | DHF/DSS (36) | 140 | Thai | Stephens et al., 2002 |
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2nd | DV-1, DV-2 | DHF/DSS (103) | 140 | Thai | Stephens et al., 2002 |
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2nd | all | DHF/DSS (103) | 140 | Thai | Stephens et al., 2002 |
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- | - | DHF/DSS (51) | 95 | Malay, Chinese, Indian | Appanna et. al., 2010 |
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- | - | DHF/DSS (19) | 95 | Malay | Appanna et. al., 2010 |
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2nd | all | DHF/DSS (103) | 140 | Thai | Stephens et al., 2002 |
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2nd | DV-1 | DHF/DSS (32) | 140 | Thai | Stephens et al., 2002 |
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- | - | DHF/DSS (51) | 95 | Malay, Chinese, Indian | Appanna et. al., 2010 |
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DHF/DSS (309) | 251 | Vietnamese | Fernández-Mestre et. al., 2004 | ||
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2nd | - | DSS (41) | 138 | Thai | Chiewsilp et. al., 1981 |
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- | - | DSS (152) | 250 | Vietnamese | Lan et. al., 2008 |
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- | - | DSS (170) | 200 | Vietnamese | Lan et. al., 2008 |
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DSS (96) | 200 | Vietnamese | Lan et. al., 2008 | ||
B blank | 2nd | - | DSS (41) | 138 | Thai | Chiewsilp et. al., 1981 |
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- | DV-2 | DF, DHF/DSS (120) | 189 | Cuban | Sierra et. al., 2007 |
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- | DV-2 | DF, DHF/DSS (120) | 189 | Cuban | Sierra et. al., 2007 |
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2nd | DV-3 | DF, DHF/DSS (51) | 140 | Thai | Stephens et al., 2002 |
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- | - | DF (47) | 34 | Mexican | La Fleur et. al., 2002 |
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- | - | DF (23) | 34 | Mexican | Falcón-Lezama et. al., 2009 |
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1st | - | DHF (59) | 200 | Vietnamese | Lan et. al., 2008 |
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- | - | DHF/DSS (309) | 251 | Vietnamese | Fernández et. al., 2004 |
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- | - | DHF/DSS (51) | 95 | Malay, (Chinese, Indian | Appanna et. al., 2010 |
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2nd | - | DSS (41) | 138 | Thai | Chiewsilp et. al., 1981 |
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- | - | DSS (170) | 200 | Vietnamese | Lan et. al., 2008 |
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- | - | DSS (96) | 200 | Vietnamese | Lan et. al., 2008 |
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- | - | DF, DHF/DSS (39) | 34 | Mexican | Falcón-Lezama et. al., 2009 |
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2nd | DV-2 | DF, DHF/DSS (77) | 189 | Cuban | Sierra et. al., 2007 |
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- | DV-2 | DF, DHF/DSS (120) | 189 | Cuban | Sierra et. al., 2007 |
4.2.2. HLA and hepatitis C
Hepatitis C virus (HCV) is one of the major causes of chronic liver inflammation worldwide [79,80]. HCV was first identified in 1989 [81] and has since then been the subject of intense research and clinical investigation due to the role this virus plays in causing liver disease and the ability of HCV to persist despite cellular immune defense.
The majority of the individuals infected by HCV are asymptomatic and only a small number will clear the virus whereas most individuals, approximately 50–85%, end up with persistent chronic viremia. Chronic disease can be evidenced by histopathological changes, which begin with an inflammation of the liver, often associated with fibrosis and which may progress towards cirrhosis, and in some cases, towards hepatocellular carcinoma [82,83]. An estimated 20% of chronic patients develop cirrhosis, especially 20 years after infection, and of these, 0 to 3% develop hepatocellular carcinoma [84,85].
The exact mechanisms responsible for liver damage during chronic hepatitis C have not yet been defined. The factors that influence the disease progression include viral genotype, age, gender, duration of the infection, concurrent infections and alcohol abuse; these factors taken individually, however, do not explain the reason that many patients spontaneously recover and escape from persistent infection whereas others progress towards end-stage liver disease [86-89].
In this context, these clinical features appear to be the result of the host’s immune response, a complex interaction between the innate and adaptive immune response, involved in the control of viral replication. HLA class I and II play an important role in the immune response against viral infections because they are key proteins to antigen presentation by antigen presenting cells to T lymphocytes. Several studies have analyzed HLA class I and class II in patients with hepatitis C in different populations and there is strong evidence that some, mainly HLA class II, alleles are involved in the control of viral infection by HCV. Table 1 summarizes the various HLA class II specificities that have been associated with HCV infection [90-123].
The most consistent data seems to be related to
Another allele group that has been correlated to self-limiting HCV is
Although some studies have been conducted to evaluate the influence of HLA class I in the course of hepatitis C disease and on the treatment response, the data is not yet consistent. The HLA-B35 antigen has been found more frequently in HCV carriers when compared to healthy individuals [111].
Some HLA class I alleles have been described in treated patients:
This lack of consensus in the literature may be result of the variations in the methodology of each study, such as different criteria or treatment response diagnoses, sample size, ethnic differences, mixing viral genotypes during analysis, and differences in treatment.
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Japan | Viral persistence | Aikawa et al. (1996) |
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Germany | Viral persistence | Hohler et al. (1997) |
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France | Viral clearance | Alric et al. (1997) |
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Japan | Viral persistence | Kuzushita et al. (1998) |
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Caucasians/France | Nonresponders to IFN-a therapy | Alric et al. (1999) |
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Caucasians/France | Sustained virological response | Alric et al. (1999) |
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Italy | Viral persistence | Asti et al. (1999) |
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Italy | Protection | Asti et al. (1999) |
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Italy | Viral persistence | Mangia et al. (1999) |
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Italy | Viral | Mangia et al. (1999) |
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European (UK) | Viral persistence | Thursz et al. (1999) |
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Ireland | Spontaneous clearance | Fanning et al. (2000) |
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Thailand | Viral persistence | Vejbaesya et al. (2000) |
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Caucasians/UK | Viral clearance | Harcourt et al. (2001) |
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Black/USA | Viral clearance | Thio et al. (2001) |
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Caucasians/USA | Viral clearance | Thio et al. (2001) |
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Caucasians/USA | Viral persistence | Thio et al. (2001) |
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Poland | Viral persistence | Kryczka et al. (2001) |
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France | Viral persistence | Hue et al. (2002) |
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Turkey | Protection | Yenigun & Durupinar (2002) |
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France | less severe liver disease | Renou et al. (2002) |
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Italy | Viral persistence | Scotto et al. (2003) |
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Japan | Viral persistence | Yoshizawa et al. (2003) |
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Taiwan | Sustained virological response | Yu et al. (2003) |
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Ireland | Viral persistence | McKiernan et al. (2004) |
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China | Sustained virological response | Jiao & Wang (2005) |
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Korea | Viral persistence | Yoon et al. (2005) |
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Taiwan | High viral load | Wang et al. (2005) |
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Tunisia | Viral persistence | Ksiaa et al. (2007) |
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Tunisia | Spontaneous clearance | Ksiaa et al. (2007) |
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Brazil | Viral clearance | Cursino-Santos et al. (2007) |
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USA | Viral clearance | Harris et al. (2008) |
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Egypt | Viral persistence | El-Chennawi et al. (2008) |
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Egypt | Protection | El-Chennawi et al. (2008) |
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Brazil | Viral persistence | Corghi et al. (2008) |
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Brazil | Protection | De Almeida et al. (2011) |
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Brazil | Viral clearance | De Almeida et al. (2011) |
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Brazil | Protection | Cangussu et al. (2011) |
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Spain | Sustained virological response | Rueda et al. (2011) |
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Brazil | Protection | Marangon et al. (2012) |
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Brazil | Protection | Marangon et al. (2012) |
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Brazil | Sustained virological response | Marangon et al. (2012) |
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Pakistan | Protection to HCV | Ali et al. (2013) |
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Pakistan | Viral clearance | Ali et al. (2013) |
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Pakistan | Viral persistence | Ali et al. (2013) |
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Egypt | Sustained virological response | Shaker et al. (2013) |
4.2.3. HLA and hepatitis B
Similar to HCV, Hepatitis B virus (HBV) is a hepatotrophic virus considered a serious public health problem. HBV infection is endemic in many parts of the world and more than 2 billion people are estimated to be infected with HBV [133-134].
The clinical features of the disease can vary from virus clearance to fulminating hepatitis. Some HBV carriers have an unapparent self-limiting hepatitis and others develop chronic hepatitis, which may lead to cirrhosis and in some cases to hepatocellular carcinoma [133-134].
Persistent HBV infection or HBV clearance is influenced by many factors such as level of viral replication, age at infection, gender, chronic alcohol abuse, co-infection with other hepatitis viruses, and genetic makeup, with most studies having identified susceptibility loci at HLA class II [133-134].
A meta-analysis demonstrated that
In Chinese Han populations,
The haplotypes
A genome-wide association study identified a significant association of chronic hepatitis B in Asians with 11 SNPs in a region including HLA-DPA1 and HLA-DPB1 and subsequent analyses revealed risk haplotypes (
HLA haplotype analysis indicated that
4.2.4. HLA and HIV
Human immunodeficiency virus (HIV) infection has indeed spread worldwide with over 30 million people living with HIV/AIDS. HIV infection represents a major challenge for physicians and scientists and is typically associated with an acute viral syndrome, with an asymptomatic period until the development of acquire immunodeficiency syndrome (AIDS). When left untreated the infection causes a decline in the CD4+ T cell number to less than 200 cells/mm3, resulting in immunodeficiency, opportunistic infections, and death [138].
A great number of disease-protective and disease-susceptible HLA alleles have been well characterized in HIV infection and the strongest associations seems to be related to HLA class I alleles (mainly HLA-A and B alleles) with differential rates of HIV disease outcome. Herein, we intend to review and discuss the HLA alleles related to HIV infection.
The virologic and immunologic outcomes in patients with HIV infection can be highly variable, with only a small number of individuals capable of controlling HIV replication without therapy [138]. Despite the mechanism involved in control and progress of HIV infection not yet being fully understood, the implication of some host immunogenetic factors, as the HLA molecules, in the course of disease has been well established.
Earlier studies revealed a relationship between
Regarding the association of HLA class I alleles and protection against HIV infection, the
In another study,
A large multiethnic cohort with HIV-1 controllers and progressors found diverse alleles associated with virologic and immunologic control:
Although all these alleles seem to be implicated in HIV infection the most consistent data are related to three HLA-B specificities:
Regarding HIV susceptibility and rapid disease progression,
Other unfavorable alleles have been described:
In addition, some HLA-C alleles have been described in association with HIV.
4.2.5. HLA and papillomavirus infection
Infection by human papillomavirus (HPV) is a common sexually transmitted infectious disease and most sexually active women have been infected during their lifetime. HPV infections frequently occur in healthy individuals and the high carcinogenic risk (HR) HPV types are a major causal factor for cervical cancer (CC). Persistent infection with one among approximately 15 genotypes of carcinogenic HPV causes almost all cases of cervical cancer; type 16 and HPV-18 account for more than 70% of the cervical cancers detected worldwide [156,157].
A number of genetic risk factors have been identified, but their effects are generally weak. The most prominent among the known risk factors is the HLA complex, which plays a critical role in susceptibility to CC [3]. Since the first reported association of HLA-DQ3 with CC, a large number of studies of HLA association with cervical cancer have been published with variable results depending on the ethnic group [157,158].
A study with CC described that
Some DR-DQ haplotypes containing
Protection has been mainly linked with the
Continuing trials pursue an explanation for the relationship between HLA and HPV infection. Silva (2013) showed that
A study analyzed the associations between HLA-G polymorphisms and HPV infection and squamous intraepithelial lesions (SIL) in Inuit women from Nunavik, northern Quebec. The group demonstrated that
One Korean study related the relationship between HLA and recurrent respiratory papillomatosis (RRP) and showed that the gene frequencies of
In China population, HLA-DRB alleles were associated with cervical cancer and HPV infections [166]. For the assessment of these genotypes, 69 cervical cancer patients and 201 controls were examined.
Among cervical cancer patients, the association risks differed between HPV positive and negative cases for several alleles; an increased risk of cervical cancer was observed in patients with
4.3. Parasitic diseases
4.3.1. HLA and Chagas disease
Many genetic linkage and association studies have attempted to identify genetic variations that are involved in immunopathogenesis of Chagas disease. However, the causal genetic variants underlying susceptibility remain unknown due to parasite and host complexity [167]. Susceptibility or resistance to Chagas disease involves multiple genetic variants functioning jointly, each with small or moderate effects. To identify possible host genetic factors that may influence the clinical course of Chagas disease, the role of classic and non-classic MHC genes will be addressed.
Chagas disease is an infection caused by the protozoan
The mechanisms of the transmission of Chagas infection include transmission through insect vectors mainly, but blood transfusion, contaminated food, congenital and secondary transmissions mechanism may occur [171].The phases of infection include the early or acute phase, characterized by high parasitaemia or trypomastigote circulating forms in the blood for two to four months [170]. Mortality, during this period, ranges from 5% to 10% due to episodes of myocarditis and meningocefalite [172,173].
The clinical signs are a local inflammatory reaction with formation of strong swelling at the site of entry of the parasites (chagoma or Romaña sign), fever, splenomegaly and cardiac arrhythmia [174]. During the acute phase, the majority of the infected individuals develop a humoral and cellular immune response responsible for the decrease of parasites in the blood.
Following this phase, patients progress to the chronic asymptomatic stage which affects most individuals (50 to 60%): this condition characterizes the indeterminate clinical form (IND) of the disease, and may remain in effect for long periods of time [175]. Approximately 20% to 30% of the individuals develop cardiomyopathy, which reflects a progressively damaged myocardium due to extensive chronic inflammation and fibrosis and, in terminal phases, usually presents as dilated cardiomyopathy. Chronic Chagas cardiomyopathy (CCC) is the most relevant clinical manifestation leading to death from heart failure in endemic countries. Eight to 10% have the digestive form (DF), characterized by dilation of the oesophagus or colon (megaoesophagus and megacolon). Some patients have associated cardiac and digestive manifestations, known as the mixed or cardiodigestive form [176-178].
There is a consensus that during
The spectrum of expression of Chagas disease brings strong evidence of the influence of the genetic factors on the clinical course of the disease, and the polymorphic genes involved in the innate and specific immune response is being widely studied such as the molecules and genes in the region of the HLA.
The polymorphic HLA class I (A, B and C) and II (DR, DQ and DP) molecules determine the efficiency of presentation of the
Regarding the association of HLA and Chagas disease, HLA-Dw22 was firstly associated to the susceptibility of developing the disease in Venezuelans [191]. A subsequent study compared class II allele frequencies between patients and controls and identified a decreased frequency of
As to the association of HLA and the clinical form of CCC, the first publication related HLA-B40 antigen, in the presence of Cw3, with a resistance to cardiac manifestations in Chilean patients [200], which was later confirmed [201]. However,
The studies conducted with the mixed or cardiodigestive form revealed that
Another study showed that contrarily, the polymorphism of HLA-DR and -DQ molecules did not influence the susceptibility to different clinical forms of Chagas' disease or the progression to severe Chagas' cardiomyopathy [205].
The polymorphism of MICA may be involved in the susceptibility to various diseases; however this association has been suggested to be secondary, due to the strong linkage disequilibrium with HLA-B alleles.
These different results between the HLA allele and haplotypes and Chagas disease could be the result of the variability of HLA allele’s distribution in different ethnic groups, the selection of the patients and the clinical form, and the biological variability of the parasite, among other factors. Nevertheless, genetic factors related to the HLA system reflect an important role in susceptibility or protection to Chagas disease and its clinical forms.
4.3.2. HLA and malaria
Malaria is an infectious disease caused by intracellular protozoan of the genus
The antibody response generated during malaria infections is of particular interest, since the production of specific IgG antibodies is required for acquisition of clinical immunity. However, variations in antibody responses could result from genetic polymorphism s of the HLA class II genes. Given the increasing focus on the development of subunit vaccines, studies of the influence of class II alleles on the immune response in ethnically diverse populations is important, prior to the implementation of vaccine trials. Junior et al.( 2012) showed that
The Fulani of West Africa have been shown to be less susceptible to malaria and to mount a stronger immune response to malaria than sympatric ethnic groups.
Trials have been performed seeking to determine the associations between HLA-A, B, and DRB1 group of alleles and severe malaria in northern Ghana.
To test for associations between HLA alleles and the severity of malaria in a Thai population, polymorphisms of HLA-B and HLA-DRB1 genes were investigated in 472 adult patients in northwest Thailand with
Individuals from Mumbai, an area of low and seasonal
5. Concluding remarks
Many genetic linkage and association studies have attempted to identify HLA variations that are involved in immunopathogenesis of infection diseases. However, in the infection diseases multiple genetic variants functioning jointly, each with small or moderate effects, may protect against diseases, or could contribute to aggression and tissue damage. Different results between the alleles and haplotypes HLA and infection diseases could be caused by: variability of HLA alleles distribution in different ethnic groups; the typing test (serological or molecular techniques); the methods of statistical analyses (chi-square test, logistic or linear regression) and interpretation (
The characterisation of the susceptibility genes and their variants has important implications, not only for a better understanding of disease pathogenesis, but for the control and development of new therapeutic strategies for infectious diseases. Using the basic knowledge acquired in the studies of the influence of genetics upon the immune response against parasite in different populations, one can look for proteins that induce the immunological phenotype needed for protection. At present, vaccination is an effective preventive measurement for these disorders, and researches for peptides with the best-predicted binding affinities for HLA molecules are an alternative. Overall, this type of analysis could potentially define high-risk patient groups, and result in effective therapeutic strategies for infectious disorders.
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