The human major histocompatibility complex (MHC), also referred to as human leukocyte antigen (HLA), is a series of molecules that are closely related to the regulation of the immune response. The HLA complex is composed of many genes, which can be divided into three subclasses: the class I, II, and III region. Each subclass contains different genes, including the classical HLA-A, HLA-B, and HLA-C genes, the nonclassical HLA-E, HLA-F and HLA-G genes, and the HLA-DP, HLA-DQ, and HLA-DR genes, as well as some variable genes. Because of its highly polymorphic nature and the extensive linkage disequilibrium of this region, the HLA region of the genome is one of the most fascinating and valuable genetic regions that has been discovered. With the development of HLA genotyping technologies, research examining the correlations between HLA genes and diseases has made great progress. Hundreds of diseases have been confirmed to be associated with the HLA region.
To date, numerous methods have been used to genotype HLA alleles during disease-association testing, including polymerase chain reaction (PCR)-based HLA genotyping methods, real-time PCR, Sanger sequencing and next-generation sequencing (NGS). One PCR-based genotyping technology, the sequence-specific oligonucleotide probe assay (SSO), utilizes short probes that are complementary to a limited number of known HLA alleles. The sequence-specific primer assay, which was used as a supplementary approach to SSO genotyping, was based on the extension of primers with 3′ ends. Both of these methods remain the primary approaches used for low- and intermediate-resolution HLA genotyping. Sanger sequencing has been widely used to genotype HLA alleles, and numerous commercial kits for HLA genotyping have been developed based on this technology. During the past decade, a genome-wide association study (GWAS) method was developed through imputation and the high-throughput use of NGS to perform HLA genotyping.
Meaningful progress has been made in HLA genetic research during the last three decades, leading to important leaps in the understanding of the mechanisms underlying human diseases. Here, we reviewed our current understanding of HLA molecules and genetic susceptibility in human diseases.
Database search strategy
The authors used keywords to search for terms related to HLA variations and diseases. The authors searched the PubMed database (https://www.ncbi.nlm.nih.gov/pubmed/) for full-text articles published between 1980 and 2019, in the English language, using medical subheading (MeSH) Terms. The literature retrieval strategy was as follows. Two primary terms, MHC (MeSH Terms) and HLA (MeSH Terms), were combined with each of the following secondary terms: (a) genetic, (b) susceptibility, (c) allele, (d) human diseases, (e) immunology, (f) GWAS, and (g) NGS. The authors screened the reference lists from included studies to identify other studies that might be useful. The authors first reviewed the titles and abstracts before acquiring the full articles. The primary content extracted from potential studies focused on the methods and results pertaining to HLA and diseases.
Traditional analysis of human leukocyte antigen and diseases
Human leukocyte antigen and tumors
Immune surveillance and immune escape are closely related to the onset of tumors. The pathogenesis of tumors has been found to be associated with the abnormal regulation of HLA class I and II molecules. Tumorigenesis is closely connected with T cell-based immune surveillance. Tumor cells can escape CD8+ T cell surveillance and death when HLA I gene variations lead to the loss of HLA I antigen expression or reductions in HLA I antigen density, resulting in tumor formation and development. Because of the genetic instability of tumors, neoantigens, called tumor-associated antigens, are generated. Classically, tumor-associated antigens are generated from apoptotic or necrotic cells and are presented by class II molecules to CD4+ T cells, ultimately activating CD8+ cytotoxic T cells that discriminate tumor cells via HLA class I molecules. In addition, solid neoplasias can secrete HLA class II antigens and serve as nonprofessional antigen-presenting cells (APCs) that imitate the proliferation of autologous CD4+ T cells, intuitively.
In developed countries, acute lymphoblastic leukemia (ALL) comprises nearly 80% of childhood leukemia diagnoses. A number of studies have revealed associations between various class I (HLA*A2,*A8, *B12, *Cw3, and Cw4*)[11,12] and class II (DPB1*0201, DPB1*0601, and HLA-DR53) HLA alleles and the risk of developing ALL.[13–17] In a study that assessed the relationships between a large sample of HLA alleles and childhood ALL risk, four HLA-A alleles were found to have meaningful protective effects, whereas six alleles were associated with a predisposition towards high-risk pediatric ALL. Using high-throughput genotyping techniques in leukemic patients, DPB1*0201 was found to have a higher frequency in children with ALL. Therefore, HLA genotypes may play critical and significant roles that change the environmental risks and affect the development of high-risk pediatric ALL.
The HLA-A*0207 and B*4601 alleles and their haplotypes increased the risks of developing nasopharyngeal carcinomas. In addition, this finding could extend the definition of the haplotype to include HLA class II alleles.HLA-DR and HLA-DQ showed strong linkages with this carcinoma. Carriers of the HLA-DQw3 antigen have a 7.1-fold higher risk of developing squamous cell carcinoma than carriers of other HLA class II genotypes, using the serological typing method. A subsequent report indicated that the frequencies of the DQB1*0301 and *0303 alleles were higher in cervical squamous cell carcinoma patients than in the general population.DRB1*04 and DRB1*11 were confirmed to be significantly associated with the occurrence of cervical intraepithelial neoplasia.HLA-A29, HLA-B12, and HLA-A1 were positively related to hepatocellular carcinoma (HCC) in American Caucasians, Greeks and South Africans, respectively. Additionally, HLA-A19, HLA-B35, HLA-DR3, and HLA-DQ1 were notably related to HCC in Italian patients (Table 1). When the frequencies of HLA class I and II antigens were evaluated, HLA-Cw7, HLA-B8, and HLA-DR3 showed significant differences between HCC patients and controls.
Human leukocyte antigen and autoimmune diseases
Genes in the HLA region encode HLA class I and II molecules and cytokines that are involved in T cell recognition and the stimulation of autoimmune reactions. According to one study, HLA I-associated disorders can be treated as intermediate diseases between innate and adaptive immunity. The remarkably strong association between ankylosing spondylitis (AS) and HLA-B27 was first reported in 1973.[26,27] Over 90% of AS patients carry HLA-B27, whereas only 4% to 7% of the normal population carries HLA-B27. In addition to HLA-B27, AS has also been associated with HLA-B*1403, HLA-Bw60 increases the risk of AS in HLA-B27-positive patients, and HLA-DR genes that are associated with AS susceptibility have also been identified. In addition, HLA-A*29, HLA-B*38, HLA-B*49, HLA-B*52, HLA-DRB1*11, and HLA-DPB1*03:01 have been associated with HLA-B27-negative AS patients in a single-stranded conformational polymorphism typing study. Because of its unique properties, HLA-B27 has served as a clinical diagnostic biomarker in recent years.
The rheumatoid arthritis (RA) risk locus was first identified in approximately 1980, and this research clarified the contribution of HLA-DRB1 alleles in the HLA locus. Many studies have demonstrated that HLA-DRB1*04:01, *04:04, *01:01, and *10:01 are strongly related to RA. In addition, not only are the HLA-DRB1*0401/*0404 haplotypes related to the risk of RA seropositivity but they have also been linked to the earlier onset of expedited joint damage and rheumatoid nodule symptoms. The frequency of the HLA-DRB1 allele is variable among different populations. HLA-DRB1*0405 and HLA-DRB1*1402 have primarily been associated with Asian and American RA patients, respectively.
HLA genes have been shown to be related to most autoimmune disorders, especially AS and RA, which have been associated with the HLA II genes. Furthermore, HLA II gene variations can generate abnormally high expression levels of HLA II molecules on the surfaces of non-APCs, which can induce T cell-mediated immune responses, causing the occurrence of autoimmunity.
Human leukocyte antigen and infectious diseases
Different types of infections have been closely linked to immunodeficiency. If CD8+ or CD4+ T cells have difficulty identifying the HLA I or II antigens on the cell surface, pathogenic microorganisms cannot be eliminated from the body, resulting in chronic viral infections. Many studies have shown that immune deficiency disorders are related to HLA expression levels, including HLA-B and HLA-C. For example, the human immunodeficiency virus (HIV) primarily attacks CD4+ T cells, resulting in acquired immunodeficiency syndrome (AIDS), which causes human immune system deficiency. If CD8+ T cells cannot recognize abnormal HLA I molecules, they cannot provide cellular immune protection against HIV viruses.
Virions lacking HLA-C tend to have low infectivity and increased sensitivity to neutralizing antibodies. The protective HLA class I molecules restrict the effects of HIV1-specific CD8+ T cells on dendritic cell function by interacting specifically with innate myelomonocytic HLA class I receptors. Bi-directional interactions between these two specific cell types contribute to natural HIV-1 immune control, highlighting the significance of regulatory interactions between innate and adaptive immune activities during effective antiviral immunologic defenses.[36,39]HLA-B*35 and HLA-Cw*04 were consistently associated with the development of AIDS-defining conditions. The HLA heterozygosity of class I loci delayed AIDS onset in Caucasian patients infected with HIV-1, whereas individuals who were homozygous at one or more loci rapidly progressed to AIDS and death. Moreover, previous studies provided sufficient evidence to confirm that HLA-B*57 is associated with a reduced risk of AIDS.[41–43]HLA-B*1503 was associated with a poor prognosis after HIV-2 infection, and HLA-B*0801 was associated with susceptibility to infection. Moreover, the presence of HLA-B*w4 in HIV-1-infected individuals was associated with a decreased risk of male-to-female HIV-1 transmission. The HLA-G*01:01:01 phenotype was associated with resistance to HIV-1 infections, and women with HLA-G*01:01:01 are significantly less likely to seroconvert than women without this allele. HLA-DRB1*15:02 and HLA-DRB1*03:01 were associated with low and high viremia, respectively.
Human leukocyte antigen and immunological rejection
The transplantation of an HLA mismatched graft can generate donor-specific antibodies, which results in antibody-mediated rejection, graft loss, and complicated repeat transplantation. These donor-specific antibodies are guided by exotic epitopes presented on the mismatched HLA antigens of the donor. The MHC class I-related chain gene A (MICA), within the HLA class I genes, represents a new family of proteins encoded by this gene. Unlike classical HLA molecules, these proteins are not involved in antigen presentation to T cells. MICA interacts with natural killer group 2D, leading to the activation of antigen-specific T lymphocyte-mediated cytotoxicity, natural killer cell responses and cytokine production. Additionally, polymorphic MICA antigens are capable of inducing antibodies that can kill target cells in the presence of complement. Therefore, MICA is unique to the extent that it plays a significant role in linking the adaptive and innate immune responses during transplantation.
Human leukocyte antigen and skin diseases
HLA-Cw6 has been well documented for its strong genetic association with psoriasis. The detection of class II antigens has revealed HLA-DR7 to be a risk factor for psoriasis susceptibility. In addition, HLA-DQA1*02:01 and HLA-DQB1*03:03 were also shown to be related to psoriasis. Using family-based, case-control association studies and linkage disequilibrium analyses, studies identified HLA-DRB4*0101 in the Dutch population,HLA-DQB1*0303 in a Chinese Han population,[53,54] and HLA-DQA1*0302 and HLA-DQB1*0503 to be risk factors for vitiligo, whereas HLA-DQA1*0501 showed an affirmative and protective effect against vitiligo. By using the standard microlymphocytotoxicity technique, HLA-A24 was shown to be meaningfully related to atopic dermatitis.HLA-DRB1*0402, HLA-DRB1*1401, and HLA-DQB1*0503 were consistently reported to be associated with pemphigus vulgaris. To date, PCR-based HLA genotyping using traditional methods, such as sequence-specific primer assays (SSOP) and sequence-based genotyping, has improved the genotyping resolution of HLA and resulted in great achievements in HLA research (Table 1). However, several limitations of these methods have appeared, including their time-consuming protocols, low throughput, ambiguity, and phase-free data.
Human leukocyte antigen and genome-wide association studies
The HLA region is characterized by high linkage disequilibrium (LD) levels, which leads to difficulty when genotyping using high-throughput methods. Although HLA is underrepresented on GWAS chip arrays, GWASs have identified massive numbers of variants within the HLA gene that are associated with complex diseases. In particular, alternative uses of HLA imputation methods (eg, SNP2HLA, HLA-check, and HIBAG) have allowed the imputation of classical HLA alleles and the use of LD information to establish relationships between alleles and single nucleotide polymorphisms (SNPs) in the HLA region. These approaches can provide guidance and new directions for the study of HLA alleles.
Cancer susceptibility has been linked to the HLA loci. Immune surveillance and immune escape are closely related to the onset of tumors. Many studies have found that the pathogenesis of tumors is connected to the abnormal regulation of classical HLA molecules. Through the use of GWASs, powerful associations have emerged between HLA and lung cancer, breast cancer, prostate cancer, liver cancer, multiple myeloma, Hodgkin lymphoma,[64,65] follicular lymphoma, nasopharyngeal carcinoma, cervical cancer, and glioma. As with other diseases, through the use of considerably larger samples and meta-analysis approaches during association studies, an increasing number of rare variant associations have been reported for cancer.[70–73] The HLA variants determined through GWASs have been associated not only with cancer but also with immunological diseases.[74,75] The close connections between novel genes and pathways and common immunological disease phenotypes have also been noted. GWASs have been widely applied to autoimmune diseases, such as Graves’ disease, AS, systemic lupus erythematosus, diabetes, selective IgA deficiency, multiple sclerosis and myasthenia gravis, and multiple genetic factors have been identified for these diseases. The markers that show strong evidence of association are summarized in Table 2.
GWAS is the preferred tool for demonstrating HLA genetic associations with infectious diseases, but only a few common infectious diseases have been examined. The first GWAS of HIV-1 infection revealed HLA alleles that contributed to the viral load in asymptomatic European patients. Variants of HLA-DPA1 and HLA-DPB1 were strongly linked to protection against chronic hepatitis B virus infection in Asian populations. A susceptibility locus for dengue shock syndrome was identified by GWAS in the MHC class I polypeptide-related sequence B in Vietnamese children. The use of GWAS for infectious diseases has lagged behind the use of GWAS for common complex diseases, and only a few studies have investigated the genetic markers associated with the pathogenesis of infectious diseases. In more than 200,000 individuals with European ancestry from 23 countries, 59 risk-associated loci were identified for 17 infectious diseases, both within the HLA region and in non-HLA loci. In the HLA region, viral disease susceptibility was associated with variations in class I molecules, whereas bacterial disease susceptibility was primarily associated with variations in class II molecules. These results were consistent with those from a previous study on antigen presentation. Viruses replicate in nucleated cells, which are represented by HLA class I molecules, whereas bacteria primarily grow outside of cells and are represented by HLA class II molecules. The HLA variants are associated not only with infectious diseases but also with a variety of other diseases, such as Barrett's esophagus, metabolic disorders, obesity, schizophrenia, Parkinson's disease, age-related macular degeneration, and drug hypersensitivities. HLA variants have also been associated with human longevity and wine preferences. However, most of the HLA association studies have utilized small sample sizes, have disregarded population structures and include methodological imperfections, such as HLA genotyping errors and a lack of replication, which may lead to nonconformity with current standards of genetic epidemiological research. Most newly identified disease-related variants based on GWASs have been linked to small increases in risk (1.1–1.5-fold). However, the variants and markers described above can explain only a small fraction of the estimated heritable components of known diseases.
Human leukocyte antigen genotyping by next-generation sequencing
HLA genotyping has been performed to determine complex disease associations, and more than 100 complex diseases have been significantly associated with a variety of HLA haplotypes and alleles. The HLA gene complex is a frequent hit in GWASs because it has stronger associations with more autoimmune diseases than any other region of the human genome. Moreover, these hits commonly represent the primary components of detected genetic risks. Of all the previously reported disease-related variants with P values ≤5.0×10–8 in the newly updated National Human Genome Research Institute (NHGRI) catalog of GWASs (www.ebi.ac.uk/gwas), up to 4.8% of identified loci were mapped to the HLA region, showing a high proportion of disease-associated SNPs in this region. However, the current understanding of these associations with diseases remains very limited, for the following reasons: (1) the high diversity and numbers of polymorphisms among alleles and haplotypes; (2) the strong LD across the 4 Mb sequence of the HLA region; (3) the incomplete penetrance of known HLA genes or loci; and (4) interactions with other disease-susceptibility genes. Furthermore, 90% of disease-related SNPs are located in noncoding regions of the human genome, such as promoters, enhancers, silencers or other regulatory regions, which may be involved in transcriptional regulatory functions. Gene expression variants and expression quantitative trail loci make explaining the GWAS results for the HLA region more challenging. Attributing a pathogenic role to specific SNPs/genes/loci in the HLA region is difficult because of the high degree of polymorphisms and the complex structure of the HLA region. In addition, specific haplotypes have been reported to be genetic risk factors for immune-mediated disorders. Therefore, the understanding and comprehensive analysis of the HLA region have been hindered by the limitations of technological development.
As NGS technologies continue to advance, the challenges related to HLA regions will continue to be resolved. With the increasing read lengths, high-throughput capabilities and accuracy of developing biological detection methods, the generation of precise and accurate full-length HLA haplotypes, without phased haplotype ambiguity, is becoming possible. Known as massively parallel sequencing, NGS is a revolutionary technology that is fast becoming the gold standard for high-resolution HLA genotyping. NGS can provide key information that can overcome the complexity caused by the strong LD and high degree of polymorphisms in the HLA regions. An important feature of NGS is that it can produce more complete and better quality high-resolution genotyping data than traditional methods, at an appropriate cost. One advantage of NGS is the very high-depth coverage of sequencing, which translates into the reliable detection of minor genomic events. This superior property of NGS technologies became apparent in studies of diabetes, psoriasis, acquired aplastic anemia, RA, lupus nephritis, multiple sclerosis, myasthenia gravis, and ALL (Table 3). Commercially available HLA NGS genotyping kits, combined with software and bioinformatics, have allowed the technology to be available in all laboratories. However, many challenges and difficulties remain. First, the roles and significance of functional coding and noncoding variants in the whole genome must be explored; second, the optimal reporting level for disclosure to clinicians and the establishment of disease-related variants must be determined. A further challenge is to advance bioinformatics and functional annotations.[112,113] Finally, with increasing numbers of novel HLA sequences being provided by NGS, the naming conventions require updating. Thus far, allele names can identify nucleotide polymorphisms (for example, missense mutations or synonymous changes) but cannot provide detailed information regarding the locations of these SNPs within the genes. In summary, the new NGS technology can extend our knowledge of the HLA region to expand MHC regions, revealing the relationships between diseases and the immune system.[114,115]
The role of human leukocyte antigen in diseases
Immune surveillance and immune escape are closely related to the onset of tumors. Tumorigenesis is closely related to T cell-based immune surveillance. Tumor cells can escape CD8+ T cell recognition and death when HLA I gene variations result in reduced HLA I antigen expression or density, thus leading to tumor formation and development. Chronic inflammatory diseases are associated with immune cells and inflammatory mediators. Genes located in the HLA region encode HLA class I and class II molecules that are involved in T-cell recognition and inflammatory stimulation; thus, the classical HLA I molecules can be expressed on cells, where they can be recognized by CD8+ T cells. For example, increasing CD8+ T cell responses are specific to conserved proteins in HIV infection. Studies examining the relationship between classical HLA II molecules and disease susceptibility have shown that HLA II molecules can block antigen presentation or, if unstable, lead to an insufficient CD4+ T cell response, thereby increasing susceptibility to infection. Modifications made to HLA-DPβ1 and HLA-DRβ1 primarily resulted in defective antigen expression on CD4+ T cells or the damaged stability of HLA class II molecules, thus increasing susceptibility to hepatitis B virus infection. Notably, the downregulation of certain pro-inflammatory cytokines and HLA class II molecules, the initiation of T-cell regulatory responses, and reductions in the Th1-type and cytotoxic T cell function may explain the persistence of infection. The reduced expression of HLA class II molecules provides evidence that defects in the expression of these antigens can lead to more persistent and severe infections. Recently, studies have implied that CD4+ T cells are essential for the optimal production of interferon (IFN)-γ by CD8+ T cells, which is a protective immune response to infection, because the two intracellular processing pathways are not completely separate. When CD8+ T cells are activated, exogenous antigens stimulate HLA class I restrictive T cells, and HLA class II restrictive cytotoxic T-cells can recognize endogenous synthetic antigens. The class II molecules bind to Th2 cells and more effectively express exogenous antigens, helping B lymphocytes differentiate into plasma cells and secrete antibodies. Overall, the correlations between HLA loci and diseases reflect the complex interactions and characteristics of the host immune response to pathogen invasions. There are more than 15,000 different HLA class I and II alleles have been investigated, meaning that HLA class I and II genes are often considered to be the drivers of disease. Compared to these genes, HLA class III genes have the important function in inflammatory responses or complement cascade. In some extent, these different three types of classical genes may play a synergistic role in the pathogenesis of the diseases.
The HLA region at 6p21 encodes six classic HLA genes, including genes that play important roles in immune system regulation, cellular processes, and inflammation. HLA genotyping has benefited and will continue to benefit from different approaches. HLA gene research and disease correlation research may be able to comprehensively identify the wide degree of polymorphisms in this region by using new sequencing technology. The dynamic development of new methods and the related bioinformatics analyses will eventually expand the clinical applications of HLA genotyping beyond those available for traditional analyses. In the future, these advances will help to clarify the precise roles played by HLA variants during the study of disease mechanisms.
JG helped draft the manuscript. JG, CZ, ZZ, LT, LL and LW were involved in the literature retrieval and wrote the manuscript. LS designed, reviewed and modified the whole manuscript. All authors approved the final version.
Conflicts of interest
The authors declare that they have no conflicts to disclose.
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