IntechOpen

Home > Books > Human Leukocyte Antigen (HLA)

Open access peer-reviewed chapter

HLA Class II Allele Polymorphisms and the Clinical Outcomes of HBV Infection

Written By

Shuyun Zhang

Submitted: 21 March 2018 Reviewed: 07 September 2018 Published: 13 March 2019

DOI: 10.5772/intechopen.81366

Human Leukocyte Antigen (HLA) IntechOpen
Human Leukocyte Antigen (HLA) Edited by Batool Mutar Mahdi

From the Edited Volume

Human Leukocyte Antigen (HLA)

Edited by Batool Mutar Mahdi

Book Details Order Print

Chapter metrics overview

1,145 Chapter Downloads

View Full Metrics
Advertisement

Abstract

In 2016, the global health sector strategy (GHSS) on viral hepatitis called for elimination of hepatitis B as a major public health threat by 2030 (i.e., 90% reduction in incidence and 65% in mortality). But persistence or clearance of hepatitis B virus (HBV) infection mainly depends upon host immune responses. The human leukocyte antigen (HLA) system is the center of host immune responses. HLA genes are located in chromosome 6p21.31 and cover 0.13% of the human genome and show a high degree of polymorphism and extensive patterns of linkage disequilibrium (LD), which differ among populations. The HLA genes include HLA class I, HLA class II, and other non-HLA alleles. HLA class II gene polymorphisms are strongly associated with not only persistent HBV infection but also spontaneous HBV clearance and seroconversion, disease progression, and the development of liver cirrhosis (LC) and HBV-related hepatocellular carcinoma (HCC) in chronic hepatitis B. This chapter summarizes the reported associations of HLA class II gene polymorphisms with the outcomes of HBV infection and their related mechanisms.

Keywords

  • HBV
  • HBV infection
  • HLA
  • HLA class II gene polymorphisms

1. Introduction

Since the discovery of hepatitis B virus (HBV) by Blumberg et al. in 1965, much has been elucidated regarding its virion, infection, prevention, and treatment [1, 2]. However, HBV infection continues to be a significant public health problem that has not yet been fully addressed worldwide [3, 4].

HBV infection is caused by HBV, an enveloped DNA virus that infects the liver causing hepatocellular inflammation and necrosis. HBV infection can be either acute or chronic, and the associated illness ranges in severity from asymptomatic to symptomatic and progressive disease. Chronic hepatitis B (CHB) is defined as persistence of hepatitis B surface antigen (HBsAg) for 6 months or more [2]. The World Health Organization (WHO) reports that 80–90% of infants infected during the first year of life and 30–50% of children infected before the age of 6 years develop chronic infections; less than 5% of otherwise healthy persons who are infected as adults will develop chronic infection; and 20–30% of adults who are chronically infected will develop cirrhosis and/or liver cancer [4]. In 2015, 257 million people lived with HBV infection defined as hepatitis B surface antigen positive; and hepatitis B resulted in 887,000 deaths, mostly from complications including liver cirrhosis (LC) and hepatocellular carcinoma (HCC) [4]. Once infected with HBV, one of the main risks is the development of cirrhosis, hepatic decompensation, and ultimately HCC [2, 3, 4, 5, 6]. In 2016, the global health sector strategy (GHSS) on viral hepatitis called for elimination of viral hepatitis as a major public health threat by 2030 (i.e., 90% reduction in incidence and 65% in mortality) [5]. In 2017, WHO’s first-ever Global hepatitis report presented the baseline values for each of the core indicators of the strategy [6].

The prevention component of elimination is on track with respect to hepatitis B vaccination, blood safety, and injection safety [7, 8, 9, 10]. A promising but limited start in hepatitis testing and treatment needs to be followed by immediate and sustained action so that we reach the service coverage targets required to achieve elimination by 2030 [3]. Levrero et al. [11], Vyas et al. [12], and Yoo et al. [13] reviewed that multiple emerging drug therapies are currently in the early stages of development as part of the growing effort to find a true cure for HBV. But persistence or clearance of HBV infection mainly depends upon host immune responses.

The major histocompatibility complex (MHC) was discovered in the mouse in 1936 [14]. The human leukocyte antigen (HLA) system, MHC in humans, is the center of host immune responses [15, 16, 17]. HLA genes are located in chromosome 6p21.31 [18] and cover 0.13% of the human genome [19] and show a high degree of polymorphism and extensive patterns of linkage disequilibrium (LD), which differ among populations. The HLA genes include HLA class I, HLA class II, and other non-HLA alleles [20]. HLA class I alleles include the three classic HLA gene loci: HLA-A, HLA-B, and HLA-C; three non-classic HLA-E, HLA-F, and HLA-G gene loci, which show limited polymorphism compared to the classic class I loci; and other related non-coding genes and pseudogenes [20]. The main function of HLA class I molecules, which are expressed in all nucleated cells, is to present non-self antigens derived from intracellular sources, such as viruses, to CD8+ T cells (cytotoxic T cells, CTL), which then identify and kill infected cells [21]. CD8+ T cells interact with the cognate peptide-MHC I complexes via their T-cell receptor (TCR) and co-receptor molecule CD8. HLA class II alleles include the classic gene loci HLA-DR, HLA-DQ, and HLA-DP and also the non-classic HLA-DO and HLA-DM loci [20]. The classic genes are expressed on the surface of professional antigen-presenting cells (APCs), which take up antigens derived from extracellular sources [22], such as bacteria or food, and present them to CD4+ T helper cells. This leads to the secretion of various small proteins, including cytokines, which regulate other immune cells such as macrophages or B cells. In turn, macrophages can destroy ingested microbes, and activated B cells can secrete antibodies. CD4+ T cells interact with the cognate peptide-MHC II complexes via their TCR and the co-receptor molecule CD4. Non-classic molecules are exposed in internal membranes in lysosomes, which help load antigenic peptides on to classic MHC class II molecules. Over the past 50 years, polymorphisms in the HLA locus have been shown to influence many critical biological traits and individuals’ susceptibility to complex, autoimmune, and infectious diseases [17, 23, 24]. Since 1979, Kew et al. [25] started the research for the association between histocompatibility antigens and HBV infection, and a plenty of researches demonstrated that the highly polymorphic HLA classes I and II genes can affect the ability of HLA molecules to trigger immune responses, which affects the outcomes of HBV infection, and discrepant conclusions were reached in different cohorts [26, 27]. HLA class II gene polymorphisms are strongly associated with not only persistent HBV infection but also spontaneous HBV clearance and seroconversion, disease progression, and the development of LC and HBV-related HCC in chronic hepatitis B [28, 29, 30]. This chapter summarizes the reported associations of HLA class II gene polymorphisms with susceptibility to HBV infection, resolution, and disease progression and their related mechanisms.

Advertisement

2. HLA class II gene and the clinical outcomes of HBV infection

HLA class II gene includes HLA-DRA1, -DRB1~9, -DQA1, -DQB1, -DPA1, -DPA2, -DPB1, -DPB2, -DOA, -DOB, -DMA, and -DMB with 4857 alleles known with the latest report update on April 16, 2018 (http://www.ebi.ac.uk/imgt/hla/stats.html). HLA-DRB1 has the most allelic variability with 2165 alleles, and in turn HLA-DQB1 with 1196 alleles, HLA-DPB1 with 975 alleles, and HLA-DRB3 with 157 alleles [20].

2.1. HLA class II allele polymorphism and HBV infection outcomes

HLA-DR is widely used in transplant gene matching [31] and as an activated T cell surface marker [32], and early related to the clinical outcomes of HBV infection [33]. In 2013, we reviewed the relationship between HLA class II alleles and HBV infection, there are the most number of HLA-DR alleles relatived to HBV infection, such as HLA-DRB1*03, 07, 09 and 12, may be the risk factors of HBV infection; and HLA-DRB1*04, 11, 13 and 14 may be the protect factors of HBV infection [26]. In 2016, Wang et al. also reviewed the relationship of HLA-DR alleles with HBV infection [27], including HLA-DRB1*1301-02 which is consistently associated with HBV clearance globally, such as in Gambia, Germany, Korea, and Spain; HLA-DRB1*11 and -DRB1*14 are associated with spontaneous recovery in patients with HBV subgenotype C2 infection in Northeast China; HLA-DR2, HLA-DR*0406, and HLA-DR7 antigens are associated with protective effect on acute HBV infection; and HLA-DRB1*08 and -DRB1*09 alleles, which are susceptible to HBV infection, were found in Brazilian populations determined in young and male blood donors. Meanwhile, HLA-DRB1*11/12 alleles are associated with HBV persistence globally, and HLA-DRB1*07 is the only one associated with infant susceptibility to intrauterine HBV infection and a significant negative predictor of cirrhosis. Our researches also showed that: -DRB1*13 may protect subjects from HBV infection [26]; -DRB1*12 may have a high risk for HBV infection [26]; and -DRB1*07 and 12 may be implied in viral persistence [26, 34]. Analysis still identified HLA-DRB1*12:02 as the top susceptible HLA allele associated with acute-on-chronic liver failure (ACLF) [35]. A large number of studies have been conducted to identify HLA-DRB1 genetic variants associated with HCC risk and clinical outcomes, but many of the findings in these studies are inconsistent and inconclusive [36, 37, 38]. A meta-analysis by Lin et al. reported an ethnicity-dependent association between specific HLA-DRB1 alleles and HCC risk, DRB1*07 and DRB1*12 were significantly associated with the risk of HCC in the whole populations, and DRB1*15 allele significantly increased the risk of hepatocellular carcinoma only in Asians [36]. One research by Ma et al. suggests that if genetic factors play a role in familial aggregation of hepatocellular carcinoma, the deficiency in the DRB1*11 and DRB1*12 alleles might be the risk factor at work in the Guangxi Zhuang Autonomous Region, P.R.C. [37]. Another meta-analysis by Liu et al. reported that HLA-DRB1*01 and 11 alleles were protective factors, while HLA-DRB1*12 and 14 alleles were risk factors for HCC development [38]. These findings are somewhat reasonable considering the incidence and distribution of HCC which are closely linked to environmental, dietary, and lifestyle factors, as well as genetic profiles, but the risk for HCC was not controlled for possible confounders such as HBV or HCV, which are more prone to bias than that of the randomized clinical trial studies.

HLA-DQ belongs to one of HLA class II molecules; it is also expressed as cell-surface glycoproteins that bind to exogenous antigens and present them to CD4+ T cells. HLA-DQ molecules function as a heterodimer of alpha and beta subunits which are encoded by the HLA-DQA1 and HLA-DQB1 genes, respectively. HLA-DQs are highly polymorphic especially in exon 2 which encode antigen-binding sites. Therefore, a number of alleles have been declared to be associated with persistent HBV infection [26, 27]—HLA-DQA1*0102, 0201, 0301, and 0402 and HLA-DQB1*0604, and so on associated with HBV clearance; and HLA-DQA1*0103, 0201, 0302, and 0501 and HLA DQB1*0301, and so on associated with HBV persistence [26]; the two-locus haplotype consisting of -DQA1*0501 and -DQB1*0301, and the three-locus haplotype consisting of -DQA1*0501, -DQB1*0301, and -DRB1*1102 were significantly associated with persistent HBV infection in an African-American cohort; -DQB1*0301 was associated with HBV persistence globally; in addition, -DQB1*0201 is a HBV-resistant gene, and -DQB1*0303 is a susceptibility gene of carrying HBV in Xinjiang Uygur ethnic groups of China; and -DQB1*0503 are associated with early HBeAg seroconversion in CHB children in Taiwan [27]. HLA genotyping-based analysis identified -DQB1*0601 as having the strongest association, showing a greater association with CHB susceptibility [28].

The HLA DPA1 and HLA DPB1 belong to the HLA class II alpha and beta chain paralogs, which also make a heterodimer consisting of an alpha and a beta chain on the surface of antigen-presenting cells. This HLA class II molecule also plays a central role in the immune system by presenting peptides derived from extracellular proteins. Identification of a total of five alleles, including two risk alleles (DPB1*09:01 and DPB1*05:01) and three protective alleles (DPB1*04:01, DPB1*04:02, and DPB1*02:01), would enable HBV-infected individuals to be classified into groups according to the treatment requirements. Moreover, among the five reported HLA-DPB1 susceptibility alleles, three DPB1 alleles (DPB1*05:01, *02:01, and *04:02) had primary effects on CHB susceptibility. However, the association of the remaining two alleles (DPB1*09:01 and *04:01) had come from LD with HLA-DR-DQ haplotypes (i.e., DRB1*15:02-DQB1*06:01 and DRB1*13:02-DQB1*06:04, respectively) [28, 39].

2.2. Single nucleotide polymorphisms at HLA class II gene and HBV infection outcomes

HLA gene variations are strongly associated with HBV infection outcomes in not only HLA alleles but also single nucleotide polymorphisms (SNPs) identified through genome-wide associated studies (GWASs). Recent GWASs have revealed several SNPs at HLA class II region associated with the risk of HBV infection [23, 30].

A Chinese study by Zhu et al. [40] identified two HLA-DR loci that independently drive chronic HBV infection, including HLA-DRβ113 sites 71 and rs400488. Acute-on-chronic liver failure (ACLF) is an extreme condition after severe acute exacerbation of chronic hepatitis B. Tan et al. carried out a genome-wide association study, among 1300 ACLFs and 2087 AsCs, and identified rs3129859 at HLA class II region (chromosome 6p21.32) which is associated with HBV-related ACLF. Analysis identified HLA-DRB1*12:02 as the top susceptible HLA allele associated with ACLF. The association of rs3129859 was robust in ACLF subgroups or HBV e antigen-negative chronic hepatitis B phase. Clinical traits analysis in patients with ACLF showed that the risky rs3129859*C allele was also associated with prolonged prothrombin time, faster progression to ascites development, and higher 28-day mortality [35]. SNP rs9272105 locates between HLA-DQA1 and HLA-DRB1 on 6p21.32. SNP imputation in the GWAS discovery samples revealed additional SNPs showing association, but rs9272105 remained the top SNP within the region [41], which successfully validated the associations between rs9272105 and HCC risk [42]. Of the 12 SNPs reported in HBV-related HCC GWASs, rs2647073 and rs3997872 near HLA-DRB1 were found to be significantly associated with the risk of HBV-related LC, which suggested that genetic variants associated with HBV-related hepatocarcinogenesis may already play an important role in the progression from CHB to LC [43]. A recent study reported new SNPs at HLA-DRB1 (rs35445101) associated with TP53 expression status in HBV-related hepatocellular carcinoma [30].

In 2013, Jiang et al. first found the association of HCC risk with rs9275319 at 6p21.3 located between HLA-DQB1 and HLA-DQA2, which was not reported in earlier GWASs of HCC [44]. Their following research and that of Wen et al. successfully validated the associations between rs9275319 and HCC risk [42, 43]. Three SNPs belonging to the HLA-DQ region (rs2856718, rs7453920, and rs9275572) were studied. HLA-DQ rs2856718G, rs7453920A, and rs9275572A were strongly associated with decreased risk of chronic HBV infection and natural clearance; while rs2856718A, rs7453920G, and rs9275572G served as a risk factor in HBV infection in Japanese populations and in Southeast China [45, 46, 47, 48]. Chang et al. found that rs9276370 (HLA-DQA2), rs7756516, and rs7453920 (HLA-DQB2) are significantly associated with persistent HBV infection, especially the “T-T” haplotype composed of rs7756516 and rs9276370 that is more prevalent in severe disease subgroups and associated with nonsustained therapeutic response in male Taiwan Han Chinese individuals [49]. A nearest study reported four new SNPs at HLA-DQB1 (rs1130399, rs1049056, rs1049059, and rs1049060) associated with TP53 expression status in HBV-related HCC [30].

A Chinese study by Zhu et al. [40] identified HLA-DPβ1 positions 84–87 that independently drive chronic HBV infection. In 2009, Kamatani et al. first reported two SNPs with the strongest relation to HBV infection from the HLA-DP locus: rs3077 on HLA DPA1 and rs9277535 on HLA DPB1 in Japanese and Thai populations [50, 51]. Subsequently, plenty of studies further demonstrated their roles [27, 52, 53, 54]. rs3077 and rs9277535 are significantly related to HBV persistent infection and both A alleles of these two SNPs are protection alleles in Chinese Han [55], Japanese and Korean [56], and European [57] populations, while in Chinese Zhuang subjects, only HLA-DP rs9277535A is associated with decreased risk [55]. Also, only a highly significant association of HLA-DPA1 rs3077C with HBV infection was observed in Caucasians [58]. HBeAg-negative HBV carriers with rs9277535 non-GG genotype had a higher chance to clear HBsAg. Compared to GG haplotype of rs3077 and rs9277535, GA haplotype had a higher chance of achieving spontaneous HBsAg loss in Chinese subjects of Taiwan [59]. On the whole, the present findings show that SNPs rs3077 and rs9277535 at HLA-DP locus protect against HBV infection and increase the chance of HBV clearance, while the importance of these polymorphisms as a predictor of HCC may be limited [45, 60, 61]. In a report by Hu et al., HLA-DP rs3077 showed an approaching significant effect on susceptibility to HBV persistent infection and HCC development when considering multiple testing adjustments [62]. Li et al. found evidence for the association at rs9277535 with HCC independently by imputation [41]. Thomas et al. reported that SNPs rs3077 and rs9277535 that associated most significantly with chronic hepatitis B and outcomes of HBV infection in Asians had a marginal effect on HBV recovery in European and African-American samples. However, they identified a novel variant in the HLA-DPB1 3′UTR region, 496A/G (rs9277534), which associated very significantly with HBV recovery in both European and African-American populations [63]. Hu et al. also found that the variant at rs9277534 could affect both the spontaneous clearance of HBV infection and progression from asymptomatic HBV carriers to HBV-related liver cirrhosis in southwest Han Chinese population [64]. Chang et al. found that rs9366816 near HLA-DPA3 are significantly associated with persistent HBV infection in male Taiwan Han Chinese individuals [49]. A nearest study reported a new SNP at HLA-DPB1 (rs1042153) associated with TP53 expression status in HBV-related hepatocellular carcinoma [30].

2.3. The role and mechanism of HLA class II gene variations associated with HBV infection outcomes

HLA class II genes encode proteins expressed on the surface of antigen-presenting cells such as macrophages, dendritic cells, and B cells, and thereby have a critical role in the presentation of antigens to CD4+ T-helper lymphocytes. In our previous review, there were three mechanisms related to HBV infection outcomes, including HLA molecular structure, HLA gene expression, and its regulatory [26].

HLA class II genes have many structural variants that have been linked to immune response [65, 66] to autoimmune diseases [67, 68], idiosyncratic drug toxicity (IDT) [69, 70], and infectious agents [71, 72]. But the structural variants related to HBV infection outcomes in HLA class II genes only have our previous research report [73]. We know that the HLA class II molecules are heterodimetric glycoproteins, which are able to present peptides to CD4+ T cells; the primary protein sequences (α1 and β1 chains) encoded by the second exon of the HLA class II genes comprise the peptide-binding grooves that accommodate amino acid chains of the bound peptides; the specificity of the peptide-binding grooves is governed by the properties of pockets in the grooves which include nine different structural pockets (Ps) from P1 to P9, typical pockets being P1, P4, P6, and P9, which accommodate the antigen peptide side chains; and the polymorphic residues encoded by polymorphic HLA class II genes can influence the structural (size and shape) and electrostatic properties and further function of the pockets. So, the determination of the structural and electrostatic properties of the HLA class II peptide-binding grooves associated with diseases may help identify the disease mechanism. We found that DR07 and DR12 carry amino acids Leu and His at residue 30 of HLA-DRβ1 chain, respectively, and Val at residue 57 of HLA-DRβ1 chain, difference from Tyr30 and Asp57 carried by DR04 and DR11, leading to present positive charge at P9 [73], as well as increasing size due to the absence of an intact salt bridge at P6 and P9 [73, 74]. Hence, which HLA DR07 and DR12 is sufficient to chronic HBV infection is supported by the structure characters resulting from HLA gene polymorphism.

Gene expression, that is, the qualitative and quantitative expression of mRNA transcripts from DNA templates, forms a first link in the functional path between nucleotide sequence and higher-order organismal phenotypes. Despite the undeniable importance of a controlled gene regulatory process in which proper transcripts are expressed at the correct time and location, studies have shown that there is widespread inter-individual variability with respect to gene expression, or mRNA levels, within a given cell type or tissue [75]. Early in 1986, Edwards et al. [76] examined frozen sections of human fetal spleen from 12 to 20 weeks of gestation by using polyclonal antibodies to Ig isotypes, monoclonal antibodies to HLA class II subregion locus products, B and T cells, and follicular dendritic cells. Their data suggest that class II antigens are differentially expressed on developing lymphoid cells; DR and DP expression occurring in the earliest spleens examined, with expression of DP on a subpopulation of DR-positive cells; IgD and DQ expression appears to be coincident on maturing B cells as they begin to form follicles, and an immunoregulatory role for HLA-DQ in B cell development is implicated. In fact, HLA class II gene (HLA-DR) expression level is still one of the markers for immune reaction related to disease [33, 77]. In 2017, we reviewed the association of HLA-DR expression level with diseases and reported our studies about the characteristics of HLA-DR expression in patients with different outcomes of HBV infection. Compared to persons with no HBV marker, HBV infection and vaccination induce increased expression of HLA-DR, especially in the clearance of HBV infection [78]. Genetic variants that influence HLA mRNA expression might also affect antigen presentation and many “gene expression-associated SNPs” (eSNPs) have been found for HLA genes [79, 80]. An integrated approach combining genotype information with genome-wide gene expression data in relevant tissues can identify genetic variations that are both regulatory and disease causing [81]. Cavalli et al. believed that a majority of causal genetic variants underlying complex diseases appear to involve regulatory elements, rather than coding variations [82]. Kaur et al. reported that structural and regulatory diversity shape HLA-C protein expression levels and that quantitative variation in the expression of HLA-C can influence the clinical course of HIV infection and the risk of graft-versus-host disease [83]. By influencing HLA mRNA expression, rs3077 and rs9277535 variants, both are noncoding variation (3′UTR) in the HLA-DPA1 and HLA-DPB1 region, and are related to enhanced clearance of hepatitis B virus infection [57, 63] and increased risk of graft-versus-host disease in mismatched hematopoietic cell transplant recipients [84, 85]. These findings were identified by a study about mapping of hepatic expression quantitative trait loci (eQTLs) in a Han Chinese population by Wang et al. [86].

eQTLs, namely, the discovery of genetic variants, explain variation in gene expression levels which has significant differences in mean expression levels between population, tissue or cell type [75, 87]. Typically, in the eQTL mapping literature, regulatory variants have been characterized as either cis or trans acting, reflecting the predicted nature of interactions and of course depending on the physical distance from the gene they regulate. Conventionally, variants within 1–2 Mb (megabase) on either side of a gene’s TSS were called cis, while those at least 5 Mb downstream or upstream of the TSS or on a different chromosome were considered trans acting [87]. The most significant GWAS SNPs are strong eQTLs and proposing candidate disease genes. Multiple variants of low-effect sizes affect multiple genes by gene regulatory network. A network component can be viewed as a cis effect that transmits its signal in trans essentially making the cis SNP a trans SNP as well [87]. Such studies have offered promise not just for the characterization of functional sequence variation but also for the understanding of basic processes of gene regulation and interpretation of genome-wide association studies [75, 87].

Up to now, many research findings have demonstrated that HLA class II gene variations, including allele polymorphisms and SNPs, are associated with HBV infection outcomes by influencing the molecular structure and the expression level of HLA class II molecules expressed on the cell surface. As the researches progress with methodological improvements, such as the prediction of gene expression [88] and PrediXcan analysis [89], more structure variations, cis SNPs and trans SNPs, were found underlying this disease. This can help understand the mechanisms linking genome-wide association loci to the disease, and implement precise individualized prevention, diagnosis, and treatment of the disease.

Advertisement

Acknowledgments

This work was supported by Wu Jieping Medical Foundation [Grant number 320.6750.18230].

Advertisement

Conflict of interest

None.

References

  1. 1. Blumberg BS, Alter HJ, Visnich S. A “new” antigen in leukemia sera. Journal of the American Medical Association. 1984;252(2):252-257. DOI: 10.1001/jama.1984.03350020054026
  2. 2. WHO Guidelines Approved by the Guidelines Review Committee. Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection. Geneva: World Health Organization; 2015. PMID: 26225396
  3. 3. Hutin YJ, Bulterys M, Hirnschall GO. How far are we from viral hepatitis elimination service coverage targets? Journal of the International AIDS Society. 2018;21(Suppl 2):e25050. DOI: 10.1002/jia2.25050
  4. 4. WHO. Hepatitis B. 2017. Available from: New hepatitis data highlight need for urgent global response
  5. 5. WHO. Global Health Sector Strategy on Viral Hepatitis, 2016-2021. 2016. Available from: http://apps.who.int/iris/bitstream/10665/246177/1/WHO-HIV-2016.06-eng.pdf?ua=1
  6. 6. WHO. Global Hepatitis Report. 2017. Available from: http://www.who.int/hepatitis/publications/global-hepatitis-report2017/en/ Google Scholar
  7. 7. Lin CL, Kao JH. Review article: The prevention of hepatitis B-related hepatocellular carcinoma. Alimentary Pharmacology & Therapeutics. 2018;48(1):5-14. DOI: 10.1111/apt.14683
  8. 8. Tang LSY, Covert E, Wilson E, Kottilil S. Chronic hepatitis B infection: A review. Journal of the American Medical Association. 2018;319(17):1802-1813. DOI: 10.1001/jama.2018.3795
  9. 9. Duffell EF, Hedrich D, Mardh O, Mozalevskis A. Towards elimination of hepatitis B and C in European Union and European Economic Area countries: Monitoring the World Health Organization's global health sector strategy core indicators and scaling up key interventions. Euro Surveillance. 2017;22(9):pii:30476. DOI: 10.2807/1560-7917.ES.2017.22.9.30476
  10. 10. Stępień M, Zakrzewska K, Rosińska M. Significant proportion of acute hepatitis B in Poland in 2010-2014 attributed to hospital transmission: Combining surveillance and public registries data. BMC Infectious Diseases. 2018;18(1):164. DOI: 10.1186/s12879-018-3063-3
  11. 11. Levrero M, Testoni B, Zoulim F. HBV cure: Why, how, when? Current Opinion in Virology. 2016;18:135-143. DOI: 10.1016/j.coviro.2016.06.003
  12. 12. Vyas AK, Jindal A, Hissar S, Ramakrishna G, Trehanpati N. Immune balance in hepatitis B infection: Present and future therapies. Scandinavian Journal of Immunology. 2017;86(1):4-14. DOI: 10.1111/sji.12553
  13. 13. Yoo J, Hann HW, Coben R, Conn M, DiMarino AJ. Update treatment for HBV infection and persistent risk for hepatocellular carcinoma: Prospect for an HBV cure. Diseases. 2018;6(2):pii:E27. DOI: 10.3390/diseases6020027
  14. 14. Gorer PA. The detection of a hereditary antigenic difference in the blood of mice by means of human group a serum. Journal of Genetics. 1936;32:17-31. DOI: 10.1007/BF02982499
  15. 15. Kelly A, Trowsdale J. Introduction: MHC/KIR and governance of specificity. Immunogenetics. 2017;69(8-9):481-488. DOI: 10.1007/s00251-017-0986-6
  16. 16. Meyer D, C Aguiar VR, Bitarello BD, C Brandt DY, Nunes K. A genomic perspective on HLA evolution. Immunogenetics. 2018;70(1):5-27. DOI: 10.1007/s00251-017-1017-3. Epub 2017 Jul 7
  17. 17. Phillips KP, Cable J, Mohammed RS, Herdegen-Radwan M, Raubic J, Przesmycka KJ, et al. Immunogenetic novelty confers a selective advantage in host-pathogen coevolution. Proceedings of the National Academy of Sciences of the United States of America. 2018;115(7):1552-1557. DOI: 10.1073/pnas.1708597115
  18. 18. Singh R, Kaul R, Kaul A, Khan K. A comparative review of HLA associations with hepatitis B and C viral infections across global populations. World Journal of Gastroenterology. 2007;13(12):1770-1787. DOI: 10.3748/wjg.v13.i12.1770
  19. 19. Shiina T, Hosomichi K, Inoko H, Kulski JK. The HLA genomic loci map: Expression, interaction, diversity and disease. Journal of Human Genetics. 2009;54(1):15-39. DOI: 10.1038/jhg.2008.5
  20. 20. Robinson J, Halliwell JA, Hayhurst JH, Flicek P, Parham P, Marsh SGE. The IPD and IPD-IMGT/HLA database: Allele variant databases. Nucleic Acids Research. 2015;43:D423-D431. DOI: 10.1093/nar/gku1161
  21. 21. Bailey A, Dalchau N, Carter R, Emmott S, Phillips A, Werner JM, et al. Selector function of MHC I molecules is determined by protein plasticity. Scientific Reports. 2015;5:14928. DOI: 10.1038/srep14928
  22. 22. Holling TM, Schooten E, van Den Elsen PJ. Function and regulation of MHC class II molecules in T-lymphocytes: Of mice and men. Human Immunology. 2004;65:282-290. DOI: 10.1016/j.humimm.2004.01.005
  23. 23. Matzaraki V, Kumar V, Wijmenga C, Zhernakova A. The MHC locus and genetic susceptibility to autoimmune and infectious diseases. Genome Biology. 2017;18(1):76. DOI: 10.1186/s13059-017-1207-1
  24. 24. Naranbhai V, Carrington M. Host genetic variation and HIV disease: From mapping to mechanism. Immunogenetics. 2017;69(8-9):489-498. DOI: 10.1007/s00251-017-1000-z
  25. 25. Kew MC, Gear AJ, Baumgarten I, Dusheiko GM, Maier G. Histocompatibility antigens in patients with hepatocellular carcinoma and their relationship to chronic hepatitis B virus infection in these patients. Gastroenterology. 1979;77(3):537-539 222645
  26. 26. Yu XY, Zhang SY. Development of relationship research between human leukocyte antigen and clinical changes of hepatitis B viral infections. Chinese Journal of Infectious Diseases. 2013;31(10):635-638
  27. 27. Wang L, Zou ZQ, Wang K. Clinical relevance of HLA gene variants in HBV infection. Journal of Immunology Research. 2016;2016:9069375. DOI: 10.1155/2016/9069375
  28. 28. Nishida N, Ohashi J, Khor SS, Sugiyama M, Tsuchiura T, Sawai H, et al. Understanding of HLA-conferred susceptibility to chronic hepatitis B infection requires HLA genotyping-based association analysis. Scientific Reports. 2016;6:24767. DOI: 10.1038/srep24767
  29. 29. Qiu B, Jiang W, Olyaee M, Shimura K, Miyakawa A, Hu H, et al. Advances in the genome-wide association study of chronic hepatitis B susceptibility in Asian population. European Journal of Medical Research. 2017;22(1):55. DOI: 10.1186/s40001-017-0288-3
  30. 30. Liao X, Yu L, Liu X, Han C, Yu T, Qin W, et al. Genome-wide association pathway analysis to identify candidate singlenucleotide polymorphisms and molecular pathways associated with TP53 expression status in HBV-related hepatocellular carcinoma. Cancer Management and Research. 2018;10:953-967. DOI: 10.2147/CMAR.S163209
  31. 31. Kang SS, Park WY, Jin K, Park SB, Han S. Characteristics of recipients with 10 or more years of allograft survival in deceased donor kidney transplantation. Transplantation Proceedings. 2018;50(4):1013-1017. DOI: 10.1016/j.transproceed.2018.02.040
  32. 32. Kandilarova SM, Georgieva AI, Mihaylova AP, Baleva MP, Atanasova VK, Petrova DV, et al. Immune cell subsets evaluation as a predictive tool for hepatitis B infection outcome and treatment responsiveness. Folia Medica (Plovdiv). 2017;59(1):53-62. DOI: 10.1515/folmed-2017-0008
  33. 33. van den Oord JJ, de Vos R, Desmet VJ. In situ distribution of major histocompatibility complex products and viral antigens in chronic hepatitis B virus infection: Evidence that HBc-containing hepatocytes may express HLA-DR antigens. Hepatology. 1986;6(5):981-989. PMID: 3530950
  34. 34. Zhang SY, Gu HX, Li D, Yang SF, Zhong ZH, Li XK, et al. Association of HLA polymorphism with HBV infection and genotypes. Japanese Journal of Infectious Diseases. 2006;59(6):353-357. PMID: 17186951
  35. 35. Tan W, Xia J, Dan Y, Li M, Lin S, Pan X, et al. Genome-wide association study identifies HLA-DR variants conferring risk of HBV-related acute-on-chronic liver failure. Gut. 2018;67(4):757-766. DOI: 10.1136/gutjnl-2016-313035
  36. 36. Lin ZH, Xin YN, Dong QJ, Wang Q, Jiang XJ, Zhan SH, et al. Association between HLA-DRB1 alleles polymorphism and hepatocellular carcinoma: A meta-analysis. BMC Gastroenterology. 2010;10:145. DOI: 10.1186/1471-230X-10-145
  37. 37. Ma S, Wu J, Wu J, Wei Y, Zhang L, Ning Q, et al. Relationship between HLA-DRB1 allele polymorphisms and familial aggregations of hepatocellular carcinoma. Current Oncology. 2016;23(1):e1-e7. DOI: 10.3747/co.23.2839
  38. 38. Liu L, Guo W, Zhang J. Association of HLA-DRB1 gene polymorphisms with hepatocellular carcinoma risk: A meta-analysis. Minerva Medica. 2017;108(2):176-184. DOI: 10.23736/S0026-4806.16.04571-7
  39. 39. Nishida N, Sawai H, Kashiwase K, Minami M, Sugiyama M, Seto WK, et al. New susceptibility and resistance HLA-DP alleles to HBV-related diseases identified by trans-ethnic association study in Asia. PLoS One. 2014;9(2):e86449. DOI: 10.1371/journal.pone.0086449
  40. 40. Zhu M, Dai J, Wang C, Wang Y, Qin N, Ma H, et al. Fine mapping the MHC region identified four independent variants modifying susceptibility to chronic hepatitis B in Han Chinese. Human Molecular Genetics. 2016;25(6):1225-1232. DOI: 10.1093/hmg/ddw003
  41. 41. Li S, Qian J, Yang Y, Zhao W, Dai J, Bei JX, et al. GWAS identifies novel susceptibility loci on 6p21.32 and 21q21.3 for hepatocellular carcinoma in chronic hepatitis B virus carriers. PLoS Genetics. 2012;8(7):e1002791. DOI: 10.1371/journal.pgen.1002791
  42. 42. Wen J, Song C, Jiang D, Jin T, Dai J, Zhu L, et al. Hepatitis B virus genotype, mutations, human leukocyte antigen polymorphisms and their interactions in hepatocellular carcinoma: A multi-centre case-control study. Scientific Reports. 2015;5:16489. DOI: 10.1038/srep16489
  43. 43. Jiang DK, Ma XP, Wu X, Peng L, Yin J, Dan Y, et al. Genetic variations in STAT4,C2,HLA-DRB1 and HLA-DQ associated with risk of hepatitis B virus-related liver cirrhosis. Scientific Reports. 2015;5:16278. DOI: 10.1038/srep16278
  44. 44. Jiang DK, Sun J, Cao G, Liu Y, Lin D, Gao YZ, et al. Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus-related hepatocellular carcinoma. Nature Genetics. 2013;45(1):72-75. DOI: 10.1038/ng.2483
  45. 45. Al-Qahtani AA, Al-Anazi MR, Abdo AA, Sanai FM, Al-Hamoudi W, Alswat KA, et al. Association between HLA variations and chronic hepatitis B virus infection in Saudi Arabian patients. PLoS One. 2014;9(1):e80445. DOI: 10.1371/journal.pone.0080445
  46. 46. Zhang X, Jia J, Dong J, Yu F, Ma N, Li M, et al. HLA-DQ polymorphisms with HBV infection: Different outcomes upon infection and prognosis to lamivudine therapy. Journal of Viral Hepatitis. 2014;21(7):491-498. DOI: 10.1111/jvh.12159
  47. 47. Xu T, Sun M, Wang H. Relationship between HLA-DQ gene polymorphism and hepatitis B virus infection. BioMed Research International. 2017;2017:9679843. DOI: 10.1155/2017/9679843
  48. 48. Xu T, Zhu A, Sun M, Lv J, Qian Z, Wang X, et al. Quantitative assessment of HLA-DQ gene polymorphisms with the development of hepatitis B virus infection, clearance, liver cirrhosis, and hepatocellular carcinoma. Oncotarget. 2017;9(1):96-109. DOI: 10.18632/oncotarget.22941
  49. 49. Chang SW, Fann CS, Su WH, Wang YC, Weng CC, Yu CJ, et al. A genome-wide association study on chronic HBV infection and its clinical progression in male Han-Taiwanese. PLoS One. 2014;9(6):e99724. DOI: 10.1371/journal.pone.0099724
  50. 50. Kamatani Y, Wattanapokayakit S, Ochi H, Kawaguchi T, Takahashi A, Hosono N, et al. A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. Nature Genetics. 2009;41(5):591-595. DOI: 10.1038/ng.348
  51. 51. Howell JA, Visvanathan K. A novel role for human leukocyte antigen-DP in chronic hepatitis B infection: A genomewide association study. Hepatology. 2009;50(2):647-649. DOI: 10.1002/hep.23147
  52. 52. Mohamadkhani A, Katoonizadeh A, Poustchi H. Immune-regulatory events in the clearance of HBsAg in chronic hepatitis B: Focuses on HLA-DP. Middle East Journal of Digestive Diseases. 2015;7(1):5-13. PMID: 25628847
  53. 53. Wasityastuti W, Yano Y, Ratnasari N, Triyono T, Triwikatmani C, Indrarti F, et al. Protective effects of HLA-DPA1/DPB1 variants against hepatitis B virus infection in an Indonesian population. Infection, Genetics and Evolution. 2016;41:177-184. DOI: 10.1016/j.meegid.2016.03.034
  54. 54. Akgöllü E, Bilgin R, Akkız H, Ülger Y, Kaya BY, Karaoğullarından Ü, et al. Association between chronic hepatitis B virus infection and HLA-DP gene polymorphisms in the Turkish population. Virus Research. 2017;232:6-12. DOI: 10.1016/j.virusres.2017.01.017
  55. 55. Wang L, Wu XP, Zhang W, Zhu DH, Wang Y, Li YP, et al. Evaluation of genetic susceptibility loci for chronic hepatitis B in Chinese: Two independent case-control studies. PLoS One. 2011;6(3):e17608. DOI: 10.1371/journal.pone.0017608
  56. 56. Nishida N, Sawai H, Matsuura K, Sugiyama M, Ahn SH, Park JY, et al. Genome-wide association study confirming association of HLA-DP with protection against chronic hepatitis B and viral clearance in Japanese and Korean. PLoS One. 2012;7(6):e39175. DOI: 10.1371/journal.pone.0039175
  57. 57. O'Brien TR, Kohaar I, Pfeiffer RM, Maeder D, Yeager M, Schadt EE, et al. Risk alleles for chronic hepatitis B are associated with decreased mRNA expression of HLA-DPA1 and HLA-DPB1 in normal human liver. Genes and Immunity. 2011;12(6):428-433. DOI: 10.1038/gene.2011.11
  58. 58. Vermehren J, Lötsch J, Susser S, Wicker S, Berger A, Zeuzem S, et al. A common HLA-DPA1 variant is associated with hepatitis B virus infection but fails to distinguish active from inactive Caucasian carriers. PLoS One. 2012;7(3):e32605. DOI: 10.1371/journal.pone.0032605
  59. 59. Cheng HR, Liu CJ, Tseng TC, Su TH, Yang HI, Chen CJ, et al. Host genetic factors affecting spontaneous HBsAg seroclearance in chronic hepatitis B patients. PLoS One. 2013;8(1):e53008. DOI: 10.1371/journal.pone.0053008
  60. 60. Liao Y, Cai B, Li Y, Chen J, Tao C, Huang H, et al. Association of HLA-DP/DQ and STAT4 polymorphisms with HBV infection outcomes and a minimeta-analysis. PLoS One. 2014;9(11):e111677. DOI: 10.1371/journal.pone.0111677
  61. 61. Yu L, Cheng YJ, Cheng ML, Yao YM, Zhang Q, Zhao XK, et al. Quantitative assessment of common genetic variations in HLA-DP with hepatitis B virusinfection, clearance and hepatocellular carcinoma development. Scientific Reports. 2015;5:14933. DOI: 10.1038/srep14933
  62. 62. Hu L, Zhai X, Liu J, Chu M, Pan S, Jiang J, et al. Genetic variants in human leukocyte antigen/DP-DQ influence both hepatitis B virus clearance and hepatocellular carcinoma development. Hepatology. 2012;55(5):1426-1431. DOI: 10.1002/hep.24799
  63. 63. Thomas R, Thio CL, Apps R, Qi Y, Gao X, Marti D, et al. A novel variant marking HLA-DP expression levels predicts recovery from hepatitis B virusinfection. Journal of Virology. 2012;86(12):6979-6985. DOI: 10.1128/JVI.00406-12
  64. 64. Hu Z, Yang J, Xiong G, Shi H, Yuan Y, Fan L, et al. HLA-DPB1 variant effect on hepatitis B virus clearance and liver cirrhosis development among southwest Chinese population. Hepatitis Monthly. 2014;14(8):e19747. DOI: 10.5812/hepatmon.19747
  65. 65. The MHC sequencing consortium. Complete sequence and gene map of a human major histocompatibility complex. Nature. 1999;401(6756):921-923. PMID: 10553908
  66. 66. Natarajan K, Jiang J, May NA, Mage MG, Boyd LF, McShan AC, et al. The role of molecular flexibility in antigen presentation and T cell receptor-mediated signaling. Frontiers in Immunology. 2018;9:1657. DOI: 10.3389/fimmu.2018.01657
  67. 67. Wieczorek M, Abualrous ET, Sticht J, Álvaro-Benito M, Stolzenberg S, Noé F, et al. Major histocompatibility complex (MHC) class I and MHC class II proteins: Conformational plasticity in antigen presentation. Frontiers in Immunology. 2017;8:292. DOI: 10.3389/fimmu.2017.00292
  68. 68. Misra MK, Damotte V, Hollenbach JA. Structure-based selection of human metabolite binding P4 pocket of DRB1*15:01 and DRB1*15:03, with implications for multiple sclerosis. Genes and Immunity. Jan 20, 2018. DOI: 10.1038/s41435-017-0009-5
  69. 69. Hirasawa M, Hagihara K, Abe K, Ando O, Hirayama N. In silico and in vitro analysis of interaction between ximelagatran and human leukocyte antigen (HLA)-DRB1*07:01. International Journal of Molecular Sciences. 2017;18(4):pii:E694. DOI: 10.3390/ijms18040694
  70. 70. Hirasawa M, Hagihara K, Abe K, Ando O, Hirayama N. Interaction of nevirapine with the peptide binding groove of HLA-DRB1*01:01 and its effect on the conformation of HLA-peptide complex. International Journal of Molecular Sciences. 2018;19(6):pii: E1660. DOI: 10.3390/ijms19061660
  71. 71. Delgado JC, Baena A, Thim S, Goldfeld AE. Aspartic acid homozygosity at codon 57 of HLA-DQ beta is associated with susceptibility to pulmonary tuberculosis in Cambodia. Journal of Immunology. 2006;176(2):1090-1097. DOI: https://doi.org/10.4049/jimmunol.176.2.1090
  72. 72. Sun WX, Xia Y, Zhang SY. Crystal model of human Leukocyte antigen and its application in disease research. International Journal of Immunology. 2015;38(2):173-177. DOI: 10.3760/cma.j.issn.1673-4394.2015.02.017
  73. 73. Xia Y, Sun WX, Li XK, Wang HY, Yu XY, Jin X, et al. Amino acids at positions 30β1 and 57β1 of HLA-DR confer susceptibility to or protection from chronic hepatitis B virus infection. International Journal of Clinical and Experimental Pathology. 2016;9(3):3816-3827. www.ijcep.com. ISSN: 1936-2625/IJCEP0020899
  74. 74. Chow IT, James EA, Tan V, Moustakas AK, Papadopoulos GK, Kwok WW. DRB1*12:01 presents a unique subset of epitopes by preferring aromatics in pocket 9. Molecular Immunology. 2012;50(1-2):26-34. DOI: 10.1016/j.molimm.2011.11.014
  75. 75. Stranger BE, Raj T. Genetics of human gene expression. Current Opinion in Genetics & Development. 2013;23(6):627-634. DOI: 10.1016/j.gde.2013.10.004
  76. 76. Edwards JA, Durant BM, Jones DB, Evans PR, Smith JL. Differential expression of HLA class II antigens in fetal human spleen: Relationship of HLA-DP, DQ, and DR to immunoglobulin expression. Journal of Immunology. 1986;137(2):490-497. PMID: 3522732
  77. 77. Pan W, Luo Q, Yan X, Yuan L, Yi H, Zhang L, et al. A novel SMAC mimetic APG-1387 exhibits dual antitumor effect on HBV-positive hepatocellular carcinoma with high expression of cIAP2 by inducing apoptosis and enhancing innate anti-tumor immunity. Biochemical Pharmacology. 2018;154:127-135. DOI: 10.1016/j.bcp.2018.04.020
  78. 78. Jin X, Xia Y, Li XK, Wang D, Du B, Zhang SY. The characteristics of HLA-DR expression in patients with different outcomes of HBV infection. International Journal of Immunology. 2017;40(6):31-36. DOI: 10.3760/cma.j.issn.1673-4394.2017.06.007
  79. 79. Dixon AL, Liang L, Moffatt MF, Chen W, Heath S, Wong KC, et al. A genome-wide association study of global gene expression. Nature Genetics. 2007;39(10):1202-1207. DOI: 10.1038/ng2109
  80. 80. Emilsson V, Thorleifsson G, Zhang B, Leonardson AS, Zink F, Zhu J, et al. Genetics of gene expression and its effect on disease. Nature. 2008;452(7186):423-428. DOI: 10.1038/nature06758
  81. 81. Schadt EE, Molony C, Chudin E, Hao K, Yang X, Lum PY, et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biology. 2008;6(5):e107. DOI: 10.1371/journal.pbio.0060107
  82. 82. Cavalli G, Hayashi M, Jin Y, Yorgov D, Santorico SA, Holcomb C, et al. MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo. Proceedings of the National Academy of Sciences of the United States of America. 2016;113(5):1363-1368. DOI: 10.1073/pnas.1523482113
  83. 83. Kaur G, Gras S, Mobbs JI, Vivian JP, Cortes A, Barber T, et al. Structural and regulatory diversity shape HLA-C protein expression levels. Nature Communications. 2017;8:15924. DOI: 10.1038/ncomms15924
  84. 84. Petersdorf EW, Malkki M, O'hUigin C, Carrington M, Gooley T, Haagenson MD, et al. High HLA-DP expression and graft-versus-host disease. The New England Journal of Medicine. 2015;373(7):599-609. DOI: 10.1056/NEJMoa1500140
  85. 85. Schöne B, Bergmann S, Lang K, Wagner I, Schmidt AH, Petersdorf EW, et al. Predicting an HLA-DPB1 expression marker based on standard DPB1 genotyping: Linkage analysis of over 32,000 samples. Human Immunology. 2018;79(1):20-27. DOI: 10.1016/j.humimm.2017.11.001
  86. 86. Wang X, Tang H, Teng M, Li Z, Li J, Fan J, et al. Mapping of hepatic expression quantitative trait loci (eQTLs) in a Han Chinese population. Journal of Medical Genetics. 2014;51(5):319-326. DOI: 10.1136/jmedgenet-2013-102045
  87. 87. Nica AC, Dermitzakis ET. Expression quantitative trait loci: Present and future. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 2013;368(1620):20120362. DOI: 10.1098/rstb.2012.0362
  88. 88. Zeng P, Zhou X, Huang S. Prediction of gene expression with cis-SNPs using mixed models and regularization methods. BMC Genomics. 2017;18(1):368. DOI: 10.1186/s12864-017-3759-6
  89. 89. Zeng P, Wang T, Huang S. Cis-SNPs set testing and predixcan analysis for gene expression data using linear mixed models. Scientific Reports. 2017;7(1):15237. DOI: 10.1038/s41598-017-15055-8

Written By

Shuyun Zhang

Submitted: 21 March 2018 Reviewed: 07 September 2018 Published: 13 March 2019

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Continue reading from the same book

View All
Chapter 1 Introductory Chapter: Concept of Human Leukocyte A...

By Batool Mutar Mahdi

3176 downloads

Chapter 2 HLA Allele Frequencies in Pediatric and Adolescent...

By Maria Anagnostouli and Maria Gontika

1290 downloads

Chapter 3 Donor-Specific Anti-HLA Antibodies in Organ Transp...

By Tsukasa Nakamura, Hidetaka Ushigome, Takayuki Shir...

2164 downloads