Q J Med 2001; 94: 287-291
© 2001 Association of Physicians
Editorial |
MHC and the viral hepatitides
Division of Medicine, Imperial College School of Medicine, St Mary's Hospital, London
The outcome of a number of infectious diseases varies significantly between individuals. This is particularly evident for hepatitis B and hepatitis C virus infections, where the outcomes may range from asymptomatic self-limiting infection to fulminant liver failure or to cirrhosis with hepatocellular carcinoma. The factors which determine the outcome in a particular individual are largely unknown, but for convenience can be classified into three groups: viral determinants, environmental determinants and host determinants. The response of an individual to the infection is fundamentally controlled by their genetic makeup, and therefore host factors can be interpreted as host genetic factors. The identification of host genetic factors which influence the outcome of HBV and HCV infection has recently been the subject of intense study, and high on the list of candidate genes which influence the course of these viral hepatitides are those within the major histocompatibility complex.
The major histocompatibility complex is a large group of genetic loci on the short arm of chromosome 6 that were originally discovered through research on models of transplant compatibility. A number of these loci encode the human leukocyte antigens HLA class I and HLA class II, which we now know to be key molecules in the antigen presentation system at the core of adaptive immunity. In addition to the HLA molecules, a third region of the MHC encodes a variety of genes including cytokines, complement components and molecules involved in the antigen processing and presentation pathways. HLA molecules bind antigenic peptide fragments in a groove on the exterior surface of the molecule. The HLA-peptide complex is recognized by T-cell receptors (TCR) expressed on the surface of CD4+ T helper cells (Th) or CD8+ cytotoxic T lymphocytes (CTL). Interaction between HLA molecule, peptide and TCR in the context of appropriate costimulatory signals may initiate T-cell activation, proliferation and cytokine release.
MHC class I loci encode the HLA class I molecules, which interact with CTL, and MHC class II molecules encode the HLA class II molecules, which interact with Th cells. HLA class I molecules are present, or can be induced, on virtually every nucleated cell in the body, whereas HLA class II molecules are usually only expressed by professional antigen-presenting cells.
HLA class I molecules form heterodimers with ß2-macroglobulin on the cell membrane. Endogenously synthesized polypeptides (including viral proteins) in the cell cytoplasm are partially digested by the proteasome complex and transported to the endoplasmic reticulum by the transporter associated with antigen presentation (TAP) proteins.1 In the endoplasmic reticulum, peptide fragments are loaded into the HLA class I groove.
HLA class II molecules are encoded by two different MHC class II loci: one encoding an alpha chain and the other encoding a beta chain. Alpha-beta heterodimer structures are stabilized by an invariant chain polypeptide and translocated to the cellular lysosomal compartment, where they encounter exogenously-derived peptides which have been ingested by the antigen-presenting cell. Antigenic peptides competitively bind to the HLA class II molecule, and the trimeric complex is then transported to the cell membrane.
The MHC loci display an unprecedented degree of polymorphism compared to other regions of the human genome. It has been argued that this degree of polymorphism within a population is required to avoid the devastating effects of infectious diseases, which have been the major causes of mortality during mammalian evolution and remain the most serious threat to health in developing countries. The degree of polymorphism in the MHC region has probably been generated and maintained by selection pressures on the population exerted by infectious diseases. The mechanism through which pathogen-driven selection pressure accounts for the genetic diversity is unclear, but there is some evidence that it works through heterozygote advantage.2 Heterozygotes appear to be more capable of controlling an infection, presumably because their higher number of HLA molecules is capable of presenting a wider range of antigenic peptides to the immune system, thereby minimizing the opportunity for pathogens to evade T-cell recognition.
The key role of MHC class I and II-encoded molecules in antigen presentation has naturally generated the hypothesis that polymorphism at these loci may explain the variation in outcomes from infectious diseases and the development of autoimmune diseases. Recently, as a result of substantial improvements in genotyping techniques and carefully designed disease association studies, evidence has been provided to substantiate these hypotheses.
A number of early studies reported strong associations for specific MHC class I or II alleles with chronic HBV infection (Table 1
). These associations were not reproducible, as illustrated by the study of Mota in Argentina reporting an association of Bw35 with persistence, and van Hattum reporting that Bw35 was associated with self-limiting infection.3,4 These conflicting results probably arose due to small sample sizes and uneven distributions of ethnic groups within the study populations. Further problems resulted from the degree of allelic resolution achieved by the HLA typing method. Serological typing methods, principally based on the microlymphocytotoxicity assay, are only capable of defining broad groups of HLA alleles, whereas modern molecular genetic techniques define narrow groups of closely-related alleles or, where necessary, identify specific alleles individually.
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In The Gambia, the MHC class II allele DRB1*1302 was found to be associated with spontaneous resolution of HBV infection, and this report was rapidly followed by a European study which confirmed that this allele and the related allele DRB1*1301 also conferred resistance to chronic infection in Europeans.5,6 A recent study in Korea found an association between HLA-DR13 alleles and clearance of HBV infection.7 There is therefore a highly reproducible association between the HLA-DR13 alleles and clearance of HBV infection that is consistent across the major ethnic divisions (Table 1
).
In addition to investigating the role of MHC polymorphisms controlling the outcome of HBV infection, there has also been considerable interest in the outcome of HBV vaccination. Failure to respond to the HBV vaccine which is made from the small HBV surface antigen (HBsAg) occurs in around 5% of vaccinees and has been associated with HLA-DR3, DR4 and DR7 fairly consistently around the world (Table 2). A new vaccine preparation, which includes parts of the PreS1 and PreS2 antigens as well as the small HBsAg, appears to overcome the vaccine non-response in an MHC genotype-dependent manner.8
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Many studies have investigated the role of MHC class II polymorphisms in the outcome of HCV infection (Table 3
). Most have addressed self-limiting vs. persistent infection, and in a group of well-designed studies, a consistent association has emerged. The haplotype HLA-DRB1*1101—HLA-DQB1*0301 is found more frequently in people who have cleared the virus spontaneously (HCV antibody-positive and HCV RNA-negative on at least two occasions). Analysis of the pooled data from all these studies appears to implicate the DQB1 locus rather than the DRB1 locus, although in Northern European populations it is difficult to unravel the effects of linkage disequilibrium (Table 4).
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Two studies performed in Ireland on a population of women infected with an HCV-contaminated batch of rhesus immunoglobulin from a common source found an association of viral clearance with HLA-DRB1*01 alleles.9,10 This association has not been reported elsewhere, suggesting that the resistance to infection associated with HLA-DRB1*01 may only apply to the genotype 1b viral strain which was responsible for this outbreak.
In patients with chronic HCV infection, the rate of progression of their liver disease may also be influenced by MHC polymorphisms. No clear association has emerged (Table 5 ). However, one study suggested that HLA-DRB1*03 and HLA-DQB1*0201 may confer susceptibility to cirrhosis, although in another study these alleles have been associated with persistent infection.11,12 Similarly the response to interferon therapy has not been consistently associated with specific MHC class II alleles, although this may arise through the small size of most studies.13
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There have been remarkably few studies addressing the role of MHC class I loci in the outcome of HCV infection. It is unclear whether the lack of published reports reflects publication bias against negative studies (which would suggest that MHC class I polymorphisms are not important in the outcome of infection) or whether few people have undertaken these studies. An abstract recently presented in the US suggested that HLA-Cw04 is associated with viral persistence, which may be of particular interest as HLA-C locus products interact with natural killer (NK) lymphocytes.14
Processing of antigenic peptides presented by HLA class I molecules involves the transport associated with antigen processing (TAP) molecules encoded by the TAP1 and TAP2 loci in the MHC class III region.15 A Japanese study suggested that polymorphisms in the TAP2 gene influenced the progression of liver disease.16
There are a number of reasons for studying the associations of MHC polymorphisms and the outcome of infection. The biologist is looking for an explanation why some patients recover from infection with no sequelae while others develop end-stage liver disease and hepatocellular carcinoma. The immunologist is looking for mechanisms which confer protective immunity to the infection, and the clinician is looking for prognostic markers to guide the management of individual patients.
The mechanism underlying the association of MHC class II alleles and resistance to persistent infection has not been elucidated, but it is commonly assumed that the HLA molecules encoded by these alleles are capable of presenting immunodominant peptide epitopes more efficiently to T helper cells than those encoded by other alleles. Identification of the specific peptide epitopes derived from the virus presented by these HLA molecules may provide suitable vaccine candidates both for prophylactic and therapeutic use. The term reverse immunogenetics has been applied to the process of eluting peptides from the cleft of HLA molecules, sequencing the peptides and using the data to predict epitopes from viral sequences.17 We have used this process to predict a number of epitopes from HCV which have been confirmed with cellular immunology studies.18
Predicting the outcome of either HBV or HCV infection based on the MHC genotype is unlikely to be clinically useful for a number of reasons. Even if clear disease associations have been established, the relative risk conferred by possession of a specific allele is not particularly high (usually between 2 and 4), and as a result of the high degree of polymorphism at the MHC loci, the population attributable risk for an allele, taking into account the allele frequency in the general population, is usually low. Furthermore, clear associations have been established with clearance or persistence of the hepatitis viruses, but this is rarely an issue to the clinician. Clinical utility will only arise when genetic-based disease markers are available to predict which patients will get progressive liver disease or which patients will respond to a given treatment.
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