Genetic susceptibility to chronic hepatitis B virus infection (2006)

See article in J. Gastroenterol. Hepatol. 2006; 21: 1163–1169. Areas of the world in which hepatitis B virus (HBV) infection is endemic are diminishing progressively due to improved hygiene and nutrition, elimination of HBV from blood supplies, and vaccination. Yet, in some countries, there is still a pool of carriers of HBV, representing a continuing potential source of new infections. Acute HBV infection is often subclinical, such that the risk of chronicity among acutely infected healthy individuals is hard to estimate, although previously cited figures of about 10% can be realistically downgraded to about 5%.1 However, this risk is increased substantially by any cause of immunological deficiency, whether this be a result of immaturity exemplified by neonatal infection, debilitating disease such as renal failure exemplified by past outbreaks of HBV infection in dialysis units, or malnutrition often accompanying intravenous drug use. Such global states of immunological deficiency in humans are revealed by antigenic challenge; for T cell deficiency by impaired expression of cutaneous delayed type hypersensitivity using a panel of microbial test antigens;2 and for B cell deficiency by a decreased capacity for specific antibody synthesis after immunization.3 These immune response deficits are acquired in contrast to the likely wide, although as yet unascertained, range of deficits that are genetically determined. Of these genetic deficits, two in particular were investigated by Cheong et al., whose article appears in this issue.4 Finally there are, in addition to the aforementioned host factors, various viral factors that can influence the outcome after an acute HBV infection, including the dose of the infecting inoculum (blood transfusion or needlestick injury), genotype of the infecting virus, or kinetics of viral replication.5 Specifically, Cheong et al. examined effects among the Korean population of inherited single nucleotide polymorphisms (SNPs) in the promoter regions of two important pleiofunctional T cell cytokines, interleukin (IL)-10 and tumor necrosis factor (TNF)-α. There are likely to be a number of polymorphisms of genes or their promoters that encode these cytokines, although as yet only a few have been identified sufficiently well to assess their capacity to influence disease risk among human populations. For IL-10, there are biallelic polymorphisms in the gene promoter at positions −1082, −819 and −592 with, because of linkage disequilibrium, three haplotypes designated as GCC, ACC and ATA; homozygotes for the C allele at −592 (C/C genotype) are ‘high IL-10 producers’ in contrast to carriers of the ATA haplotype who are ‘low IL-10 producers’. For TNF-α, there are G or A polymorphisms at positions −308 and −288, with carriers of the −308 A allele being ‘high TNF-α producers’ in contrast to carriers of the G/G genotype who are ‘low TNF-α producers’. Before considering results, four points need be mentioned. The first is to distinguish (a) susceptibility to HBV infection and its clearance, from (b) levels of ongoing inflammatory activity generated if chronic infection does become established. The second is to take account of known immunogenetic influences on risk for HBV infection, and particularly human leukocyte antigen (HLA) alleles that influence efficiency of presentation of antigenic peptides (self or foreign) to CD4-positive or CD8-positive T lymphocytes: various of the HLA alleles reported to influence such susceptibility are cited by Cheong et al. There is supporting information too that HLA influences the capacity of an individual to mount a durable protective response to a vaccine prepared from the surface antigen of the virus (HBsAg).6,7 Notably, the gene for one of the cytokines studied, TNF-α, is located within the major histocompatibility complex (MHC) and alleles at this locus are in strong linkage disequilibrium with alleles at the HLA loci. 8,9 It is of interest that the −308 A allele is carried on the A1, B8, DR3 haplotype and is associated with viral clearance. The third need is the awareness that in natural infection with HBV, all arms of the protective immune system are mobilized, providing for efficient T cell responses to core antigens, and efficient B cell responses to surface antigens, indicating the likely existence of many immunogenetic influences on outcome of infection, most if not all likely to be of small magnitude. The fourth need is the recognition of the multiple physiological roles in immunity of IL-10 and TNF-α. However, characteristically, IL-10 is a cytokine that promotes helper T cell type 2 responses and production of IL-4, and has anti-inflammatory and antifibrotic effects, whereas, characteristically, TNF-α is a T helper cell type 1 (Th1) cytokine with potent proinflammatory activities resulting in cell death, virus elimination and fibrogenesis. Given the properties of IL-10 and TNF-α, gene polymorphisms that determine high or low producer phenotypes would be expected to influence, at least to some degree, the outcome of infectious/inflammatory diseases affecting any tissue, including HBV infection of the liver. However, the reported results for HBV infection have some inconsistencies, either because the phenotypic effects of cytokine gene polymorphisms are individually weak, or the human populations sampled have been relatively small. Cheong et al. were able to demonstrate differences, using a substantial study population of 412 patients with chronic HBV infection (72 inactive infection, 261 chronic hepatitis, 78 cirrhosis) and 72 uninfected controls, together with informative statistical procedures including multivariate analysis. HBV persistence was more frequent among carriers of the −592 A allele for the IL-10 promoter (low producers) than among those with the −592 C/C genotype (high producers), and among the −308 G haplotype homozygotes for the TNF-α promoter (low responders) than among those with the −308 A allele (high producers). The results for IL-10 were at variance with other reported data, and perhaps counter-intuitive. However Cheong et al. draw on the pleiofunctionality of IL-10, as although IL-10 should be inhibitory for Th1 responses such that high rather than low production should favor persistence of infection, IL-10 can have enhancing effects on the level of CD8+ cytotoxic T cell responses that would favor clearance of HBV infection, so explaining the data. In contrast, no effects of various IL-10 polymorphisms in autoimmune liver diseases, including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), proved informative according to a review by Donaldson.10 In the case of TNF-α, which is an HBV-inhibitory cytokine, results were intuitive, as carriers of the −308 A genotype (high TNF-α producers) were more frequent in the clearance group, whereas carriers of the G/G genotype (haplotype homozygotes, low TNF-α producers) were more frequent in the HBV persistence group. Moreover, interestingly and expectedly, carriers of the −308 A allele for TNF-α have an enhanced disease susceptibility for AIH and PSC, wherein inflammatory and fibrotic features are prominent. As mentioned, however, there is linkage disequilibrium of the TNF-α−308 A allele with the prevalent high risk HLA 8.1 haplotype that is associated with hyper-responsiveness of the immune system and with a range of diseases of autoimmune etiology. This trio of immune hyper-responsiveness, autoimmunity, and viral clearance is well worthy of deeper exploration. Summing up, inherited SNPs in the promoter for two cytokine genes studied, IL-10 and TNF-α, had a demonstrable capacity among Koreans to influence clearance of HBV infection. The effects were small and, as pertains also for chronic inflammatory autoimmune diseases, the risk for chronicity after hepatitis virus infection will likely be conferred in part by environmental elements and in part by the combined inheritance of multiple low-risk genetic elements that operate at many different stages of the immune response. Among these, not surprisingly, are HLA alleles, as noted in reports that HLA-B35 is associated (weakly) with susceptibility to chronic infection with HBV,11–13 in line with a tendency for Class II HLA alleles to associate with autoimmune diseases and Class I alleles with some chronic infectious diseases. The author thanks Dr Brian Tait for kind advice.