IL-10 haplotypes as possible predictors of spontaneous clearance of HCV infection
Introduction
Clinical determinants of chronic or self-limiting hepatitis C virus (HCV) infection are still unknown. So far, analyses of the variable outcome of acute infection have focused mainly on viral factors, such as genotype or viral load; however, the susceptibility to either clear the infection or develop a progressive disease might be influenced by the host's genetic background.
In recent years, increasing attention has been drawn to the significance of host variation of cytokine levels in inflammatory and immune responses [1]. T-helper (Th) cytokines have been proposed to be important in the host response to HCV [2], [3]. Pro-inflammatory cytokines, such as IFNγ, TNFα, and IL-2, produced by T-helper type 1 (Th1) CD4+ cells, are required for host antiviral immune responses, whilst T-helper type 2 (Th2) anti-inflammatory cytokines, such as IL-4 and IL-10, down-regulate the Th1 response. In a proportion of patients with untreated chronic HCV infection, Cacciarelli et al. [4] reported elevated serum levels of IL-2, IL-4, and IL-10. These in vivo results have received in vitro confirmation by the demonstration of a long lasting increase of IL-10 production by CD4+ T cells following HCV infection of the cells [5]. Serum IFNγ and TNFα levels have also been found elevated in HCV infection, probably secondary to their production by cytotoxic T lymphocytes (CTL) in the liver [6].
The striking difference between individuals in the ability to produce IL-10, TNFα, or IFNγ after in vitro stimulation has been ascribed to polymorphisms within the genomic regulatory regions or within signal sequences of the respective genes [7], [8], [9], [10]. Several polymorphic sites within the promoter region of the IL-10 gene have been described; the combination of three single nucleotide polymorphisms at positions −1117, −854, and −627 from the transcription start site produces three different haplotypes (GCC, ACC, and ATA), which are associated with differential IL-10 expression: the ATA haplotype might be responsible for a diminished IL-10 expression, while the GCC haplotype correlates with high levels [7], [8].
Within the first intron of the human IFNγ gene, a variable length dinucleotide (CA) repeat sequence with different alleles has been described: an allele of 119 base pairs (bp) has been associated with high in vitro IFNγ production, whereas alleles of 123 and 125 bp characterize low IFNγ levels [9], [10]. In the TNFα gene, the presence of G or A nucleotide at position −308 of the promoter region generates three potential genotypes A/A or A/G, and G/G, which correspond phenotypically to the production of high or low levels of TNFα, respectively [11], [12]. The role of a second single nucleotide polymorphism at position −238 of the TNFα gene is not clear yet [13].
In HCV chronic infection, polymorphisms with high IL-10 production have been associated to a poor response to interferon treatment [14], [15]. The −238 A allele in the TNFα gene promoter has been associated with development of chronic HCV infection [16]. No data are available on IFNγ genetic variability in HCV infection. We sought to test the hypothesis that genetic polymorphisms of IL-10, IFNγ, and TNFα in patients with HCV infection would affect both the clinical outcome of the infection and the response to antiviral treatment.
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Patients
Two hundred and sixty-five anti-HCV positive patients were enrolled into the study. They were divided into two main categories on the basis of investigation documenting a still ongoing infection with liver disease (Group 1, N=170) or a past (cleared) infection (Group 2, N=100). The criteria for inclusion into Group 1 were a positive HCV RNA level in serum at repeat testing and a chronic liver damage at histology. Of the 170 patients included in Group 1, 120 patients had abnormal ALT levels and
Results
As expected, main clinical and virologic features differed among the four subgroups of patients (Table 2): patients in subgroup 1A were older and mainly infected with genotype 1; whereas patients in subgroup 1B were predominantly females and mostly infected with genotype non-1.
In the total population of the 270 anti-HCV positive patients, alleles and genotype frequencies of the three genes under investigation were not differently distributed from those observed in the 145 healthy, normal
Discussion
The aim of the present study was to test the hypothesis that inheritance of polymorphisms of the TNFα, IL-10 and IFNγ promoter genes might influence susceptibility to and persistence of HCV infection, clinical features of liver disease, and response to antiviral treatment. By using appropriate control groups, we have found that inheritance of −1117A, −854T, and −627A alleles combined as an extended haplotype of the IL-10 gene was significantly associated to a spontaneous eradication of the HCV
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