Introduction
Hepatitis C virus infection cause about 3% chronic hepatitis in more than 70% of infected patients, while 20–30% of patients recover spontaneously [2]. The host immune response to HCV lead to pathogenesis and outcome of viral infections. The immune system is able to clear many viruses in the acute phase of infection. Innate immune responses are the first line of defense against viral infections and interferons are responsible for the activate of an antiviral state in cells and for the activation and regulation of the cellular components of innate immunity, such as natural killer cells [6]. Type I IFNs (comprising several IFN-? and IFN-?) are produced by cells infected with viruses and by key sentinel cells of the innate immune system: macrophages and dendritic cells . Importantly, macrophages and DCs do not have to be infected by viruses in order to produce IFNs. Instead, they constantly sample material from the outside, including virus containing remnants of apoptotic cells and intact viral particles. Degradation processes in the endosomes then expose viral nucleic acids to recognition by TLRs. Type II IFN (IFN-?) is produced by NK and natural killer T cells as part of the innate immune response, and by antigen-specific T cells (both CD4+ Th1 and CD8+ cytotoxic T lymphocytes). Virus infections are sensed by the toll-like receptor (TLR) dependent pathway [7,8] and the cytosolic pathway, activate by binding RNA of virus to the RNA helicases retinoic acid inducible gene-1 (RIG-1) and melanoma differentiation antigen 5 (Mda5) [9,10]. Both pathways converge on the activation of the key transcription factors NF-jB and the interferon regulatory factor (IRF) 3 and 7. Activated IRF3 and NF-jB bind to response elements in the promoters of type I and III IFN genes. All types of IFNs induce an antiviral state by the transcriptional activation of hundreds of genes. The specific set of genes differs between IFNs and target cell type. In general, IFN-as and IFN-ks induce a largely overlapping set of genes in cells that express receptors for both IFN-a and IFN-k [11], whereas the IFN-c-induced gene set is more distinct [12,13]. The number of genes regulated by IFNs also differs between cells. For instance, pegylated IFN-a significantly induces 200 to 300 genes in the liver, but nearly 2000 genes in peripheral blood mononuclear cells (PBMCs) [14. Natural killer (NK) cells are large granular lymphocytes that account for the majority of innate immune cells in the human liver [45,46]. Indeed, they are significantly increased in the liver compared to the peripheral blood although this becomes
especially evident in chronic HCV infection. NK cells play an important role in the control of viral infections. They have direct antiviral as well as regulatory effects [46,47]. The direct antiviral effects are mediated by direct cytolytic (e.g., TRAIL or perforinmediated) or non-cytolytic (e.g., IFN-c mediated) effector functions. Several lines of evidence support a relevant role of NK cells in acute HCV infection. For example, genetic studies have demonstrated that genes encoding the inhibitory NK cell receptor KIR2DL3 and its human leukocyte antigen C group 1 (HLA-C1) ligand directly influence resolution of HCV infection in patients homozygous for these genes [48]. Furthermore, KIR2DL3+- NKG2A_ NK cells have been suggested to control early HCV infection prior to seroconversion and may thus result in an apparent state of ‘‘natural resistance’’ to HCV in persons who inject drugs .However, some viruses, like hepatitis C virus (HCV) and hepatitis B virus (HBV), can evade the host immune responses and establish a persistent infection [3]. The precise role of the immune response in patients with HCV infection, in particular the relationship between the levels of inflammatory/regulatory cytokines and the course. Of HCV infection, is still unclear. that these cytokines can trigger distinct patterns of protective or immunopathological responses and that they are involvedin the clearance or establishment of chronic HCV infection [4]. However, the balance of proinflammatory and regulatory cytokines appears to be important in determining the course of HCV infection [5]. Cytokines play an important role in differentiation, maturation, and functional activation of immune cells [6]. Cytokines are produced bymultiple cell types such asNKcells and macrophages CD4+T cells and CD8+T cells. Responses are referred to as Th1-like and Th2-like after the original description of the cytokine profiles produced by subsets of CD4+T cells [7]. Th1-like responses include IL-2, TNF-??, and IFN-?? secretion and are required for generation of cytotoxic T lymphocytes and NK cell activation during the host antiviral immune response. Th2-like responses produce IL-4 and IL-10, which help augment antibody production and inhibit development of the Th1 response [8]. IL-10 is a pleiotropic cytokine produced by macrophages T-helper 2 (Th2) cells and B-lymphocytes,