hepatitis c virus ( hcv ) is noncytopathic virus that causes chronic hepatitis and hepatocellular carcinoma ( hcc ) .
around 30% of chc patients exhibit pnalt and show milder disease activity and slower progression to hepatic cirrhosis [ 26 ] . however , it is reported that about 40% of these progress to the active stage of inflammation , but the incidence of hcc in the pnalt was lower than that in those with elevated alt levels .
cellular and humoral immune responses to hcv play an important role in the pathogenesis of active and nonactive chronic hepatitis .
numerous studies have indicated that failure of the cellular immune response , including type 1 helper t cells ( th1 ) hypo - responsiveness , cytotoxic t lymphocyte ( ctl ) exhaustion , excessive function of cd4 +  cd25 +  foxp3 + regulatory t cells , and failure of lymphoid cells via direct binding and/or infection in b cells , t cells , nk cells , and dcs occurs in chc patients [ 921 ] . since the liver damage in chc
is mainly induced by th1 and/or ctl related responses [ 2224 ] , these responses might be strongly suppressed in pnalt .   given
the involvement of immune responses , genetic factors including polymorphism of hla and cyotokine - related genes could also contribute to the activity of inflammation in chc patients [ 2537 ] .
many groups , including us , have reported on the relationship between certain hla and alt levels in chc patients [ 25 , 2729 ] . moreover ,
some groups indicated the polymorphism of certain cytokines - related genes contributed to the level of inflammation [ 3037 ] . in a genomewide association study ( gwas ) , il28b polymorphism was shown to influence the outcome of peg - ifn and rbv therapy . however , although the relationship between il28b polymorphism and pnalt is still unclear , a possible relationship between il28b polymorphism and the activity of inflammation has been reported [ 39 , 40 ] . in this review
, we focused on the possible immunopathological aspects of pnalt and summarize various studies about the mechanism and genetic host factors involved in the immune suppression in chc patients .
innate immune systems are important for the initial step of viral infection [ 41 , 42 ] ( figure 1 ) .
toll - like receptors ( tlrs ) are a family of innate immune - recognition receptors that recognize molecular patterns associated with microbial pathogens including single and double - strand rna .
hcv interferes with the innate immune response and the induction of ifn - beta via the hcv ns3/4a protease activity , which inhibits the phosphorylation of irf-3 , a key transcriptional regulator of the ifn response [ 43 , 44 ] .
hcv ns3 protein interacts directly with tbk1 , and this binding results in the inhibition of the association between tbk1 and irf-3 , which leads to the inhibition of irf-3 activation .
however , since little is known about the direct relationship between the suppression of tlr signaling and pnalt , the level of tlr signaling suppression might contribute to the immunopathogenesis of pnalt .
in addition to the intracellular immune reaction of hepatocytes , monocytes , nk , and nk - t cells are responsible for the rapid reaction in hcv infection ( figure 1 ) .
many groups have described that nk and nk - t cells were suppressed in chc patients [ 4653 ] . however , whether nk and nk - t cells would be suppressed in chc patients is still controversial .
the function of nk cells is regulated by a balance of inhibitory and activating signals , which are mediated by the differential expression of receptors .
takehara and hayashi recently reported that the expression of the inhibitory receptor cd94/nkg2a is upregulated on nk cells in chc patients .
another group reported that exposure to hcvcc modulates the pattern of cytokines produced by nk cells , leading to reduced antiviral activity .
previously , it was reported that hcv - core and ns3 protein triggered the inflammatory pathway via tlr2 , which might affect viral recognition and activation of the immune system .
it was also reported that peripheral blood monocyte expression of tlr2 but not of tlr4 correlated significantly with the serum alt levels . concerning the mechanisms of monocyte - suppression
, it was clearly demonstrated that macrophage cell lines expressing ns3 , ns3/4a , ns4b , or ns5a inhibited the activation of the tlr2 , tlr4 , tlr7 , and tlr9 signaling pathways . among the hcv individual proteins ,
ns5a bound to myd88 , a major adaptor molecule in tlr , inhibited the recruitment of interleukin-1 receptor - associated kinase 1 to myd88 and impaired the cytokine production in response to tlr ligands .
these results indicated that the activation of monocytes was probably suppressed in low alt and pnalt chc patients .
after the innate immune period , the adaptive immune system including cd4 + t cells , cd8 + cyototoxic t cells , b cells , and dendritic cells should be involved in a more effective immune response to hcv .
the hcv antigen - driven proliferation of cd4 + t cells is weak in patients who develop persistent hcv infection [ 57 , 58 ] .
it has been demonstrated that depletion of cd4 + t cells results in a weak cd8 + t cell response , which partly controls viremia , followed by viral persistence in chimpanzee infection studies . in addition , an appropriate th1 response is essential to eradicate hcv .
it has been reported that an increased th2 cytokine response may reduce the inflammatory and biochemical activity . moreover
, various studies have indicated that failure of the adaptive immune response , including th1 hypo - responsiveness , cd8 + ctl exhaustion , excessive function of cd4 + cd25 + foxp3 + regulatory t cells , and failure of lymphoid cell via direct binding and/or infection in b cells , t cells , and dcs occurs in chc patients [ 921 ] .
previously , we reported the direct suppressive effect of hcv on t cell- and b cell - immunity in chc by using a lymphotropic hcv strain [ 1417 ] . however , since the contribution of lymphotropic hcv to the pathogenesis of pnalt is still not clear , the biological significance of lymphotropic hcv needs to be analyzed in future studies .
studies about the relationship between the infectivity of lymphotropic hcv and pnalt are ongoing in our laboratory .
tregs constitutively express cd25 ( the il2 receptor alpha - chain ) in the physiological state . in human
, this tregs population , defined as cd4 + cd25 + foxp3 + cells , constitutes 5% to 10% of peripheral cd4 + t cells and has a broad repertoire that recognizes various types of self and nonself antigen .
antigens induced by hcv might induce tregs to escape from immunological pressure as reported in persistent infection of eb virus , hepatitis b virus , and hiv [ 6367 ] ( figure 2 ) .
more recently , itose et al . reported that the frequencies of naturally occurring - treg in chc patients were significantly higher than those in healthy individuals .
another group also described that their suppressor ability is stronger in patients with pnalt than that in those with active chc hepatitis .
these two studies could be direct evidence about the relationship between pnalt and the function of tregs .
moreover , a unique subset of lymphocytes might contribute to the immune suppression in pnalt   ( figure 2 ) .
cd8 + ctls are able to recognize viral antigens synthesized within infected cells in the form of short peptides associated with hla class i molecules . on the other hand ,
cd4 + th cells are able to recognize antigens associated with hla class ii molecules [ 70 , 71 ] .
individuals that are heterozygous at hla class i  loci are able to present a greater variety of antigenic peptides to ctl resulting in a broader immune response .
hla class i heterozygosity was found at a higher rate in patients with slow progression to aids in hiv-1 infection .
however , hla class i heterozygosity did not affect the inflammatory levels of chc patients in our previous study .
the frequency of hla - a2 tended to be higher in patients with pnalt than in those with elevated alt level .
a specific hla class ii allele has been reported to influence the disease severity   or viral clearance in chronic hepatitis c .
yoshizawa et al . reported that the frequencies of drb1 * 12 ( * 1201 and * 1202 ) , dqb1 * 0301 , and drb3 * 03 alleles were higher in patients with asymptomatic hcv carriers than those in liver cirrhosis patients .
large - scale studies might be able to verify the ethnic , gender , age , and other genetic factors and determine the influence of the hla allele on pnalt .  
numerous studies indicated that various kinds of cytokine - related gene polymorphism were involved in the immunopathogenesis of chc .
il10 is a suppressive cytokine that could contribute to the persistence of hcv infection and low inflammation level in chc .
mangia et al . reported that the il-10 ata haplotype was more frequent in patients with spontaneous hcv rna clearance ( 36.0% ) than that in patients with persistent infection ( 23% ) . on the other hand
, another group reported that no effect of il-1beta and il-10 gene polymorphism on the degree of hepatocellular injury was apparent based on the alt levels .
however , a gender effect is clearly observed in women carrying the gg high il-10 producer genotype .
the higher levels of il-10 present in such individuals are associated with a higher risk of inefficient clearance of the hcv and the development of a chronic hcv infection together with a lower risk of progression to cirrhosis in female patients .
these reports indicated that il-10-related gene polymorphism might affect the level of inflammation in certain conditions .
ccr5delta32 , a 32-base pair deletion of the cc chemokine receptor ( ccr ) 5 gene , is associated with slower human immunodeficiency virus disease progression in heterozygotes and protection against infection in homozygotes .
reported that heterozygosity for ccr5delta32 was significantly associated with spontaneous hepatitis c viral clearance and with significantly lower hepatic inflammatory scores .
in addition to these gene polymorphisms , polymorphism of tgf - beta , tnf - alfa , il2 , ifn - g , and oas-1 genes might contribute to the level of inflammation [ 3032 , 35 , 74 ] .
a genomewide association of il28b with the response to pegylated interferon and ribavirin was reported .
then , another group reported that different cytokine profiles induced by the il28 polymorphism resulted in different interferon stimulated genes and il28 expression during chronic hcv infection .
they reported that the expression of il28 , mxa , pkr , oas1 , and isg15 in hepatic cells was significantly lower in patients with the response - favorable ( rs8099917 ) t / t genotype compared to those with t / g or g / g genotypes .
a future study might be able to determine the relationship between il28 polymorphism and pnalt .
in chc patients , there are many kinds of immune - suppressive mechanisms . however , although the immunopathogenesis of pnalt has not been clarified yet , the complexities of immune reactions likely contribute to the difficulties of determining the detailed mechanisms of pnalt .
recently , the technologies of gwas , immunoassay with increased numbers of multicolor flow cytometry analysis , and chimera mice with human hepatocytes and lymphocytes have been developed .
these technologies , together with previous data , might be able to clarify the immunopathogenesis of pnalt in chc .
 patients with chronic hepatitis c ( chc ) virus infection who have persistently normal alanine aminotransferase levels ( pnalt ) have mild inflammation and fibrosis in comparison to those with elevated alt levels . 
 the cellular immune responses to hcv are mainly responsible for viral clearance and the disease pathogenesis during infection . however , since the innate and adaptive immune systems are suppressed by various kinds of mechanisms in chc patients , the immunopathogenesis of chc patients with pnalt is still unclear . in this review , 
 we summarize the representative reports about the immune suppression in chc to better understand the immunopathogenesis of pnalt . 
 then , we summarize and speculate on the immunological aspects of pnalt including innate and adaptive immune systems and genetic polymorphisms of hla and cytokines . 
1. Introduction
2. Mechanism of Immune Suppression in CHC Patients
3. HLA and Cytokine-Related Gene Polymorphism and ALT Level
4. Concluding Remarks