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Abstract

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  2. Abstract
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See article in J. Gastroenterol. Hepatol. 2012; 27: 273–278.

The relatively recent description of T helper cells that produce IL-17 (Th17 cells)1,2 disturbed the previous accepted paradigm of a division of CD4 T helper cells into type 1 (Th1) cells, which predominantly produce cytokines such as interleukin (IL)-2, interferon (IFN)-γ and tumor necrosis factor (TNF)-α that promulgate cellular immune response to intracellular pathogens including viruses and intracellular bacteria, and type 2 (Th2) cells; the latter predominantly produce cytokines such as IL-4, IL-5 and IL-13 that promote aspects of the humoral immune response required for defense against other pathogens, such as parasites. The description of the Th17 arm of the T helper response has led to intense interest regarding its roles both in host defense and in the pathogenesis of a wide range of immune-mediated pathologies.

Human Th17 cells develop under the influence of various combinations of a range of cytokines including transforming growth factor (TGF)-β, IL-6, IL-21 and IL-23, and are dependent upon expression of the transcription factors retinoic acid-related orphan receptor c (ROR-c) and signal transducer and activator of transcription 3 (STAT3; reviewed in Miossec et al.3 and Crome et al.4). They secrete a number of cytokines, including IL-17A and IL-17F, IL-21, IL-22, and IL-26, although many of the effector functions of these cells appear to be mediated by IL-17A.3,4 This cytokine has a wide variety of functions, including important pro-inflammatory properties via induction of neutrophil development and recruitment, and as a recruitment and survival factor for macrophages. Given these effects, the role of Th17 cells as a trigger of innate immune responses occurring following antigen-specific stimulation has led them to be described as a bridge between innate and adaptive immunity.5

Th17 cells are particularly thought to play a role in immune responses at mucosal and epithelial surfaces.3 A role for Th17-mediated immunity in defense against infections with Candida  albicans and Staphylococcus aureus has been revealed by the demonstration that mutations within the STAT3 gene underlying the hyper-IgE syndrome inhibit the ability to develop Th17 responses in affected individuals, who are susceptible to infections with these organisms.6,7 Th17 cells are also suspected to play a role in immune responses to a range of other bacterial infections, including M. tuberculosis.3 A variety of viral infections, including herpes simplex virus, respiratory syncytial virus, and human immunodeficiency virus have also been shown to induce IL-17 responses.4 However, the role of Th17 responses in various viral infections is not entirely clear: while studies in some models suggest that Th17 is important in recruiting innate defense to mucosal sites in viral infection,8 others have suggested that IL-17 may play a role in increasing the immunopathology associated with viral infection.9

In addition to their role in host defense, Th17 responses are also thought to play a part in the pathogenesis of a variety of immune mediated pathologies, including psoriasis, rheumatoid arthritis and Crohn's disease (reviewed in Miossec et al.3 and Crome et al.4). Indeed, therapy with neutralizing antibodies against the common p40 chain of IL-12 and IL-23, the latter of which is required for development of Th17 responses, has yielded promising results in studies in a range of conditions.3,4 On this basis, such antibodies have been approved for use in psoriasis in the US and Europe, with ongoing studies in other conditions, in particular Crohn's disease.

Given the explosion of work on this cellular subset, it is unsurprising that interest in Th17 cells has also extended to studies of their role in the pathogenesis of a variety of liver conditions. Evidence for a role of IL-17 and Th17 cells has been obtained in a number of mouse models of liver injury, including schistosomal infection, primary biliary cirrhosis, and halothane induced hepatitis (recently reviewed in Hammerich et al.10). Studies in human liver disease also suggest a role for the Th17 response in autoimmune liver disease, alcoholic liver disease, non-alcoholic steatohepatitis, and hepatocellular carcinoma. Th17-mediated immunity has also been an area of interest as regards its roles both in immunity to hepatotropic viruses and its part in the pathogenesis of liver disease in chronic infection with the hepatitis B and C viruses (HBV and HCV).

In terms of viral hepatitis, the role of Th17 cells has currently been best studied in chronic HBV infection. The frequency of Th17 cells in peripheral blood has been demonstrated to be increased in individuals with chronic hepatitis B, with a positive correlation with serum alanine aminotransferase (ALT).11 The frequency of Th17 cells in the peripheral blood has also been found to be higher in subjects with acute or chronic flares of hepatitis B than in those with stable hepatitis B.12 Th17 cells were also increased in the liver in chronic HBV, and increases in Th17 frequencies were associated with viral load, ALT, and hepatitis activity index (HAI).12 In contrast, in another study, while increased numbers of Th17 cells correlated with ALT, a relationship with HBV DNA was not seen.13 The frequency of IL-17 producing cells in the chronically HBV-infected liver has also been shown to increase with higher Child–Pugh grade.14 Interestingly, despite the apparent relationship between increased Th17 cell frequency and disease severity in chronic HBV infection, the frequency of Th17 cells has been observed to increase on entecavir therapy, while the proportion of regulatory T cells falls.15 It has been hypothesized that Th17 responses in chronic HBV infection may be induced by pro-inflammatory CD16+ monocytes and macrophages, which have been shown to secrete cytokines capable of promoting Th17 responses,16 possibly at least in part mediated by increased IL-6 receptor expression by CD4 T cells.17 Interestingly, a recent study has demonstrated that much of the liver damage observed in the mouse HBV transgenic model is mediated by the Th17 type cytokine IL-22, without necessarily playing a role in the non-cytolytic control of viral replication, while the concentration of IL-22 in the serum of individuals with acute HBV infection was increased.18

Th17 responses in HCV infection are less well characterized. However, given the apparent role played in multiple other immune and inflammatory conditions, they are of obvious interest. HCV-specific Th17 cells are present in chronic HCV infection.19In vitro experiments demonstrated that the HCV NS4 protein elicited IL-10 and TGF-β expression by monocytes from HCV-infected individuals, and neutralization of these cytokines enhanced HCV-specific Th17 cell responses, suggesting potential regulation of these responses by the virus itself.19 IL-17 producing cells have also been demonstrated in the livers of HCV chronically-infected individuals in a number of studies.20,21 Th17 cytokines have also been studied in the setting of HCV anti-viral therapy. In one study, IL-17 levels were demonstrated to be elevated in the serum of subjects with chronic HCV infection; however, values did not correlate with viremia following 12 weeks of treatment with IFN-α and ribavirin.22 In contrast, in another study, serum Th17 type cytokines were found to be reduced after 12 weeks of HCV antiviral therapy, with the largest fall being seen in responders.23 In the setting of recurrent hepatitis C post-liver transplant, increased numbers of HCV-specific Th17 cells in the peripheral blood and increased levels of serum IL-17 have been observed in individuals with more severe disease.24

In this issue of the Journal of Gastroenterology and Hepatology, Chang and colleagues have further explored IL-17 producing T cells in chronic hepatitis C virus infection.25 They demonstrated an increased proportion of IL-17 producing CD8 negative T cells in the peripheral blood of HCV chronically-infected subjects following non-specific T cell stimulation, as well as a significant increase in serum IL-17 levels in these individuals. However, serum IL-17 levels did not correlate with ALT levels or plasma HCV RNA level. Instead, there was a correlation between the proportion of IL-17 producing CD8 negative T cells in the peripheral blood and ALT levels for both non-antigen specific and HCV-specific stimulation, and there was an inverse correlation with HCV RNA levels with non-specific, but not with HCV-specific stimulation. In addition, on analysis of liver biopsies from HCV-infected individuals, they found increasing numbers of IL-17 positive cells with increasing HAI scores; the correlation with serum ALT but not HCV RNA was again observed.25 While this result is very interesting, its implications are not entirely clear. In particular, as the proportion of the total infiltrate comprised by IL-17 positive cells was not characterized, it remains to be determined whether the apparent increase is a true enrichment of IL-17-producing cells associated with increasing levels of intrahepatic inflammation, or simply a function of the increased total number of cells associated with higher inflammatory scores. In addition, it should be borne in mind that a number of cell types other than Th17 lymphocytes can produce IL-17, including neutrophils, NK cells, NKT cells, and γδ T cells. Thus, the nature of the IL-17 producing cells in the livers of HCV infected individuals is not yet clear; further investigation is required before the contribution of Th17 cells to the pathogenesis of chronic hepatitis C can be established. Nevertheless, despite these caveats, these data provide tantalizing additional indications of a link between Th17 responses and liver injury in HCV infection.

The positioning of Th17 responses at the interface between the adaptive and innate immune responses, with the ability of these cells to induce tissue injuring inflammatory responses, will likely motivate much further research into the role of this arm of the helper T cell response in HCV immunopathogenesis. Despite the advent of direct acting antiviral agents in HCV treatment, it is likely that other avenues of treatment for HCV infected individuals will still be required in the foreseeable future. Treatments that interfere with Th17 responses, such as anti-IL-12/Il-23 p40 antibodies are already available, and given the intense interest in this pathway, further agents are likely to be developed. As discussed above, and summarized in Table 1, a range of data indicate that Th17 responses are involved in the pathogenesis of viral hepatitis. However, a range of outstanding questions will require answering before therapeutic interventions manipulating the Th17 response are attempted in HCV. In particular, interactions between Th17 cells and other aspects of the adaptive immune response, including regulatory T cells and Th1 responses require further exploration. In addition, while there is growing evidence of correlations between active inflammation and Th17 responses in chronic HCV infection, it is unclear whether the magnitude of Th17 responses correlate with advancing fibrosis in the non-immunosuppressed state, as has long been demonstrated for Th1 responses.26 It is likely that ongoing investigations in this area will answer these important questions, as well as provide other valuable insights into HCV pathogenesis.

Table 1.  Evidence for a role of Th17 cells in chronic viral hepatitis (see text for references)
  1. ALT, alanine aminotransferase; HAI, hepatic activity index; HCV, hepatitis C virus.

Hepatitis B
 Increased Th17 cells in peripheral blood and liver
 Positive correlation of Th17 cell frequencies with ALT and HAI
 Increased Th17 cells in acute or chronic flare
 Th17 cell numbers correlate with Child–Pugh grade
 Relationship with viral load as yet unclear
 Cell numbers increase with entecavir therapy
Hepatitis C
 HCV-specific Th17 cells present in peripheral blood and liver
 In vitro evidence of potential modulation by HCV NS4 protein
 Variable therapy-associated changes in serum Th17 cytokines described
 Increased Th17 cell numbers and serum IL-17 in severe recurrence post-transplant
 Th17 cell frequencies correlate with ALT and HAI

References

  1. Top of page
  2. Abstract
  3. References