Autoimmune hepatitis: Of host and pathogen
Authors: Eirini I. Rigopoulou, George N. Dalekos
Journal: Hepatology (2008)

We have read with considerable interest the exceptional work reported by Longhi et al.1 investigating CD8 T-cell immune responses directed against cytochrome P450IID6 (CYP2D6), the major autoantigen in patients with autoimmune hepatitis (AIH) type 2. We noticed that reactivity to p3 CYP2D6 peptide, which had homology with CYP2A68-17and CYP2A78-17, correlated with biochemical markers of disease activity, suggesting that p3-specific CD8 T cells may be involved in liver damage. It is also of interest that both CYP2A68-17and CYP2A78-17 have been reported to be cross-reactively recognized with HCV178-187 by CD8 T cells in chronic hepatitis C virus,2 whereas we have shown that anti-CYP2A6 antibody may be present in HCV patients.3 Of note, p3-specific CD8 T cells were not as effective at the cytotoxicity level,1 and this suggests a dichotomy between CD8 T-cell functions, which is a phenomenon reported in chronic HCV.4 In addition, Longhi et al. stated that on the basis of their own preliminary experiments, p3 induces the highest percentage of interferon-γ–producing CD8 T cells in CYP2D6+/HCV+ patients. In a previous work of the same group published in Gastroenterology,5 the investigation of cellular immunity directed against CYP2D6 in AIH showed that apart from AIH patients, patients with HCV infection presented CYP2D6-specific CD4 responses (among 73 pathological controls with various diseases, these responses were found exclusively in HCV-infected patients as 3/6 anti-CYP2D6 antibody–negative HCV patients had significant CD4 responses to a CYP2D6 peptide mimicking HCV). Taken together, these pioneer studies1, 5 raise the possibility that HCV may trigger AIH through a mechanism of molecular mimicry. This issue6-10 has been recently revisited by Krawitt in New England Journal of Medicine11 and Manns and Vogel in HEPATOLOGY.7 There is a possibility, however, that AIH and viral hepatitis do not have a pathogenetic connection but can be simultaneously present in an individual.11 We feel that this issue needs to be highlighted for several reasons: In our experience, diagnosis of AIH in patients infected with hepatitis B virus (HBV) and HCV is not as rare in Mediterranean countries as has been previously considered, and this may also be the case in other countries in which viral hepatitides are endemic.11 From our records, we estimate that 4-5 cases of AIH with coexistent chronic HBV and/or HCV infections correspond to every 100 cases of AIH. We therefore agree with Dr. Krawitt's view that because chronic viral hepatitis appears to be very common, the prevalence of AIH may be higher than reported because of concomitant chronic HCV or HBV or both. CYP2D6-specific CD8 and CD4 T-cell responses in this unique group of patients with concomitant HCV and AIH type 2 have not been investigated so far. The scoring of the International Autoimmune Hepatitis Group discourages the diagnosis of AIH in this special group of patients; such patients get −3 points for the presence of viral hepatitis and −3 points for non–AIH-related histological features (such as steatosis or nodular-appearing infiltrates characteristic in patients with chronic HCV).12 We believe that the contribution of an AIH component to the overall clinical picture of chronic HBV or HCV patients should cautiously be considered. This would particularly be the case when transaminasemia exists but viremia due to hepatitis viruses (as detected by polymerase chain reaction techniques) is absent or very low and when autoantibodies acquire the features that are typical of AIH. Such features include detection by indirect immunofluorescence of the tubular pattern associated with smooth muscle antibodies, the homogeneous pattern associated with antinuclear antibodies, and the staining of the P3 portion of the proximal tubules typical of liver kidney microsomal seropositivity.10, 13 Physicians and clinical gastrohepatologists need to be aware of the possibility of AIH in HBV or HCV patients. Such patients need to be treated with caution for the underlying diseases as the presence of AIH appears to predispose to severe adverse reactions during antiviral treatment with interferon-alpha.14, 15 The magnitude of aminotransferase activity can be such that suspension of treatment is required. Conversely, immunosuppressive treatment may lead to the exacerbation of the underlying viral disease. Learning more about the hierarchy and evolution of tolerance of CYP2D6-specific CD4 T-cell autoimmunity along with the definition of immunodominant human leukocyte antigen class I–restricted epitopes within known CYP2D6 sequences for the CYP2D6-specific CD8 T-cell responses in concomitant HCV and AIH-2 cases may advance our understanding of the host-pathogen interactions and perhaps assist in the design of the therapeutic intervention urgently needed. Eirini I. Rigopoulou* , George N. Dalekos* , * Academic Liver Unit and Research Lab of Internal Medicine, Department of Medicine Larissa Medical School, University of Thessaly, Larissa, Greece, Research Group of Investigational Medicine, Institute of Biomedical Research and Technology, Centre for Research and Technology–Thessaly, Larissa, Greece.