Role of hepatitis E virus (HEV) infection in the induction of autoimmune hepatitis (AIH)
Final Report Abstract
In this project, we had the aim to investigate if cross-reactive T cells play a role in the onset of autoimmune hepatitis (AIH), as a result of hepatitis E virus (HEV) infection. In this context, T cells cross-reactivity is used to describe how a single T cell is able to recognize both a HEV peptide and another (unrelated) self-peptide. As the selfpeptide is constantly present in the body, induction of cross-reactive T cell responses, i.e. by HEV infection may result in auto-immunity. Indeed, we observed a trend towards more frequent HEV-specific CD8+ T cell responses that cross-recognized autoantigens in AIH patients compared with healthy controls. At this stage, this is not statistically significant and more experiments are required. In addition, we discovered a cross-reactive T cell clone isolated from a healthy donor, which recognized an HEV epitope and a fragment associated with apoptosis, the programmed cell death event that takes place to remove unwanted cells. Even though the two peptides share only minimal sequence similarity, our evidence showed that the T cell clone could bind both MHC-peptide complexes. By sequencing the TCR repertoire we identified that multiple glycines in the TCR V-beta CDR3 region may be the reason for the high flexibility of the TCR and the crossreactivity. We genetically engineered the T cell receptor (TCR) and cloned this TCR into T cells. Indeed, the TCR recognized both the HEV epitope and a HEV transfected tumor cell but also the apoptotic antigen. As TCR gene therapy is a potential therapy for tumors but also chronic virus infections, we decided to focus more on determining T cell clones that possess potent immune response against the HEV virus. This is an important task, as our finding could be developed into novel T cell based therapy for those suffering lifelong from chronic hepatitis due to HEV, particularly organ transplant patients. So far the problem of cross-reactivity of such a TCR with autoantigens has not been considered in this detail but this might be relevant and explain some immune mediated adverse events of such a therapeutic approach.
Publications
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‘Identification of a highly cross-reactive CD8+ T cell repertoire that recognizes an HEV peptide and an apoptotic epitope’, Z Gastroenterol 2016; 54(12): 1343-1404
CF Soon, AA Markova, HH Wedemeyer, MP Manns, M Cornberg, S Zhang
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(2017) ’Hepatitis E virus ORF 1 induces proliferative and functional T-cell responses in patients with ongoing and resolved hepatitis E.’ Liver Int. 38:266-277
Al-Ayoubi J, Behrendt P, Bremer B, Suneetha PV, Gisa A, Rinker F, Manns MP, Cornberg M, Wedemeyer H, Kraft ARM
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‘Identification of a highly cross-reactive CD8+ T cell repertoire that recognizes a hepatitis E virus peptide and an apoptotic epitope’, J Hepatol 2017; Volume 66, Issue 1, Supplement, Page S327
C.F. Soon, A. Markova, H.H. Wedemeyer, M. Manns, S. Zhang, M. Cornberg
