Next-generation immunosequencing reveals pathological T cell architecture in autoimmune hepatitis

TY - JOUR

T1 - Next-generation immunosequencing reveals pathological T cell architecture in autoimmune hepatitis

AU - Schultheiß, Christoph

AU - Germany, Department of Internal Medicine IV Oncology/Hematology Martin-Luther-University Halle-Wittenberg

AU - Willscher, Edith

AU - Oberle, Anna

AU - Fanchi, Lorenzo

AU - Bonzanni, Nicola

AU - Wildner, Nils H

AU - Schulze-Zur-Wiesch, Julian

AU - Weiler-Normann, Christina

AU - Lohse, Ansgar W

AU - Binder, Mascha

N1 - © 2020 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

PY - 2021/4

Y1 - 2021/4

N2 - BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a chronic liver disease that regularly relapses when immunosuppression is tapered. It is thought to be driven by T-cells, whereas the etiologic impact of an apparently deregulated B lineage system, as evidenced by hypergammaglobulinemia and autoantibodies, remains elusive. We set out to investigate T and B cell repertoires supporting chronic inflammation in AIH.APPROACH AND RESULTS: T and B cell receptor (TCR/BCR) and human leukocyte antigen (HLA) next-generation immunosequencing were used to record immune signatures from a cohort of 60 patients with AIH and disease controls. Blood and liver B lineage immune metrics were not indicative of a dominant directional antigen selection apart from a slight skewing of IGHV-J genes. More importantly, we found strong AIH-specific TRBV-J skewing not attributable to the HLA-DRB1 specificities of the cohort. This TCR repertoire bias was generated as a result of peripheral T cell (de)selection and persisted in disease remission. Using a clustering algorithm according to antigenic specificity, we identified liver TCR clusters that were shared between patients with AIH but were absent or deselected in patients with other liver pathologies.CONCLUSIONS: Patients with AIH show profound and persisting T-cell architectural changes that may explain high relapse rates after tapering immunosuppression. Liver T-cell clusters shared between patients may mediate liver damage and warrant further study.

AB - BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a chronic liver disease that regularly relapses when immunosuppression is tapered. It is thought to be driven by T-cells, whereas the etiologic impact of an apparently deregulated B lineage system, as evidenced by hypergammaglobulinemia and autoantibodies, remains elusive. We set out to investigate T and B cell repertoires supporting chronic inflammation in AIH.APPROACH AND RESULTS: T and B cell receptor (TCR/BCR) and human leukocyte antigen (HLA) next-generation immunosequencing were used to record immune signatures from a cohort of 60 patients with AIH and disease controls. Blood and liver B lineage immune metrics were not indicative of a dominant directional antigen selection apart from a slight skewing of IGHV-J genes. More importantly, we found strong AIH-specific TRBV-J skewing not attributable to the HLA-DRB1 specificities of the cohort. This TCR repertoire bias was generated as a result of peripheral T cell (de)selection and persisted in disease remission. Using a clustering algorithm according to antigenic specificity, we identified liver TCR clusters that were shared between patients with AIH but were absent or deselected in patients with other liver pathologies.CONCLUSIONS: Patients with AIH show profound and persisting T-cell architectural changes that may explain high relapse rates after tapering immunosuppression. Liver T-cell clusters shared between patients may mediate liver damage and warrant further study.

U2 - 10.1002/hep.31473

DO - 10.1002/hep.31473

M3 - SCORING: Journal article

C2 - 32692457

VL - 73

SP - 1436

EP - 1448

JO - HEPATOLOGY

JF - HEPATOLOGY

SN - 0270-9139

IS - 4

ER -