Next-generation immunosequencing reveals pathological T cell architecture in autoimmune hepatitis
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Next-generation immunosequencing reveals pathological T cell architecture in autoimmune hepatitis. / Schultheiß, Christoph; Germany, Department of Internal Medicine IV Oncology/Hematology Martin-Luther-University Halle-Wittenberg; Willscher, Edith; Oberle, Anna; Fanchi, Lorenzo; Bonzanni, Nicola; Wildner, Nils H; Schulze-Zur-Wiesch, Julian; Weiler-Normann, Christina; Lohse, Ansgar W; Binder, Mascha.
In: HEPATOLOGY, Vol. 73, No. 4, 04.2021, p. 1436-1448.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -