Next-generation immunosequencing reveals pathological T cell architecture and reactive B cell dysregulation in autoimmune hepatitis

Background & 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 while 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 & Results: T and B cell receptor (TCR/BCR) repertoire and HLA next-generation sequencing were used to record immune signatures from a cohort of 60 AIH patients 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. High plasma levels of IL-10 suggested that the rather non-specific B cell dysregulation could be seen as a regulatory response, since IL-10 is a dampener of excessive T cell activation while at the same time promoting immunoglobulin class switch recombination and secretion. 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: AIH patients 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.