Immune Alterations in Patients With Type 1 Autoimmune Hepatitis Persist Upon Standard Immunosuppressive Treatment

Abstract

Autoimmune hepatitis (AIH) is a rare disease characterized by an immune attack of the liver. This study consists of a comprehensive analysis of immune alterations related to AIH at diagnosis, and during remission phase under treatment. A total of 37 major lymphocyte populations were analyzed from the peripheral blood of new‐onset AIH patients (AIHn; n = 14), AIH patients with controlled disease (n = 11), and healthy subjects (n = 14). Liver biopsy analyses were performed to complete the blood phenotypic analysis. Four blood lymphocyte populations were significantly altered in AIHn patients at diagnosis compared with healthy subjects. Levels of mucosal‐associated invariant T cells (MAIT), Type 1/Type 17 helper (Th1/ Th17) cells, clusters of differentiation (CD4) T cells, and invariant natural killer T cells were decreased, whereas MAIT granzyme B+ (GrB) cells were increased. A trend toward an increase of CD8+CD161+GrB+ cells was also observed. These alterations were not restored with standard immunosuppressive treatments. In the liver of AIHn patients, CD4, forkhead box P3 (Foxp3), and MAIT cell markers were enriched in the portal tract, and CD8, CD161, and GrB markers were enriched in the hepatic lobule. During remission, the hepatic lobule was clear of infiltrating T cells, but residual CD4 and MAIT cells were found in the portal tract, where Foxp3 was decreased, as previously described. In vitro, MAIT cells were functionally altered in AIH patients. Ex vivo MAIT cell activity (GrB) was linked to severe fibrosis. Conclusion: Our work proposes a global view of the lymphocyte alterations from diagnosis to remission phase in AIH patients. The absence of blood immune homeostasis restoration and the persistence of a CD4 infiltrate in the liver under standard immunosuppression could form the basis of the high risk of relapse observed in AIH. (Hepatology Communications 2018; 00:000‐000)

Mucosal-associated invariant T cells and disease

“…In in vitro experiments, stool extracts from patients with alcoholic liver disease induced MAIT cell depletion and suppressed their antibacterial cytokine (IL-17, TNF and IFNγ) responses and the expression of PLZF and RORγt, which are involved in MAIT cell maturation and effector functions 83 . These data suggest that MAIT cell functional defects in patients with alcohol-related liver disease could contribute to this population's high suscepti bility to bacterial infection, which is also described during autoimmune hepatitis 82 . Interestingly, prophylactic administration of antibiotics to patients with severe alcoholic cirrhosis, a treatment usually administered so as to avoid bacterial infections, partially prevents blood MAIT cell reduction and activation 69 .…”

“…TaBle 3 and Fig. 2 illustrate the diversity of MAIT cell localization 16,18,73,[77][78][79]82,86,89,[96][97][98][99][100] . Mouse models allow the analysis of MAIT cells in tissues that are hard to access in humans.…”

“…Indeed, alterations of MAIT cell responses in vitro suggest an exhausted status. After phorbol myristate acetate-ionomycin stimulation or upon MR1-dependent activation, MAIT cells from patients with autoimmune and immune-mediated diseases are usually less activated and produce fewer T helper 1 (T H 1)-type cytokines than MAIT cells from controls 16,18,73,77,78,82,83,[85][86][87]89,93 . In patients with SLE, MAIT cell exhaustion has been associated with dysfunction of the Ca 2+ -calcineurin-NFAT1 signalling pathway downstream of TCR stimulation 89 .…”

Immunopathogenesis of Autoimmune Hepatitis†

“…One illustration of the relationship between these aberrant T cell phenotypes and clinical challenges in AIH was recently reported by Renand et al The high incidence of relapse in AIH despite prolonged biochemical remission is well known, and the authors demonstrate a reduction of the peripheral Th1/Th17 cytokine profile of memory CD4 T cells and elevation of granzyme B–producing MAIT cells in newly diagnosed patients with AIH compared with control subjects. Furthermore, patients with AIH who achieved biochemical remission also failed to correct these Th1/Th17 and MAIT cell imbalances, demonstrating that a deeper immunological restoration of tolerance does not occur despite satisfactory resolution of hepatitis using standard immunosuppression.…”

Sat0020 blood Rna Sequencing Reveals Immunological Processes Associated With the Response to Abatacept in Rheumatoid Arthritis

“…Notably, C-type lectin CD161 +CD8+ T-cells displaying a polyfunctional memory profile directed against several common viruses have been reported. Furthermore, CD161+ Tcells are involved in the pathogenesis of early stage autoimmune hepatitis (3). CD161 expression on proteinase 3 (PR3)-specific T-cells in comparison to other antigen-specific T-cells has not been described in GPA as yet.…”