Abstract
Autoimmune hepatitis (AIH) is an immune‐mediated liver disease currently treated by immunosuppressive medications with significant side effects. Thus, novel mechanistic treatments are greatly needed. We performed prospective deep immunophenotyping of blood immune cells in patients with acute AIH before and after corticosteroid therapy. Blood samples from 26 patients with acute AIH (United Kingdom‐AIH Consortium) were phenotyped by flow cytometry at baseline and 4 months after starting corticosteroids. Pretreatment liver tissues were stained for forkhead box P3‐positive (FOXP3POS) regulatory T cells (Tregs), clusters of differentiation (CD)56POS natural killer (NK) cells, and chemokine (C‐X‐C motif) ligand 10. Chemokine secretion by cultured primary hepatocyte and biliary epithelial cells was measured by enzyme‐linked immunosorbent assay. Functional coculture assays with stimulated NK cells and Tregs were performed. CD161 ligand, lectin‐like transcript‐1 expression by intrahepatic immune cells was demonstrated with flow cytometry. Frequencies of NKbright cells declined with therapy (P < 0.001) and correlated with levels of alanine aminotransferase (P = 0.023). The Treg:NKbright ratio was lower pretreatment, and Tregs had an activated memory phenotype with high levels of CD39, cytotoxic T lymphocyte antigen 4, and FOXP3 but also high programmed death ligand 1, indicating exhaustion. Coculture experiments suggested the Tregs could not efficiently suppress interferon‐γ secretion by NK cells. Both Tregs and NK cells had high expression of liver infiltration and T helper 17 plasticity‐associated marker CD161 (P = 0.04). Pretreatment and CD161pos NK cells expressed high levels of perforin and granzyme B, consistent with an activated effector phenotype (P < 0.05). Lectin‐like transcript 1, a ligand for CD161, is expressed on intrahepatic B cells, monocytes, and neutrophils. Conclusion: Activated effector NK cells, which correlate with biochemical measurements of hepatitis, and exhausted memory Tregs are increased in the blood of patients with treatment‐naive AIH and decline with corticosteroid therapy. Inadequate regulation of NK cells by exhausted FOXP3pos Tregs may play a role in AIH pathogenesis and contribute to liver injury. (Hepatology Communications 2018;2:421‐436)
Highlights
Autoimmune hepatitis (AIH) is an immunemediated liver disease characterized by interface and lobular hepatitis[1] comprising infiltrates of both effector and regulatory T lymphocytes (Tregs).(1,2) There have been no new therapies for AIH for more than 3 decades, and it is becoming increasingly clear that there are limitations to the longterm safety and efficacy of the nonspecific and empirical treatment in current use.[3]
We studied the baseline and month 4 peripheral immunophenotype in 26 patients
The study was not designed to report the alterations in total cell numbers with therapy but rather to discuss the influence of therapy on the ratios of the different innate and adaptive immune subsets and to describe the changes in their individual phenotypes; as such, this study offers important insight into the subsets whose relative precedence may be key to AIH pathogenesis and crucial to target in future targeted therapies
Summary
Autoimmune hepatitis (AIH) is an immunemediated liver disease characterized by interface and lobular hepatitis[1] comprising infiltrates of both effector and regulatory T lymphocytes (Tregs).(1,2) There have been no new therapies for AIH for more than 3 decades, and it is becoming increasingly clear that there are limitations to the longterm safety and efficacy of the nonspecific and empirical treatment in current use.[3]. One of the challenges in studying the immune status in patients who are treatment naive is the rapid initial response to corticosteroid treatment. This means that most patients are started on therapy before they can be investigated. In the vast majority of patients, this treatment is with corticosteroid or immunosuppressive therapy, which by nature alters immune activation status. Studies have been performed to dissect the immune cell composition of patients with AIH on treatment, the immune balance between regulatory and effector cells in the treatment-naive state and during longitudinal follow-up of patients with acute AIH on maintenance immunosuppression is not known
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