Increased Intrahepatic Expression of Immune Checkpoint Molecules in Autoimmune Liver Disease

Jilkova, Zuzana Macek; Hilleret, Marie Noelle; Gerster, Théophile; Stürm, Nathalie; Mercey-Ressejac, Marion; Zarski, Jean–Pierre; Leroy, Vincent; Marche, Patrice N.; Costentin, Charlotte; Decaens, Thomas

doi:10.3390/cells10102671

Cited by 7 publications

(12 citation statements)

References 33 publications

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“…It was not possible to explore the role of IS on hepatic B cells. Nonetheless, several groups clearly demonstrated that, by IHC, intrahepatic B cell numbers and or proportions decline sharply following IS ( 10 , 20 , 22 ), which was even bigger compared to the CD4 and CD8 cell number reductions. This may cause to question of whether or not B cells are incumbent as a “driver” in the pathogenesis of AIH ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

“…Few studies have been conducted to date, mostly on adults, to better understand how IS medications affect systemic and/or intrahepatic lymphocytes in patients with AIH (3,10,(20)(21)(22). Most notably, by means of immunohistochemistry (IHC), Diestelhorst et al noted a sharp decline (>50%) in intrahepatic Tregs proportions, following IS in children with AIH.…”

Section: Discussionmentioning

confidence: 99%

“…Nonetheless, one recent paper did report the intrahepatic CTLA-4 expression on total CD4 T and CD8 T cells within the liver. The proportion of CTLA-4 was similar between normal livers and adult AIH livers, whether they were under treatment or not ( 22 ).…”

Section: Discussionmentioning

confidence: 99%

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Standard immunosuppressive treatment reduces regulatory B cells in children with autoimmune liver disease

et al. 2023

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IntroductionAutoimmune hepatitis (AIH) is a chronic liver disease caused by a perturbed immune system. The scarcity of short- and long-term immune monitoring of AIH hampered us to comprehend the interaction between immunosuppressive medication and immune homeostasis.Methods and patientsWe recruited children with AIH at the time of diagnosis and at the 1st, 3rd, 6th, 12th, 18th, and 24th months of immunosuppression (IS). We also enrolled children with AIH being on IS for >2 years. Children with drug-induced liver injury (DILI), and those receiving tacrolimus after liver transplantation (LT), were enrolled as disease/IS control subjects. Healthy children (HC) were also recruited. Peripheral blood mononuclear cells (PBMCs) were isolated from all participants. Healthy liver tissue from adult donors and from livers without inflammation were obtained from children with hepatoblastoma. By using flow cytometry, we performed multi-parametric immune profiling of PBMCs and intrahepatic lymphocytes. Additionally, after IS with prednisolone, tacrolimus, rapamycin, or 6-mercaptopurine, we carried out an in vitro cytokine stimulation assay. Finally, a Lifecodes SSO typing kit was used to type HLA-DRB1 and Luminex was used to analyze the results.ResultsUntreated AIH patients had lower total CD8 T-cell frequencies than HC, but these cells were more naïve. While the percentage of naïve regulatory T cells (Tregs) (CD4+FOXP3lowCD45RA+) and regulatory B cells (Bregs, CD20+CD24+CD38+) was similar, AIH patients had fewer activated Tregs (CD4+FOXP3highCD45RA-) compared to HC. Mucosal-associated-invariant-T-cells (MAIT) were also lower in these patients. Following the initiation of IS, the immune profiles demonstrated fluctuations. Bregs frequency decreased substantially at 1 month and did not recover anymore. Additionally, the frequency of intrahepatic Bregs in treated AIH patients was lower, compared to control livers, DILI, and LT patients. Following in vitro IS drugs incubation, only the frequency of IL-10-producing total B-cells increased with tacrolimus and 6MP. Lastly, 70% of AIH patients possessed HLA-DR11, whereas HLA-DR03/DR07/DR13 was present in only some patients.ConclusionHLA-DR11 was prominent in our AIH cohort. Activated Tregs and MAIT cell frequencies were lower before IS. Importantly, we discovered a previously unrecognized and long-lasting Bregs scarcity in AIH patients after IS. Tacrolimus and 6MP increased IL-10+ B-cells in vitro.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Standard immunosuppressive treatment reduces regulatory B cells in children with autoimmune liver disease

et al. 2023

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“…In the course of T cells-mediated autoimmune responses against hepatocytes, in addition to alterations in the immune effects of T cells subsets, alterations in T cells immune checkpoints are also included. Detection in liver tissue of AIH patients not only observed aggregation of CD4 + and CD8 + T cells overexpressed by immune checkpoint PD-1 and 4-1BB, but also found that PD-1 + CD8 + T cells were strongly associated with disease activity and degree of liver injury in AIH patients rather than PD-1 + CD4 + T cells [ 90 ]. In addition, a study isolated circulating SLA-specific CD4 + T cells.…”

Section: Imbalance Of Liver Immune Microenvironment and Liver Diseasesmentioning

confidence: 99%

Mesenchymal stem cells-based therapy in liver diseases

Han

Jin

2022

Mol Biomed

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Multiple immune cells and their products in the liver together form a complex and unique immune microenvironment, and preclinical models have demonstrated the importance of imbalances in the hepatic immune microenvironment in liver inflammatory diseases and immunocompromised liver diseases. Various immunotherapies have been attempted to modulate the hepatic immune microenvironment for the purpose of treating liver diseases. Mesenchymal stem cells (MSCs) have a comprehensive and plastic immunomodulatory capacity. On the one hand, they have been tried for the treatment of inflammatory liver diseases because of their excellent immunosuppressive capacity; On the other hand, MSCs have immune-enhancing properties in immunocompromised settings and can be modified into cellular carriers for targeted transport of immune enhancers by genetic modification, physical and chemical loading, and thus they are also used in the treatment of immunocompromised liver diseases such as chronic viral infections and hepatocellular carcinoma. In this review, we discuss the immunological basis and recent strategies of MSCs for the treatment of the aforementioned liver diseases. Specifically, we update the immune microenvironment of the liver and summarize the distinct mechanisms of immune microenvironment imbalance in inflammatory diseases and immunocompromised liver diseases, and how MSCs can fully exploit their immunotherapeutic role in liver diseases with both immune imbalance patterns.

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“…As interface hepatitis is a histological feature of AIH, pathogenic CD4 + T cells with autoantigen specificity are enriched in this lesion (10,11). Furthermore, there is a strong association between disease activity and abundance of liver infiltrating T cells (12). However, molecular mechanisms of activation and recruitment of T cells in AIH remain poorly elucidated.…”

Section: Introductionmentioning

confidence: 99%

Intrahepatic activated leukocyte cell adhesion molecule induces CD6highCD4+ T cell infiltration in autoimmune hepatitis

et al. 2022

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Background and objectivesAutoimmune hepatitis (AIH) is characterized by the expansion and accumulation of pathogenic T cells in liver. Although CD6 and its ligand activated leukocyte cell adhesion molecule (ALCAM) are involved in the evolution of multiple inflammatory diseases, their roles in the pathogenesis of AIH remain unknown. Herein, we aimed to investigate ALCAM-CD6 axis in AIH development.MethodsImmunohistochemistry was performed to examine hepatic expression of CD6 and ALCAM. The concentration of serum ALCAM was evaluated by ELISA. The phenotypes of liver infiltrating T cells were determined by flow cytometry. Primary human CD4+ T cells were used for functional studies.ResultsOur data showed that patients with AIH exhibited significantly higher expression of CD6 in the liver as compared to primary biliary cholangitis (PBC), chronic hepatitis B (CHB), non-alcoholic liver disease (NAFLD), and healthy controls (HC). In addition, hepatic CD6 expression was strongly correlated with disease severity of AIH. CD6 was mainly expressed on CD4+ T cells in the liver and intrahepatic CD6highCD4+ T cells demonstrated stronger proinflammatory response and proliferation features than CD6low counterparts in both AIH and HC. ALCAM, the ligand of CD6, was highly expressed in the hepatocytes of AIH and serum ALCAM was strongly associated with clinical indices of AIH. Interestingly, close spatial location between CD6+CD4+ T cells and ALCAM+ hepatocytes was observed. Finally, we found that CD6highCD4+ T cells showed enhanced capacity of trans-endothelial migration in vitro, which could be promoted by recombinant ALCAM.ConclusionsOur study found that ALCAM-CD6 axis was upregulated in the AIH liver, suggesting a potential target for alleviating AIH.

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Increased Intrahepatic Expression of Immune Checkpoint Molecules in Autoimmune Liver Disease

Cited by 7 publications

References 33 publications

Standard immunosuppressive treatment reduces regulatory B cells in children with autoimmune liver disease

Standard immunosuppressive treatment reduces regulatory B cells in children with autoimmune liver disease

Mesenchymal stem cells-based therapy in liver diseases

Intrahepatic activated leukocyte cell adhesion molecule induces CD6highCD4+ T cell infiltration in autoimmune hepatitis

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