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Regulatory T-cell deficiency leads to features of autoimmune liver disease overlap syndrome in scurfy mice
INTRODUCTION: Scurfy mice have a complete deficiency of functional regulatory T cells (Treg) due to a frameshift mutation in the Foxp3 gene. The impaired immune homeostasis results in a lethal lymphoproliferative disorder affecting multiple organs, including the liver. The autoimmune pathology in sc...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10561387/ https://www.ncbi.nlm.nih.gov/pubmed/37818371 http://dx.doi.org/10.3389/fimmu.2023.1253649 |
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author | Yilmaz, Kaan Haeberle, Stefanie Kim, Yong Ook Fritzler, Marvin J. Weng, Shih-Yen Goeppert, Benjamin Raker, Verena K. Steinbrink, Kerstin Schuppan, Detlef Enk, Alexander Hadaschik, Eva N. |
author_facet | Yilmaz, Kaan Haeberle, Stefanie Kim, Yong Ook Fritzler, Marvin J. Weng, Shih-Yen Goeppert, Benjamin Raker, Verena K. Steinbrink, Kerstin Schuppan, Detlef Enk, Alexander Hadaschik, Eva N. |
author_sort | Yilmaz, Kaan |
collection | PubMed |
description | INTRODUCTION: Scurfy mice have a complete deficiency of functional regulatory T cells (Treg) due to a frameshift mutation in the Foxp3 gene. The impaired immune homeostasis results in a lethal lymphoproliferative disorder affecting multiple organs, including the liver. The autoimmune pathology in scurfy mice is in part accompanied by autoantibodies such as antinuclear antibodies (ANA). ANA are serological hallmarks of several autoimmune disorders including autoimmune liver diseases (AILD). However, the underlying pathogenesis and the role of Treg in AILD remain to be elucidated. The present study therefore aimed to characterize the liver disease in scurfy mice. METHODS: Sera from scurfy mice were screened for ANA by indirect immunofluorescence assay (IFA) and tested for a wide range of AILD-associated autoantibodies by enzyme-linked immunosorbent assay, line immunoassay, and addressable laser bead immunoassay. CD4(+) T cells of scurfy mice were transferred into T cell-deficient B6/nude mice. Monoclonal autoantibodies from scurfy mice and recipient B6/nude mice were tested for ANA by IFA. Liver tissue of scurfy mice was analyzed by conventional histology. Collagen deposition in scurfy liver was quantified via hepatic hydroxyproline content. Real-time quantitative PCR was used to determine fibrosis-related hepatic gene expression. Hepatic immune cells were differentiated by flow cytometry. RESULTS: All scurfy mice produced ANA. AILD-associated autoantibodies, predominantly antimitochondrial antibodies, were detected at significantly higher levels in scurfy sera. CD4(+) T cells from scurfy mice were sufficient to induce anti-dsDNA autoantibodies and ANA with an AILD-related nuclear envelope staining pattern. Liver histology revealed portal inflammation with bile duct damage and proliferation, as in primary biliary cholangitis (PBC), and interface hepatitis with portal-parenchymal necroinflammation, as found in autoimmune hepatitis (AIH). In scurfy liver, TNFα and fibrosis-related transcripts including Col1a1, Timp1, Acta2, Mmp2, and Mmp9 were upregulated. The level of proinflammatory monocytic macrophages (Ly-6C(hi)) was increased, while M2-type macrophages (CD206(+)) were downregulated compared to wildtype controls. Despite severe hepatic inflammation, fibrosis did not develop within 25 days, which is close to the lifespan of scurfy mice. DISCUSSION: Our findings suggest that Treg-deficient scurfy mice spontaneously develop clinical, serological, and immunopathological characteristics of AILD with overlapping features of PBC and AIH. |
format | Online Article Text |
id | pubmed-10561387 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-105613872023-10-10 Regulatory T-cell deficiency leads to features of autoimmune liver disease overlap syndrome in scurfy mice Yilmaz, Kaan Haeberle, Stefanie Kim, Yong Ook Fritzler, Marvin J. Weng, Shih-Yen Goeppert, Benjamin Raker, Verena K. Steinbrink, Kerstin Schuppan, Detlef Enk, Alexander Hadaschik, Eva N. Front Immunol Immunology INTRODUCTION: Scurfy mice have a complete deficiency of functional regulatory T cells (Treg) due to a frameshift mutation in the Foxp3 gene. The impaired immune homeostasis results in a lethal lymphoproliferative disorder affecting multiple organs, including the liver. The autoimmune pathology in scurfy mice is in part accompanied by autoantibodies such as antinuclear antibodies (ANA). ANA are serological hallmarks of several autoimmune disorders including autoimmune liver diseases (AILD). However, the underlying pathogenesis and the role of Treg in AILD remain to be elucidated. The present study therefore aimed to characterize the liver disease in scurfy mice. METHODS: Sera from scurfy mice were screened for ANA by indirect immunofluorescence assay (IFA) and tested for a wide range of AILD-associated autoantibodies by enzyme-linked immunosorbent assay, line immunoassay, and addressable laser bead immunoassay. CD4(+) T cells of scurfy mice were transferred into T cell-deficient B6/nude mice. Monoclonal autoantibodies from scurfy mice and recipient B6/nude mice were tested for ANA by IFA. Liver tissue of scurfy mice was analyzed by conventional histology. Collagen deposition in scurfy liver was quantified via hepatic hydroxyproline content. Real-time quantitative PCR was used to determine fibrosis-related hepatic gene expression. Hepatic immune cells were differentiated by flow cytometry. RESULTS: All scurfy mice produced ANA. AILD-associated autoantibodies, predominantly antimitochondrial antibodies, were detected at significantly higher levels in scurfy sera. CD4(+) T cells from scurfy mice were sufficient to induce anti-dsDNA autoantibodies and ANA with an AILD-related nuclear envelope staining pattern. Liver histology revealed portal inflammation with bile duct damage and proliferation, as in primary biliary cholangitis (PBC), and interface hepatitis with portal-parenchymal necroinflammation, as found in autoimmune hepatitis (AIH). In scurfy liver, TNFα and fibrosis-related transcripts including Col1a1, Timp1, Acta2, Mmp2, and Mmp9 were upregulated. The level of proinflammatory monocytic macrophages (Ly-6C(hi)) was increased, while M2-type macrophages (CD206(+)) were downregulated compared to wildtype controls. Despite severe hepatic inflammation, fibrosis did not develop within 25 days, which is close to the lifespan of scurfy mice. DISCUSSION: Our findings suggest that Treg-deficient scurfy mice spontaneously develop clinical, serological, and immunopathological characteristics of AILD with overlapping features of PBC and AIH. Frontiers Media S.A. 2023-09-25 /pmc/articles/PMC10561387/ /pubmed/37818371 http://dx.doi.org/10.3389/fimmu.2023.1253649 Text en Copyright © 2023 Yilmaz, Haeberle, Kim, Fritzler, Weng, Goeppert, Raker, Steinbrink, Schuppan, Enk and Hadaschik https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Yilmaz, Kaan Haeberle, Stefanie Kim, Yong Ook Fritzler, Marvin J. Weng, Shih-Yen Goeppert, Benjamin Raker, Verena K. Steinbrink, Kerstin Schuppan, Detlef Enk, Alexander Hadaschik, Eva N. Regulatory T-cell deficiency leads to features of autoimmune liver disease overlap syndrome in scurfy mice |
title | Regulatory T-cell deficiency leads to features of autoimmune liver disease overlap syndrome in scurfy mice |
title_full | Regulatory T-cell deficiency leads to features of autoimmune liver disease overlap syndrome in scurfy mice |
title_fullStr | Regulatory T-cell deficiency leads to features of autoimmune liver disease overlap syndrome in scurfy mice |
title_full_unstemmed | Regulatory T-cell deficiency leads to features of autoimmune liver disease overlap syndrome in scurfy mice |
title_short | Regulatory T-cell deficiency leads to features of autoimmune liver disease overlap syndrome in scurfy mice |
title_sort | regulatory t-cell deficiency leads to features of autoimmune liver disease overlap syndrome in scurfy mice |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10561387/ https://www.ncbi.nlm.nih.gov/pubmed/37818371 http://dx.doi.org/10.3389/fimmu.2023.1253649 |
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