8 results on '"Sebode M"'
Search Results
2. Auto-aggressive CXCR6 + CD8 T cells cause liver immune pathology in NASH.
- Author
-
Dudek M, Pfister D, Donakonda S, Filpe P, Schneider A, Laschinger M, Hartmann D, Hüser N, Meiser P, Bayerl F, Inverso D, Wigger J, Sebode M, Öllinger R, Rad R, Hegenbarth S, Anton M, Guillot A, Bowman A, Heide D, Müller F, Ramadori P, Leone V, Garcia-Caceres C, Gruber T, Seifert G, Kabat AM, Mallm JP, Reider S, Effenberger M, Roth S, Billeter AT, Müller-Stich B, Pearce EJ, Koch-Nolte F, Käser R, Tilg H, Thimme R, Boettler T, Tacke F, Dufour JF, Haller D, Murray PJ, Heeren R, Zehn D, Böttcher JP, Heikenwälder M, and Knolle PA
- Subjects
- Acetates pharmacology, Animals, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes pathology, Cell Death drug effects, Cell Death immunology, Diet, High-Fat adverse effects, Disease Models, Animal, Humans, Interleukin-15 immunology, Interleukin-15 pharmacology, Liver drug effects, Male, Mice, Mice, Inbred C57BL, CD8-Positive T-Lymphocytes immunology, Liver immunology, Liver pathology, Non-alcoholic Fatty Liver Disease immunology, Non-alcoholic Fatty Liver Disease pathology, Receptors, CXCR6 immunology
- Abstract
Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer
1,2 . The accumulation of metabolites leads to cell stress and inflammation in the liver3 , but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6+ CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6+ CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6+ CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity.- Published
- 2021
- Full Text
- View/download PDF
3. Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver.
- Author
-
Preti M, Schlott L, Lübbering D, Krzikalla D, Müller AL, Schuran FA, Poch T, Schakat M, Weidemann S, Lohse AW, Weiler-Normann C, Sebode M, Schwinge D, Schramm C, Carambia A, and Herkel J
- Subjects
- Animals, Autoantigens immunology, Hepatocytes immunology, Immune Tolerance, Lymphocyte Count, Mice, Autoimmunity, Liver immunology, T-Lymphocytes, Regulatory immunology, Thymus Gland immunology
- Abstract
The liver is an immune-privileged organ that can deactivate autoreactive T cells. Yet in autoimmune hepatitis (AIH), autoreactive T cells can defy hepatic control and attack the liver. To elucidate how tolerance to self-antigens is lost during AIH pathogenesis, we generated a spontaneous mouse model of AIH, based on recognition of an MHC class II-restricted model peptide in hepatocytes by autoreactive CD4+ T cells. We found that the hepatic peptide was not expressed in the thymus, leading to deficient thymic deletion and resulting in peripheral abundance of autoreactive CD4+ T cells. In the liver, autoreactive CD4+ effector T cells accumulated within portal ectopic lymphoid structures and maturated toward pathogenic IFN-γ and TNF coproducing cells. Expansion and pathogenic maturation of autoreactive effector T cells was enabled by a selective increase of plasticity and instability of autoantigen-specific Tregs but not of nonspecific Tregs. Indeed, antigen-specific Tregs were reduced in frequency and manifested increased IL-17 production, reduced epigenetic demethylation, and reduced expression of Foxp3. As a consequence, autoantigen-specific Tregs had a reduced suppressive capacity, as compared with that of nonspecific Tregs. In conclusion, loss of tolerance and the pathogenesis of AIH were enabled by combined failure of thymic deletion and peripheral regulation.
- Published
- 2021
- Full Text
- View/download PDF
4. TNF-Producing Th1 Cells Are Selectively Expanded in Liver Infiltrates of Patients with Autoimmune Hepatitis.
- Author
-
Bovensiepen CS, Schakat M, Sebode M, Zenouzi R, Hartl J, Peiseler M, Li J, Henze L, Woestemeier A, Schramm C, Lohse AW, Herkel J, and Weiler-Normann C
- Subjects
- Adult, Aged, Amino Acyl-tRNA Synthetases immunology, Autoantigens immunology, Biomarkers, Cytokines biosynthesis, Cytokines genetics, Female, Gene Expression, Hepatitis, Autoimmune diagnosis, Humans, Liver immunology, Liver pathology, Liver Function Tests, Lymphocyte Activation, Lymphocyte Count, Male, Middle Aged, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Hepatitis, Autoimmune etiology, Hepatitis, Autoimmune metabolism, Liver innervation, Liver metabolism, Th1 Cells immunology, Th1 Cells metabolism, Tumor Necrosis Factors biosynthesis
- Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that is believed to be driven by a CD4
+ T cell response to liver Ags. However, the pathogenic function of CD4+ effector T cells in AIH is not fully understood. To characterize liver-infiltrating lymphocytes in AIH, we determined the cytokine production of infiltrating cells obtained from biopsy material by quantitative RT-PCR and flow cytometry. A cytokine quantitiative RT-PCR array of AIH specimens revealed that TNF was the most strongly upregulated cytokine, as compared with control livers. To confirm this finding, we determined the frequencies of TNF-producing CD4+ T cells in peripheral blood and in liver biopsy specimens in comparison with those of CD4+ T cells producing IFN-γ or IL-17. In AIH, TNF-producing CD4+ T cells were significantly expanded, both in blood and liver, whereas IL-17-producing CD4+ T cells were not. However, the majority of the TNF-producing CD4+ T cells in AIH also produced IFN-γ, suggesting that TNF producers might represent a pathogenic activation state of Th1 cells. Ag-specific stimulation of PBMC from AIH patients with the AIH-associated autoantigen SEPSECS resulted in significant TNF production only in patients manifesting SLA/LP autoantibodies targeting SEPSEC but not in healthy individuals who do not manifest this reactivity. Taken together, our findings indicated that TNF-producing CD4+ T cells are expanded in AIH, both in blood and in liver. TNF-producing CD4+ T cells in AIH seem to be aberrantly activated Th1 cells. Our findings provide a rationale for therapeutic efforts using TNF blockade in AIH., (Copyright © 2019 by The American Association of Immunologists, Inc.)- Published
- 2019
- Full Text
- View/download PDF
5. Inflammatory Phenotype of Intrahepatic Sulfatide-Reactive Type II NKT Cells in Humans With Autoimmune Hepatitis.
- Author
-
Sebode M, Wigger J, Filpe P, Fischer L, Weidemann S, Krech T, Weiler-Normann C, Peiseler M, Hartl J, Tolosa E, Herkel J, Schramm C, Lohse AW, and Arrenberg P
- Subjects
- Adult, Aged, Antigens, CD1d analysis, Cytokines blood, Female, Humans, Male, Middle Aged, Natural Killer T-Cells immunology, Phenotype, Receptors, Chemokine blood, Hepatitis, Autoimmune immunology, Liver immunology, Sulfoglycosphingolipids immunology
- Abstract
Background: Natural Killer T (NKT) cells are CD1d-restricted innate-like T cells that can rapidly release stored cytokines upon recognition of lipid antigens. In mice, type I NKT cells seem to promote liver inflammation, whereas type II NKT cells seem to restrict hepatitis. Here, we aimed at characterizing the role of human type I and type II NKT in patients with autoimmune hepatitis (AIH). Methods: NKT cells were analyzed by flow cytometry in peripheral blood and liver of AIH patients and control groups. α-galactosylceramide-loaded or sulfatide-loaded tetramers were used to detect type I or II NKT cells, respectively. Hepatic CD1d was stained by in situ -hybridization of liver biopsies. Results and Conclusions: Type II NKT cells were more prevalent in human peripheral blood and liver than type I NKT cells. In AIH patients, the frequency of sulfatide-reactive type II NKT cells was significantly increased in peripheral blood (0.11% of peripheral blood leukocytes) and liver (3.78% of intrahepatic leukocytes) compared to healthy individuals (0.05% and 1.82%) and patients with drug-induced liver injury (0.06% and 2.03%; p < 0.05). Intrahepatic type II NKT cells of AIH patients had a different cytokine profile than healthy subjects with an increased frequency of TNFα (77.8% vs. 59.1%, p < 0.05), decreased IFNγ (32.7% vs. 63.0%, p < 0.05) and a complete lack of IL-4 expressing cells (0% vs. 2.1%, p < 0.05). T cells in portal tracts expressed significantly more CD1d-RNA in AIH livers compared to controls. This study supports that in contrast to their assumed protective role in mice, human intrahepatic, sulfatide-reactive type II NKT cells displayed a proinflammatory cytokine profile in patients with AIH. Infiltrating T cells in portal areas of AIH patients overexpressed CD1d and could thereby activate type II NKT cells.
- Published
- 2019
- Full Text
- View/download PDF
6. Autoantibodies in Autoimmune Liver Disease-Clinical and Diagnostic Relevance.
- Author
-
Sebode M, Weiler-Normann C, Liwinski T, and Schramm C
- Subjects
- Autoantibodies blood, Diagnosis, Differential, Gastrointestinal Microbiome immunology, Humans, Mass Screening, Cholangitis, Sclerosing diagnosis, Cholestasis diagnosis, Hepatitis diagnosis, Hepatitis, Autoimmune diagnosis, Liver pathology, Liver Cirrhosis, Biliary diagnosis, Serologic Tests methods
- Abstract
Testing for liver-related autoantibodies should be included in the workup of patients with hepatitis or cholestasis of unknown origin. Although most of these autoantibodies are not disease specific, their determination is a prerequisite to diagnose autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), and they are components of the diagnostic scoring system in these diseases. In primary sclerosing cholangitis (PSC), on the other hand, autoantibodies are frequently present but play a minor role in establishing the diagnosis. In PSC, however, data on antibodies suggest a link between disease pathogenesis and the intestinal microbiota. This review will focus on practical aspects of antibody testing in the three major autoimmune liver diseases AIH, PBC, and PSC.
- Published
- 2018
- Full Text
- View/download PDF
7. Autoimmune hepatitis: From current knowledge and clinical practice to future research agenda.
- Author
-
Sebode M, Hartl J, Vergani D, and Lohse AW
- Subjects
- Animals, Azathioprine therapeutic use, Drug Therapy, Combination, Glucocorticoids adverse effects, Hepatitis, Autoimmune diagnosis, Hepatitis, Autoimmune epidemiology, Hepatitis, Autoimmune immunology, Humans, Immunosuppressive Agents adverse effects, Liver immunology, Liver pathology, Predictive Value of Tests, Prednisolone therapeutic use, Prednisone therapeutic use, Remission Induction, Risk Factors, Treatment Outcome, Glucocorticoids therapeutic use, Hepatitis, Autoimmune drug therapy, Immunosuppressive Agents therapeutic use, Liver drug effects
- Abstract
Autoimmune hepatitis is a chronic inflammatory liver disease. Unknown triggers lead to a mainly T cell-mediated immune response targeting the liver, the main auto-antigen of which has not been identified yet. The diagnosis of autoimmune hepatitis is based on the elevation of immunoglobulin G/hypergammaglobulinemia, detection of characteristic autoantibodies as well as a typical pattern on liver histology. Exclusion of other causes of hepatitis and response to immunosuppressive treatment support the diagnosis of autoimmune hepatitis. The mainstay of autoimmune hepatitis treatment has, from its first description to the current time, consisted of predniso(lo)ne to induce remission, in combination with azathioprine, which is used to maintain it. Nonetheless, side effects and non-response with ongoing inflammation despite standard therapy demand treatment alternatives. Only through a better understanding of the pathogenesis of autoimmune hepatitis can a more selective and effective treatment be offered to patients in the future. Until this goal is reached, improvement of diagnostic approaches and optimization of current therapy rank highest on the research agenda for autoimmune hepatitis., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2018
- Full Text
- View/download PDF
8. "Autoimmune(-Like)" Drug and Herb Induced Liver Injury: New Insights into Molecular Pathogenesis.
- Author
-
Sebode M, Schulz L, and Lohse AW
- Subjects
- Autoantibodies, Chemical and Drug Induced Liver Injury pathology, Diagnosis, Differential, Hepatitis, Autoimmune pathology, Herbal Medicine, Humans, Liver immunology, Chemical and Drug Induced Liver Injury immunology, Dietary Supplements adverse effects, Hepatitis, Autoimmune immunology, Liver drug effects, Liver injuries, Phytotherapy adverse effects
- Abstract
Idiosyncratic drug-induced liver injury (DILI) and hepatic injury due to herbal and dietary supplements (HDS) can adapt clinical characteristics of autoimmune hepatitis (AIH), such as the appearance of autoantibodies and infiltration of the liver by immune competent cells. To describe these cases of DILI/HDS, the poorly-defined term "autoimmune(-like)" DILI/HDS came up. It is uncertain if these cases represent a subgroup of DILI/HDS with distinct pathomechanistic and prognostic features different from "classical" DILI/HDS. Besides, due to the overlap of clinical characteristics of "immune-mediated" DILI/HDS and AIH, both entities are not easy to differentiate. However, the demarcation is important, especially with regard to treatment: AIH requires long-term, mostly lifelong immunosuppression, whereas DILI/HDS does not. Only through exact diagnostic evaluation, exclusion of differential diagnoses and prolonged follow-up can the correct diagnosis reliably be made. Molecular mechanisms have not been analysed for the subgroup of "autoimmune(-like)" DILI/HDS yet. However, several pathogenetic checkpoints of DILI/HDS in general and AIH are shared. An analysis of these shared mechanisms might hint at relevant molecular processes of "autoimmune(-like)" DILI/HDS., Competing Interests: The authors declare no conflict of interest.
- Published
- 2017
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.