Titel: | Crosstalk between Hepatocytes and CD4+ T cells in Autoimmune Hepatitis | Sprache: | Englisch | Autor*in: | Niersch, Jennifer | Schlagwörter: | Autoimmune Hepatitis; Organoids; Immunology | Erscheinungsdatum: | 2024-03 | Tag der mündlichen Prüfung: | 2024-10-04 | Zusammenfassung: | Autoimmune hepatitis (AIH) is a chronic liver disease characterized by severe inflammation and resulting in liver cirrhosis. The exact mechanisms leading to an overshooting immune response damaging hepatocytes and loss of tolerance remain unidentified. However, several studies have shown that dysregulated T cell mediated responses against hepatic autoantigens are considered to contribute to AIH. Specifically, these studies have identified enhanced frequencies of pro-inflammatory TNF and IFNγ producing CD4+ T cells in AIH. However, the initial pro-inflammatory signals that activate autoimmune CD4+ T cells and trigger cytokine secretion remain unknown. Innate immune responses activated by pathogen-associated molecular patterns (PAMPs) are important regulators of T cell responses. Toll like receptors are pathogen recognition pattern receptors, recognizing foreign structures such as double-stranded (ds) RNA typically derived from viruses. Activation of TLRs initiates inflammatory immune responses to control pathogens. However, a dysregulated TLR response can result in an inappropriate production of inflammatory cytokines and contribute to an initiation of autoimmune diseases. Recent studies have suggested that TLR3, TLR4 and TLR5 may be involved in liver diseases. We hypothesize that in AIH, dysregulated TLR responses result in an elevated expression of pro-inflammatory cytokines that may activate local immune cells, such as T cells, resulting in tissue damage of hepatocytes. Therefore, we first investigated hepatocyte functionality in AIH and secondly determined the consequences of the dysregulated T cells in AIH on hepatocytes. Recently, organoid systems have emerged as in vitro models to study diseases in humans. For this, we established 3D human liver organoids from livers from individuals with and without AIH. First, we determined the phenotypic characteristics of human liver organoids to appraise their use as a model to study liver diseases, including the expression of hepatocyte markers, such as albumin and Cyp3A4. Next, TLR signaling was examined using organoids from AIH affected individuals and non-AIH individuals, which included the quantification of TLR expression, followed by the stimulation of human liver organoids with TLR3 ligand poly I:C to quantify the resulting cytokine and chemokine expression. These results showed that TLR3 is expressed by hepatocytes in low levels, however, expression was similar between organoids generated from AIH-derived livers and non-AIH affected individuals. Furthermore, although a trend was observed towards higher expression of pro-inflammatory cytokine IL-6 and chemokine CXCL9 by organoids from AIH affected livers, these results did not reach significance. However, the activation of TLR3 and the following induced cytokine and chemokine production then may attract T cells to the liver. TNF and IFNγ, which are increased produced by T cells in AIH affected livers showed a disrupted liver-organoid growth suggesting that these cytokines prevent hepatocyte regeneration. Co-cultures with AIH affected liver Tissue Resident Memory (TRM1) T cells and human liver organoids showed that the combined effect of TNF and IFNγ, secreted by T cells had a negative impact on organoid regeneration. Taken together, the findings of this thesis suggest that hepatocytes can produce pro- inflammatory cytokines and chemokines upon TLR stimulation. Furthermore, cytokines produced by T cells, such as TNF and IFNγ have detrimental effects for the health and regenerative capacity of hepatocytes. Thus, dysregulated T cell responses are a critical mediator in the inflammation and tissue damage in the liver of individuals with AIH. |
URL: | https://ediss.sub.uni-hamburg.de/handle/ediss/11196 | URN: | urn:nbn:de:gbv:18-ediss-121786 | Dokumenttyp: | Dissertation | Betreuer*in: | Bunders, Madeleine |
Enthalten in den Sammlungen: | Elektronische Dissertationen und Habilitationen |
Dateien zu dieser Ressource:
Datei | Prüfsumme | Größe | Format | |
---|---|---|---|---|
Dissertation Jennifer Niersch .pdf | 96bd53fde5b2fa9036bbc43f2322a6f5 | 10.15 MB | Adobe PDF | Öffnen/Anzeigen |
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