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Title: Neutrophil dysfunction in alcoholic hepatitis and alcohol-related cirrhosis : a contributor to immunoparesis and disease state
Author: Ryan, Jennifer Marie
ISNI:       0000 0004 7427 9622
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2018
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Background: There has been an exponential rise in the incidence of alcohol related liver disease (ALD), particularly in the UK. Alcoholic hepatitis (AAH) is the most florid form of ALD and has a high mortality rate, sepsis is a significant problem and a major contributor to mortality. Treatment for patients with AAH has not changed in decades, one of the reasons for this is the relative lack of understanding of the underlying pathophysiology. No study has longitudinally investigated changes in immune function in this condition or the impact of current treatments on host immunity. Neutrophil dysfunction has been described in cirrhosis, however there is a lack of understanding regarding the mechanisms involved and how this relates to alcohol-induced liver toxicity. In addition, whether other derangements in neutrophil function contribute to the state of immunoparesis in ALD is not well understood. Aims and methods: I sought to characterise neutrophil phenotype and responses ex vivo to bacterial challenge in patients with AAH compared with patients with alcohol related cirrhosis (ARC) and healthy controls (HC) and prospectively examine neutrophil function and the effect of current AAH therapies on innate immune function through sequential analyses. The interplay between neutrophils, ethanol and the liver was also examined by using the HL-60 cell line and creating an in vitro model. Finally, I sought to identify novel targets which may propagate immunoparesis in ALD, specifically examining the relationship of neutrophils and interferon-λ (IFN-λ) in anti-bacterial immune defenses in health and ARC. Key results: Neutrophils from patients with AAH display increased reactive oxygen species production and lactoferrin release compared to ARC and HCs. Neutrophil antibacterial activities and key detecting receptors (TLRs) are dysfunctional in AAH and in ARC. Indeed, a skewed balance between host-induced immunopathology and protective anti-pathogen immunity in AAH has been confirmed. Further to this, the studies have shown that the immune impairment is reversible and that the antibacterial immune responses can be restored. Antibodies against immunohibitory signatures, PD1 and TIM3, restored T-cell production of interferon gamma, reduced the numbers of interleukin 10-producing T cells, and increased neutrophil antimicrobial activities without exacerbating neutrophil oxidative burst. The most notable finding in the longitudinal study was the impact of steroids on phagocytic capacity, this was significantly reduced at day 7 in the prednisolone-exposed AAH patients compared to those who did not receive prednisolone, reinforcing the concept that improved stratification for steroid-prescribing is required. The differentiated HL-60 cells express many of the key receptors examined in the human study and could form the basis of future in vitro studies in this area of research. The exploration of these cells led to further questions regarding neutrophil biology and the work on the neutrophil-interferon-λ relationship both in health and ALD. The role of IFN-λ in bacterial infection was not known and the question as to whether neutrophils produce IFN-λ unanswered. Neutrophil specific IFN-λ production in response to E. coli challenge was found to be compromised in patients with ARC and correlated with severity of liver disease. These findings reveal a previously unknown function of neutrophils in the context of bacterial infection and identify a novel impairment in host immunity in patients with ARC. Conclusions: Elucidation of the above, specifically the potential for immune dysfunction reversibility and the novel finding of the deficiency in neutrophil IFN-λ function, may have important implications for therapeutic developments in an era of multi-drug resistance and within the spectrum of ALD.
Supervisor: Shawcross, Deborah Lindsay Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available