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Title: Immunomodulatory properties of alpha 1 antitrypsin : regulation of Th17 cells and neutrophil subsets in lung disease
Author: Cheadle, Charlotte Emily
ISNI:       0000 0004 7970 0279
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Alpha 1-antitrypsin is the most abundant serine protease inhibitor in the circulation, with an important role in inhibiting pulmonary neutrophil proteases. It is increased up to two-fold during pregnancy. Recent data indicate that α1-antitrypsin also has immune-regulatory functions, with independent studies suggesting the capacity of α1-antitrypsin to decrease IL- 17A production in murine models, and to upregulate IL-10 and IL-1 receptor antagonist. A genetic mutation in the gene encoding for α1-antitrypsin results in severely reduced circulating levels of the antiprotease and subsequent uncontrolled protease activity, which can lead to emphysema development in a proportion of patients. Independent studies suggest that an immune component also exists in the pathogenesis of α1-antitrypsin deficiency-associated lung disease. Neutrophils are now strongly implicated, whilst Th17 responses are strongly associated with neutrophil recruitment and activation. These data provided the rationale for investigations into the effect of α1-antitrypsin on human Th17 responses and the associated neutrophil effects. This work has investigated the hypothesis that α1-antitrypsin skews the Th17/IL-10 axis towards an anti-inflammatory profile, which in α1-antitrypsin deficient patients manifests as increased Th17 responses and alterations in the frequency and activation of neutrophil subsets. To investigate these hypotheses, α1-antitrypsin deficient patients and neonatal blood, exposed to high levels of α1-antitrypsin during pregnancy, were studied. Significantly increased frequencies of IL-17A+ cells in the PBMC population of α1-antitrypsin deficient patients were observed compared to age-matched controls following extended culture (p≤0.01) and ex vivo (p≤0.01). In depth analysis also suggested increased frequencies of putative pro-inflammatory Th17 cells, co-expressing other cytokines including IL-22, IL-17F and IFNγ, in α1-antitrypsin deficient patients. Subsequent investigations into factors contributing to this identified significantly increased frequencies of low density neutrophils in α1-antitrypsin deficient patients (p≤0.0001; n=29). Independent studies suggest low density neutrophils can have suppressive (pregnancy, cancer) or pro-inflammatory (autoimmune, inflammatory disease) effects in the immune system depending on the situation in which they are found. Analysis of this population in α1-antitrypsin deficient patients suggests indications of both a pro-inflammatory (increased neutrophil extracellular trap formation, facilitation of PBMC proliferation) and regulatory (correlates with serum vitamin d, increased regulatory Th17 cells and a reduction in total Th17s, LOX1 expression) phenotype. Studies in neonatal blood confirmed independent observations of the presence of low density neutrophils (mean 13.8%), with a high percentage expressing LOX1 (a putative granulocyticmyeloid derived suppressor cell marker; mean 44.75%). Preliminary data suggest that co3 culture with neonatal low density neutrophils significantly increases expression of GM-CSF and CXCL8 by cord blood mononuclear cells (p≤0.05). Data generated during this project suggest the presence of a dysregulated pathogenic Th17 response in α1-antitrypsin deficient patients, a factor that may contribute to the development of inflammatory lung disease. Low density neutrophils are present in α1-antitrypsin deficient patients but co-culture experiments suggest they do not directly affect Th17 responses. The role that low density neutrophils play in α1-antitrypsin deficiency remains to be elucidated, with data indicative of both pro- and anti-inflammatory phenotype in vitro. A large percentage of low density neutrophils in neonates, exposed to higher levels of α1-antitrypsin during pregnancy, express the putative marker of suppressive cells (LOX1), however in co-culture they induce T cell expression of pro-inflammatory cytokines, most notably CXCL8. This is in contrast to LDNs in PiZZ patients.
Supervisor: Hawrylowicz, Catherine Martha Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available