Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.806762
Title: The role of abnormal neutrophil activation in psoriasis
Author: Vergnano, Marta
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2020
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Abstract:
Psoriasis is a complex skin disorder that has been classified into several forms. These include common psoriasis vulgaris (PsV), a T-cell mediated disease, and Generalised Pustular Psoriasis (GPP), a rare condition associated with neutrophilic inflammation. While the genetic basis of PsV has been extensively studied, only a few innate immune genes have been associated with GPP. Neutrophils are the first cells to migrate toward sites of infection, where they recruit and activate T cells, as well as keratinocytes, thus amplifying the cutaneous inflammatory response. Hence, the current project sought to investigate the role of abnormal neutrophil activation in psoriasis. The initial focus of the study was the identification of new disease genes by means of whole-exome-sequencing. A Chinese-Malay family where several members suffered from PsV and/or GPP was first analysed, in order to identify new genetic determinants of neutrophilic skin inflammation. This uncovered a candidate disease variant in PRR13, with a second damaging change observed in an unrelated individual sequenced by the 100,000 Genomes Project. While the function of PRR13 is poorly understood, alleles at this locus have been associated with neutrophil count variation in a genome-wide study. Next, the analysis of 147 pustular psoriasis patients uncovered two individuals with a homozygous splicing variant in MPO, a gene that is crucial to the microbicidal activity of neutrophils. Importantly, the variant was associated with increased neutrophil counts. In the final stage of the project, neutrophil RNA-sequencing was undertaken in 8 GPP cases vs. 11 controls. This identified an unexpected type-I IFN signature in patient neutrophils, an observation that was also validated in a PsV cohort. Mechanistic experiments demonstrated that the up-regulation of type-I IFN genes is driven by IL-36, which potentiates IFN-α production by enhancing TLR-9 activation in plasmacytoid dendritic cells. Taken together, these findings identify new molecular pathways causing abnormal neutrophil activation in plaque and pustular forms of psoriasis.
Supervisor: Capon, Francesca ; Smith, Catherine H. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.806762  DOI: Not available
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