Genomic investigation of primary immunodeficiency
type: CreativeWork
description: Primary immunodeficiencies (PIDs) are a collection of rare diseases which effect one or more components of the human immune system and are typically considered monogenic. PID presents with features including increased susceptibility to infection, autoimmunity, autoinflammation, atopy and malignancy. The list of genes associated with these inborn errors of immunity continues to expand. However, the majority of patients clinically effected with PID still remain without a genetic diagnosis. In this thesis, I have investigated three novel monogenic associations with PID, and also explored the impacts of common genetic variation in PID-associated genes with common diseases. From analysis of whole-genome sequence data of over 800 PID probands within the NIHR BioResource Rare Disease PID cohort, I identified novel monogenic associations between PID and rare deleterious variants in SOCS1, IVNS1ABP and TRAF3. In two families with autoimmunity and immunodeficiency I investigated the impacts of heterozygous deleterious variants in SOCS1. Patients showed reduced suppressor of cytokine signalling 1 (SOCS1) protein leading to enhanced signal transducer and activator of transcription 1 (STAT1) phosphorylation. Also, due the reduction in the E3 ligase action of SOCS1, patient cells showed increased Toll-like receptor cytokine responses and hyperactivity of the Akt pathway. Thus, dysregulation of multiple immune pathways leads to autoimmunity and immunodeficiency in affected individuals. I then examined the functions and role of Influenza virus NS1A-binding protein (IVNS1ABP) in immunity through the study of three patients with IVNS1ABP haploinsufficiency. These patients presented with warts and autoimmune disease with low CD4+ T cells and aberrant expression of PD-1 and CD127. Study of patient T cells, IVNS1ABP knockdown Jurkat cell lines, and CRISPR/Cas9-mediated IVNS1ABP knockdown in primary human T cells demonstrated that reduced IVNS1ABP leads to T cell hyperactivation. Develop…
abstract: Primary immunodeficiencies (PIDs) are a collection of rare diseases which effect one or more components of the human immune system and are typically considered monogenic. PID presents with features including increased susceptibility to infection, autoimmunity, autoinflammation, atopy and malignancy. The list of genes associated with these inborn errors of immunity continues to expand. However, the majority of patients clinically effected with PID still remain without a genetic diagnosis. In this thesis, I have investigated three novel monogenic associations with PID, and also explored the impacts of common genetic variation in PID-associated genes with common diseases. From analysis of whole-genome sequence data of over 800 PID probands within the NIHR BioResource Rare Disease PID cohort, I identified novel monogenic associations between PID and rare deleterious variants in SOCS1, IVNS1ABP and TRAF3. In two families with autoimmunity and immunodeficiency I investigated the impacts of heterozygous deleterious variants in SOCS1. Patients showed reduced suppressor of cytokine signalling 1 (SOCS1) protein leading to enhanced signal transducer and activator of transcription 1 (STAT1) phosphorylation. Also, due the reduction in the E3 ligase action of SOCS1, patient cells showed increased Toll-like receptor cytokine responses and hyperactivity of the Akt pathway. Thus, dysregulation of multiple immune pathways leads to autoimmunity and immunodeficiency in affected individuals. I then examined the functions and role of Influenza virus NS1A-binding protein (IVNS1ABP) in immunity through the study of three patients with IVNS1ABP haploinsufficiency. These patients presented with warts and autoimmune disease with low CD4+ T cells and aberrant expression of PD-1 and CD127. Study of patient T cells, IVNS1ABP knockdown Jurkat cell lines, and CRISPR/Cas9-mediated IVNS1ABP knockdown in primary human T cells demonstrated that reduced IVNS1ABP leads to T cell hyperactivation. Develop…
author: Rae, William
language: eng
keywords: Immunology, Genetics, Medicine
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/0a978fa8-6f54-49a5-a1c4-525bc2a22cf7/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2021-10-12
date modified: 2026-07-22T22:24:31Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.76905