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Vaseghi-Shanjani, Maryam

University of British Columbia

Inborn errors of immunity (IEIs) are a diverse group of genetic disorders that adversely affect the function and/or development of the immune system, resulting in increased susceptibility to infections, autoimmunity, allergy, and malignancies. Primary immune regulatory disorders and primary atopic disorders are two subcategories of IEIs. While IEIs are commonly associated with frequent, severe, and unconventional infections, primary immune regulatory disorders mainly present with immune dysregulation, and primary atopic disorders with severe, early-onset allergies. These manifestations can occur with or without the typical infectious symptoms expected with IEIs. Given the recently acknowledged diversity of symptoms associated with IEIs, there is a pressing need to sequence and investigate individuals presenting with unconventional and newly identified manifestations of IEIs. The overarching goal of this thesis was to use an established pipeline of studying single patients to discover and characterize novel monogenic causes of primary immune regulatory disorders and primary atopic disorders. The discovery of these novel classes of IEIs significantly enriches our understanding of fundamental human biology, presenting new pathways for therapeutic development and repurposing, which promise substantial enhancements in patient care. By employing a comprehensive approach that included the collection of phenotypic information from patients and the use of advanced genomic sequencing and bioinformatics analyses, we identified two novel diseases caused by germline variants in IKZF2 and ZBTB7B, which encode critical transcription factors – Helios and ThPOK – that regulate broad-ranging biological processes in the human body. The first study delineates the consequences of two dominant-negative variants in Helios, revealing an association with a complex syndrome in humans characterized by immune dysregulation and developmental anomalies, thus broadening our understanding of Helios’s role in human physiology and development. The second study describes the discovery of a multimorphic variant in ThPOK, outlining its critical involvement in CD4 T cell development and its unexpected association with tissue fibrosis in humans. These findings not only demonstrate the profound impact of transcriptional regulation on immune function and disease, but also expand the diagnostic and therapeutic approaches of IEIs, enriching the future landscape of IEI management.

Text

2025-05-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88375

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/