Investigation of cellular responses in a patient with STAT1 gain-of-function mutation successfully transplanted with Ruxolitinib bridge therapy and characterization of anti-viral immune responses in DOCK8 deficiency

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Başak Kayaoğlu-PhD Thesis.pdf

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2023-1

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Kayaoğlu, Başak

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Gain-of-function mutations (GOF) in the STAT1 gene are associated with impaired STAT1 phosphorylation/dephosphorylation cycle and Th17 deficiency. A sporadic T835M mutation in the STAT1 gene was detected in a patient with chronic mucocutaneous candidiasis (CMC), viral and bacterial infections accompanied by autoimmunity. Here, we aimed to investigate the cellular level defects in the patient and how they were affected by Ruxolitinib treatment and hematopoietic stem cell transplantation (HSCT). We showed that Ruxolitinib treatment partially restored the dysregulated STAT1 phosphorylation dynamics but failed to improve Th17 deficiency, whereas both functions were normalized following HSCT. Furthermore, STAT1 GOF patient showed a dysregulated gene expression profile, which was partially improved with Ruxolitinib treatment and completely normalized with HSCT. Our results suggest that improved disease management and relatively normalized gene expression profile can be achieved with Ruxolitinib treatment before transplantation and this would be beneficial to reduce the risk of adverse outcome of HSCT. Herein, we also investigated the underlying mechanisms leading to susceptibility to viral infections in DOCK8 deficiency. Differential gene expression analysis followed by principal component analysis (PCA) on 15 patients with DOCK8 deficiency revealed that the patients clustered into two distinct groups relative to healthy controls. One group of patients showed increased expression of interferon-stimulated genes (ISGs) and immune exhaustion markers but presented with compromised type I interferon response to stimulation with several different nucleic acid ligands. Our preliminary findings indicate that this dysregulated interferon response might be the consequence of the “exhausted phenotype” of innate immune cells caused by chronically elevated interferon signature.

Subject Keywords

STAT1 GOF, Ruxolitinib, DOCK8 deficiency, viral immunity, immune exhaustion

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https://hdl.handle.net/11511/101966

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Graduate School of Natural and Applied Sciences, Thesis

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Citation Formats

B. Kayaoğlu, “Investigation of cellular responses in a patient with STAT1 gain-of-function mutation successfully transplanted with Ruxolitinib bridge therapy and characterization of anti-viral immune responses in DOCK8 deficiency,” Ph.D. - Doctoral Program, Middle East Technical University, 2023.