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

Kayaoğlu, Başak
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.


Stepwise Reversal of Immune Dysregulation Due to STAT1 Gain-of-Function Mutation Following Ruxolitinib Bridge Therapy and Transplantation
Kayaoğlu, Başak; Yilmaz, Naz Surucu; Charbonnier, Louis Marie; Geckin, Busranur; Akcay, Arzu; Eltan, Sevgi Bilgic; Ozturk, Gulyuz; ÖZEN, AHMET OĞUZHAN; Karakoc-Aydiner, Elif; Chatila, Talal A.; Gürsel, Mayda (2021-01-01)
Purpose Patients with heterozygous gain-of-function (GOF) mutations in STAT1 frequently exhibit chronic mucocutaneous candidiasis (CMC), immunodeficiency and autoimmune manifestations. Several treatment options including targeted therapies and hematopoietic stem cell transplantation (HSCT) are available for STAT1 GOF patients but modalities and outcomes are not well established. Herein, we aimed to unravel the effect of ruxolitinib as a bridge therapy in a patient with sporadic STAT1 T385M mutation to manag...
Characterization of autoinflammatory manifestations in NEMO deficiency and analysis of gene expression patterns in LRBA and CTLA-4 deficiencies
Sürücü, Naz; Gürsel, Mayda; Department of Biology (2022-2-9)
NEMO (NF-κB essential modulator, IKK-γ) deficiency that phenotypically manifests as ectodermal dysplasia with immune deficiency (EDA-ID) arises due to hypomorphic mutations in the ikbkg gene in males. Patients present with developmental impairment of ectodermal tissues accompanied with recurrent infections early in life. Herein, we investigated the underlying mechanistic conditions leading to paradoxical autoinflammatory manifestations in a case of NEMO deficiency, who later underwent HSCT. Consistent with ...
Autoinflammation in addition to combined immunodeficiency: SLC29A3 gene defect
Cagdas, Deniz; Surucu, Naz; TAN, ÇAĞMAN; ÖZGÜL, RIZA KÖKSAL; Akkaya-Ulum, Yeliz Z.; Aydinoglu, Ayse Tulay; Aytac, Selin; GÜMRÜK, FATMA; Balci-Hayta, Burcu; Balci-Peynircioglu, Banu; ÖZEN, SEZA; Gürsel, Mayda; Tezcan, Ilhan (Elsevier BV, 2020-05-01)
Introduction: H Syndrome is an autosomal recessive (AR) disease caused by defects in SLCA29A3 gene. This gene encodes the equilibrative nucleoside transporter, the protein which is highly expressed in spleen, lymph node and bone marrow. Autoinflammation and autoimmunity accompanies H Syndrome (HS).
Comparison of antioxidant enzyme activities and DNA damage in chickpea (Cicer arietinum L.) genotypes exposed to vanadium
Imtiaz, Muhammad; Mushtaq, Muhammad Adnan; Rizwan, Muhammad Shahid; Arif, Muhammad Saleem; Yousaf, Balal; Ashraf, Muhammad; Xiong Shuanglian, Xiong Shuanglian; Rizwan, Muhammad; Mehmood, Sajid; Tu, Shuxin (2016-10-01)
The present study was done to elucidate the effects of vanadium (V) on photosynthetic pigments, membrane damage, antioxidant enzymes, protein, and deoxyribonucleic acid (DNA) integrity in the following chickpea genotypes: C-44 (tolerant) and Balkasar (sensitive). Changes in these parameters were strikingly dependent on levels of V, at 60 and 120 mg V L-1 induced DNA damage in Balkasar only, while photosynthetic pigments and protein were decreased from 15 to 120 mg V L-1 and membrane was also damaged. It was...
Differential expressions and functions of phosphodiesterase enzymes in different regions of the rat heart
DERİCİ, MEHMET KÜRŞAT; SADİ, GÖKHAN; Cenik, Basar; Güray, Nülüfer Tülün; DEMİREL YILMAZ, EMİNE (Elsevier BV, 2019-02-05)
Phosphodiesterase enzymes (PDEs) are responsible for the adjustment of cyclic nucleotide levels. Alterations in PDE expressions in different tissues cause conflicts between functional and clinical effects of PDE inhibitors. Therefore, the aim of this study was to investigate the gene and protein expressions and the functional role of PDEs in atrium and ventricle of rat heart The expressions of PDEs were examined in cardiac intact tissues and enzymatically isolated cells. The effects of PDE1-5 inhibitors (vi...
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.