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
Karakoc-Aydiner, Elif
Chatila, Talal A.
Gürsel, Mayda
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 manage infections and other disease manifestations. Methods Peripheral blood mononuclear cells were isolated from the patient prior to, during ruxolitinib treatment and 6 months after HSCT. IFN-beta-induced STAT1 phosphorylation/dephosphorylation levels and PMA/ionomycin-stimulated intracellular IL-17A/IFN-gamma production in CD4(+) T cells were evaluated. Differentially expressed genes between healthy controls and the patient prior to, during ruxolitinib treatment and post-transplantation were investigated using Nanostring nCounter Profiling Panel. Results Ruxolitinib provided favorable responses by controlling candidiasis and autoimmune hemolytic anemia in the patient. Dysregulation in STAT1 phosphorylation kinetics improved with ruxolitinib treatment and was completely normalized after transplantation. T(H)17 deficiency persisted after ruxolitinib treatment, but normalized following HSCT. Consistent with the impairment in JAK/STAT signaling, multiple immune related pathways were found to be dysregulated in the patient. At baseline, genes related to type I IFN-related pathways, antigen processing, T-cell and B-cell functions were upregulated, while NK-cell function and cytotoxicity related genes were downregulated. Dysregulated gene expression was partially improved with ruxolitinib treatment and normalized after transplantation. Conclusion Our findings suggest that improved disease management and immune dysregulatory profile can be achieved with ruxolitinib treatment before transplantation and this would be beneficial to reduce the risk of adverse outcome of HSCT.


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).
CpG DNA: recognition by and activation of monocytes.
Klinman, DM; Takeshita, F; Gursel, I; Leifer, C; Ishii, KJ; Verthelyi, D; Gürsel, Mayda (2002-07-01)
Unmethylated CpG motifs present in bacterial DNA rapidly trigger an innate immune response characterized by the activation of Ig- and cytokine-secreting cells. Synthetic oligonucleotides (ODNs) containing CpG motifs mimic this activity, triggering monocytes to proliferate, secrete and/or differentiate. Analysis of hundreds of novel ODNs led to the identification of two structurally distinct classes of CpG motif that differentially activate human monocytes. ODNs of the "K"-type interact with Toll-like recept...
Differential immune activation following encapsulation of immunostimulatory CpG oligodeoxynucleotide in nanoliposomes.
Erikçi, E; Gürsel, Mayda; Gürsel, I (2011-02-01)
The immunogenicity of a vaccine formulation is closely related to the effective internalization by the innate immune cells that provide prolonged and simultaneous delivery of antigen and adjuvant to relevant antigen presenting cells. Endosome associated TLR9 recognizes microbial unmethylated CpG DNA. Clinical applications of TLR9 ligands are significantly hampered due to their pre-mature in vivo digestion and rapid clearance. Liposome encapsulation is a powerful tool to increase in vivo stability as well as...
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İçgen, Bülent; Özcengiz, Gülay; Gültekin, Güzin Candan ( TÜBİTAK, 2002-01-01)
A total of 259 clinical isolates of non-repetitive non-typhi salmonellae (NTS) were previously examined for their antibiotic resistance patterns and plasmid contents. Multi-drug resistant strains comprised 19.3% (50/259) of the isolates and almost all were Salmonella typhimurium. In the present study, 35 of these multi-drug resistant S. typhimurium isolates were further characterized for colicinogeny, lipopolysaccharide (LPS) and outer membrane protein (OMP) profiles. Fourteen of the 35 (40%) isolates were ...
Enantioselective synthesis of new chiral 2-aziridinyl phosphonates and studies of their biological activities
Doğan, Özdemir; Beksultanova, Nurzhan; ALTANLAR, NURTEN; Simsek, Duygu; KARABIYIK, HASAN (2017-02-15)
A new series of chiral aziridinyl phosphonates has been synthesized and evaluated for antibacterial and antifungal activities. For the synthesis, a Gabriel-Cromwell reaction was used to form aziridinyl phosphonates in 52-83% yield. In order to evaluate antibacterial and antifungal activities, MIC values were measured. Although most of the compounds showed insignificant activity, two of them provided low to moderate antifungal activity.
Citation Formats
B. Kayaoğlu et al., “Stepwise Reversal of Immune Dysregulation Due to STAT1 Gain-of-Function Mutation Following Ruxolitinib Bridge Therapy and Transplantation,” JOURNAL OF CLINICAL IMMUNOLOGY, pp. 0–0, 2021, Accessed: 00, 2021. [Online]. Available: