Browsing by Author "Sayar, E. H."
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Item Open Access Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant(NLM (Medline), 2018) Boisson-Dupuis, S.; Ramirez-Alejo, N.; Li, Z.; Patin, E.; Rao, G.; Kerner, G.; Lim, C. K.; Krementsov, D. N.; Hernandez, N.; Ma, C. S.; Zhang, Q.; Markle, J.; Martinez-Barricarte, R.; Payne, K.; Fisch, R.; Deswarte, C.; Halpern, J.; Bouaziz, M.; Mulwa, J.; Sivanesan, D.; Lazarov, T.; Naves, R.; Garcia, P.; Itan, Y.; Boisson, B.; Checchi, A.; Jabot-Hanin, F.; Cobat, A.; Guennoun, A.; Jackson, C. C.; Pekcan, S.; Çalışkaner, Z.; Inostroza, J.; Costa-Carvalho, B. T.; De Albuquerque, J. A. T.; Garcia-Ortiz, H.; Orozco, L.; Özçelik, Tayfun; Abid, A.; Rhorfi, I. A.; Souhi, H.; Amrani, H. N.; Zegmout, A.; Geissmann, F.; Michnick, S. W.; Muller-Fleckenstein, I.; Fleckenstein, B.; Puel, A.; Ciancanelli, M. J.; Marr, N.; Abolhassani, H.; Balcells, M. E.; Condino-Neto, A.; Strickler, A.; Abarca, K.; Teuscher, C.; Ochs, H. D.; Reisli, I.; Sayar, E. H.; El-Baghdadi, J.; Bustamante, J.; Hammarström, L.; Tangye, S. G.; Pellegrini, S.; Quintana-Murci, L.; Abel, L.; Casanova, J. -L.Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common TYK2 P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls (P = 8.37 × 10-8; odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of TYK2 selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis. CopyrightItem Open Access Type I IFN-related NETosis in ataxia telangiectasia and Artemis deficiency(Mosby, 2018) Gül, E.; Sayar, E. H.; Güngör, B.; Kara-Eroğlu, Fehime; Sürücü, N.; Keleş, S.; Güner, S. N.; Fındık, S.; Alpdündar, E.; Ayanoğlu, I. C.; Kayaoğlu, B.; Geçkin, B. N.; Şanlı, H. A.; Kahraman, Tamer; Yakıcıer, C.; Müftüoğlu, M.; Oğuz, B.; Ayvaz, D. N. Ç.; Gürsel, İhsan; Özen, S.; Reisli, İ.; Gürsel, M.Background: Pathological inflammatory syndromes of unknown etiology are commonly observed in ataxia telangiectasia (AT) and Artemis deficiency. Similar inflammatory manifestations also exist in patients with STING-associated vasculopathy in infancy (SAVI). Objective: We sought to test the hypothesis that the inflammation-associated manifestations observed in patients with AT and Artemis deficiency stem from increased type I IFN signature leading to neutrophil-mediated pathological damage. Methods: Cytokine/protein signatures were determined by ELISA, cytometric bead array, or quantitative PCR. Stat1 phosphorylation levels were determined by flow cytometry. DNA species accumulating in the cytosol of patients' cells were quantified microscopically and flow cytometrically. Propensity of isolated polymorhonuclear granulocytes to form neutrophil extracellular traps (NETs) was determined using fluorescence microscopy and picogreen assay. Neutrophil reactive oxygen species levels and mitochondrial stress were assayed using fluorogenic probes, microscopy, and flow cytometry. Results: Type I and III IFN signatures were elevated in plasma and peripheral blood cells of patients with AT, Artemis deficiency, and SAVI. Chronic IFN production stemmed from the accumulation of DNA in the cytoplasm of AT and Artemis-deficient cells. Neutrophils isolated from patients spontaneously produced NETs and displayed indicators of oxidative and mitochondrial stress, supportive of their NETotic tendencies. A similar phenomenon was also observed in neutrophils from healthy controls exposed to patient plasma samples or exogeneous IFN-α. Conclusions: Type I IFN-mediated neutrophil activation and NET formation may contribute to inflammatory manifestations observed in patients with AT, Artemis deficiency, and SAVI. Thus, neutrophils represent a promising target to manage inflammatory syndromes in diseases with active type I IFN signature.