Person: ERTEM ŞAHİNOĞLU, DENİZ
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ERTEM ŞAHİNOĞLU
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DENİZ
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Publication Open Access Mucus sialylation determines intestinal host-commensal homeostasis(2022-03-31) ÖZEN, AHMET OĞUZHAN; BARIŞ, SAFA; ERTEM ŞAHİNOĞLU, DENİZ; Yao Y., Kim G., Shafer S., Chen Z., Kubo S., Ji Y., Luo J., Yang W., Perner S. P., Kanellopoulou C., et al.Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive bacterial proteolytic degradation. Glycoproteomic profiling and biochemical analysis of ST6 mutations identified in patients show that decreased sialylation causes defective mucus proteins and congenital inflammatory bowel disease (IBD). Mice harboring a patient ST6 mutation have compromised mucus barriers, dysbiosis, and susceptibility to intestinal inflammation. Based on our understanding of the ST6 regulatory network, we show that treatment with sialylated mucin or a Foxo3 inhibitor can ameliorate IBD.Publication Open Access Homozygous IL37 mutation associated with infantile inflammatory bowel disease(NATL ACAD SCIENCES, 2021-03-09) ÖZEN, AHMET OĞUZHAN; Zhang, Zinan Z.; Zhang, Yu; He, Tingyan; Sweeney, Colin L.; Baris, Safa; Karakoc-Aydiner, Elif; Yao, Yikun; Ertem, Deniz; Matthews, Helen F.; Gonzaga-Jauregui, Claudia; Malech, Harry L.; Su, Helen C.; Ozen, Ahmet; Smith, Kenneth G. C.; Lenardo, Michael J.Interleukin (IL)-37, an antiinflammatory IL-1 family cytokine, is a key suppressor of innate immunity. IL-37 signaling requires the heterodimeric IL-18R1 and IL-1R8 receptor, which is abundantly expressed in the gastrointestinal tract. Here we report a 4-mo-old male from a consanguineous family with a homozygous loss-of-function IL37 mutation. The patient presented with persistent diarrhea and was found to have infantile inflammatory bowel disease (I-IBD). Patient cells showed increased intracellular IL-37 expression and increased proinflammatory cytokine production. In cell lines, mutant IL-37 was not stably expressed or properly secreted and was thus unable to functionally suppress proinflammatory cytokine expression. Furthermore, induced pluripotent stem cell-derived macrophages from the patient revealed an activated macrophage phenotype, which is more prone to lipopolysaccharide and IL-1 beta stimulation, resulting in hyperinflammatory tumor necrosis factor production. Insights from this patient will not only shed light on monogenic contributions of I-IBD but may also reveal the significance of the IL-18 and IL-37 axis in colonic homeostasis.Publication Open Access Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease(NATURE RESEARCH, 2021-02) ÖZEN, AHMET OĞUZHAN; Ozen, Ahmet; Kasap, Nurhan; Vujkovic-Cvijin, Ivan; Apps, Richard; Cheung, Foo; Karakoc-Aydiner, Elif; Akkelle, Bilge; Sari, Sinan; Tutar, Engin; Ozcay, Figen; Uygun, Dilara Kocacik; Islek, Ali; Akgun, Gamze; Selcuk, Merve; Sezer, Oya Balci; Zhang, Yu; Kutluk, Gunsel; Topal, Erdem; Sayar, Ersin; Celikel, Cigdem; Houwen, Roderick H. J.; Bingol, Aysen; Ogulur, Ismail; Eltan, Sevgi Bilgic; Snow, Andrew L.; Lake, Camille; Fantoni, Giovanna; Alba, Camille; Sellers, Brian; Chauvin, Samuel D.; Dalgard, Clifton L.; Harari, Olivier; Ni, Yan G.; Wang, Ming-Dauh; Devalaraja-Narashimha, Kishor; Subramanian, Poorani; Ergelen, Rabia; Artan, Reha; Guner, Sukru Nail; Dalgic, Buket; Tsang, John; Belkaid, Yasmine; Ertem, Deniz; Baris, Safa; Lenardo, Michael J.CHAPLE disease is a lethal syndrome caused by genetic loss of the complement regulatory protein CD55. Lenardo, Ozen and their colleagues report that blockade of C5 complement activation in a small cohort of pediatric patients with CHAPLE disease reduced gastrointestinal pathology and restored their immunity and growth. Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.Publication Open Access Gastrointestinal Manifestations in Children with Primary Immunodeficiencies: Single Center: 12 Years Experience(KARGER, 2019) ÖZEN, AHMET OĞUZHAN; Akkelle, Bilge S.; Tutar, Engin; Volkan, Burcu; Sengul, Ozlem K.; Ozen, Ahmet; Celikel, Cigdem A.; Ertem, DenizBackground: It has been reported that 5-50% of patients with primary immune deficiencies (PID) may present with or develop gastrointestinal (GI) manifestations. Objective: This study was aimed at analyzing GI and related endoscopic, histopathological findings in children with PID. Methods: Children with PID who were evaluated by endoscopy between 2005 and 2016 were enrolled in this study. Demographic data, growth parameters, signs and symptoms at diagnosis were obtained. Results: Of 425 children with PID, 195 had GI manifestations. Forty-seven of 195 children required endoscopic investigation, 30 (63.8%) were male, and the mean age was 7.7 +/- 5 years. The rate of consanguinity was 61.7%, and the most common symptom was chronic diarrhea (57.4%). Seventy-two percent of the patients were malnourished. Giardia intestinalis was detected in 4, and Helicobacter pylori was confirmed in 8/45 (17.7%) patients. Non-celiac villous flatting was discovered in 15.5% of patients. Twelve patients were diagnosed as having immunodeficiency associated inflammatory bowel disease (IBD)-like colitis. Conclusions: PID may present with GI manifestations or develop during the course of the disease. Investigating immunodeficiency in patients with atypical GI symptoms can provide an appropriate therapeutic option, and an improved quality of life, particularly in populations with a high rate of consanguinity.Publication Metadata only Natural history and symptomatology of Helicobacter pylori in childhood and factors determining the epidemiology of infection(2006) ÖZEN, AHMET OĞUZHAN; Özen A., Ertem D., Pehlivanoglu E.Background: High seroprevalence rates for Helicobacter pylori have been reported in developing countries, yet few studies exist determining the pattern of change in the epidemiology of H. pylori infection in children. The knowledge of acquisition and loss rates of H. pylori and the relevance to the sociodemographic properties and the symptomatology of infection may provide clues for lifestyle changes that might protect children from infection, and also, it may provide rationale for eradication, screening, and protection policies. Our aim was to conduct a prospective study to elucidate the outcome, rate of acquisition, and loss of H. pylori infection in a population of healthy children. Methods: This study is based on follow-up of 327 healthy Turkish children aged 3 to 12 years. The follow-up was conducted 6 years after the baseline examination. Helicobacter pylori status was determined by 13C-urea breath test. Children were investigated for sociodemographic variables and several symptoms. Results: Data from 136 (41%) of 327 children were available. The prevalence of infection increased from 52.9% to 56.6%, mainly increasing in children younger than 10 years. The incidence of H. pylori infection among previously uninfected children was 14%, and the loss rate of infection among previously infected children was 5.5% during the follow-up. Socioeconomic status, household density, and antibiotic use during last 6 months were inversely related to H. pylori prevalence. Children infected with H. pylori were complaining more often of headache but not of abdominal pain or dyspepsia. Conclusions: In this study, the acquisition rate of H. pylori infection was 2.5-fold higher than the loss of infection, and the acquisition mostly occurred before 10 years of age. Data regarding acquisition and loss of H. pylori infection are critical for understanding the epidemiology of infection and development of preventive and treatment strategies. © 2006 by Lippincott Williams & Wilkins.