Browsing by Author "Reisli, Ismail"

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Abatacept as a long-term targeted therapy for LRBA deficiency
(Elsevier, 2019-12) Kiykim, Ayça; Ogulur, İsmail; Dursun, Esra; Dogruel, Dilek; Karaca, Neslihan Edeer; Cogurlu, Mujde Tuba; Bilir, Ozlem Arman; Cansever, Murat; Kapakli, Hasan; Baser, Dilek; Kasap, Nurhan; Kutlug, Seyhan; Altintas, Derya Ufuk; Al-Shaibi, Ahmad; Agrebi, Nourhen; Kara, Manolya; Guven, Ayla; Somer, Ayper; Aydogmus, Cigdem; Ayaz, Nuray Aktay; Metin, Ayse; Aydogan, Metin; Uncuoglu, Aysen; Patiroglu, Turkan; Yildiran, Alisan; Guner, Sukru Nail; Keles, Sevgi; Reisli, Ismail; Aksu, Guzide; Kutukculer, Necil; Yilmaz, Mustafa; Karakoc-Aydiner, Elif; Lo, Bernice; Ozan, Ahmet; Chatila, Talal A.; Barıs, Safa; Çekiç, Şükrü; Kılıç, Sara Şebnem; Uludağ Üniversitesi/Tıp Fakültesi/Dahili Bilimler/Çocuk Sağlığı ve Hastalıkları; Uludağ Üniversitesi/Tıp Fakültesi/Dahili Bilimler/Çocuk Sağlığı ve Hastalıkları; 0000-0002-9574-1842; 0000-0001-8571-2581; L-1933-2017; 57094682600; 7102365439
BACKGROUND: LPS-responsive beige-like anchor (LRBA) deficiency presents with susceptibility to infections, autoimmunity, and lymphoproliferation. The long-term efficacy of cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (abatacept) as targeted therapy for its immune dysregulatory features remains to be established. OBJECTIVE: To determine the clinical and immunologic features of LRBA deficiency and long-term efficacy of abatacept treatment in controlling the different disease manifestations. METHODS: Twenty-two LRBA-deficient patients were recruited from different immunology centers and followed prospectively. Eighteen patients on abatacept were evaluated every 3 months for long-term clinical and immunologic responses. LRBA expression, lymphocyte subpopulations, and circulating T follicular helper cells were determined by flow cytometry. RESULTS: The mean age of the patients was 13.4 +/- 7.9 years, and the follow-up period was 3.4 +/- 2.3 years. Recurrent infections (n = 19 [86.4%]), immune dysregulation (n = 18 [81.8%]), and lymphoproliferation (n = 16 [72.7%]) were common clinical features. The long-term benefits of abatacept in 16 patients were demonstrated by complete control of lymphoproliferation and chronic diarrhea followed by immune dysregulation, most notably autoimmune cytopenias. Weekly or every other week administration of abatacept gave better disease control compared with every 4 weeks. There were no serious side effects related to the abatacept therapy. Circulating T follicular helper cell frequencies were found to be a reliable biomarker of disease activity, which decreased on abatacept therapy in most subjects. However, high circulating T follicular helper cell frequencies persisted in 2 patients who had a more severe disease phenotype that was relatively resistant to abatacept therapy. CONCLUSIONS: Long-term abatacept therapy is effective in most patients with LRBA deficiency.
Consensus Middle East and North Africa registry on inborn errors of immunity
(Springer/plenum Publishers, 2021-05-29) Aghamohammadi, Asghar; Rezaei, Nima; Yazdani, Reza; Delavari, Samaneh; Kutukculer, Necil; Topyildiz, Ezgi; Ozen, Ahmet; Baris, Safa; Karakoc-Aydiner, Elif; Kose, Hulya; Gulez, Nesrin; Genel, Ferah; Reisli, Ismail; Djenouhat, Kamel; Tahiat, Azzeddine; Boukari, Rachida; Ladj, Samir; Belbouab, Reda; Ferhani, Yacine; Belaid, Brahim; Djidjik, Reda; Kechout, Nadia; Attal, Nabila; Saidani, Khalissa; Barbouche, Ridha; Bousfiha, Aziz; Sobh, Ali; Rizk, Ragheed; Elnagdy, Marwa H.; Al-Ahmed, Mona; Al-Tamemi, Salem; Nasrullayeva, Gulnara; Adeli, Mehdi; Al-Nesf, Maryam; Hassen, Amel; Mehawej, Cybel; Irani, Carla; Megarbane, Andre; Quinn, Jessica; Marodi, Laszlo; Modell, Vicki; Modell, Fred; Al-Herz, Waleed; Geha, Raif S.; Abolhassani, Hassan; Kilic, Sara Sebnem; KILIÇ GÜLTEKİN, SARA ŞEBNEM; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları Anabilim Dalı.; 0000-0002-9454-1603; 0000-0001-6390-1074; 0000-0002-6338-6946; 0000-0002-8403-6128; 0000-0003-4150-5200; 0000-0001-8571-2581; 0000-0002-3343-6949; 0000-0001-8247-6405; 0000-0001-7047-076X; 0000-0002-7232-2629; 0000-0002-3051-3080; 0000-0001-9354-0214; 0000-0002-7209-9359; 0000-0002-7706-3910; 0000-0003-0714-2469; 0000-0002-6019-3751; 0000-0002-7394-1640; Q-6160-2016; IWD-5692-2023; B-4167-2009; R-6749-2017; ABD-5574-2021; HOF-7252-2023; AAH-1658-2021; ABF-5609-2020; AFU-4460-2022; JVE-0572-2024; GMX-2732-2022; IQU-2494-2023; KLE-3682-2024; HKN-1599-2023; B-3465-2014; HHT-0915-2022; IZE-1770-2023; P-3381-2019; T-7687-2017; AFF-7478-2022; M-4655-2018; F-5958-2017; N-5668-2017
Background Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis. Methods We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers. Results We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG). Conclusions This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation.
Mutational landscape of severe combined immunodeficiency patients from Turkey
(Wiley, 2020-06-02) Fırtına, Sinem; Ng, Yuk Yin; Ng, Özden Hatırnaz; Kıykım, Ayça; Aydiner, Elif; Nepesov, Serdar; Camcıoğlu, Yıldız; Sayar, Esra H.; Reisli, Ismail; Torun, Selda H.; Çöğürlü, Tuba; Uygun, Dilara; Şimşek, Işıl E.; Kaya, Ayşenur; Çipe, Funda; Çağdaş, Deniz; Yücel, Esra; Uygun, Vedat; Barış, Safa; Özen, Ahmet; Özbek, Uğur; Sayitoğlu, Müge; Çekiç, Şükrü; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Çocuk İmmünoloji Anabilim Dalı.; 0000-0002-9574-1842; L-1933-2017; 56117061000
Severe combined immunodeficiency (SCID) has a diverse genetic aetiology, where a clinical phenotype, caused by single and/or multiple gene variants, can give rise to multiple presentations. The advent of next-generation sequencing (NGS) has recently enabled rapid identification of the molecular aetiology of SCID, which is crucial for prognosis and treatment strategies. We sought to identify the genetic aetiology of various phenotypes of SCIDs and assessed both clinical and immunologic characteristics associated with gene variants. An amplicon-based targeted NGS panel, which contained 18 most common SCID-related genes, was contumely made to screen the patients (n = 38) with typical SCID, atypical SCID or OMENN syndrome. Allelic segregations were confirmed for the detected gene variants within the families. In total, 24 disease-causing variants (17 known and 7 novel) were identified in 23 patients in 9 different SCID genes: RAG1 (n = 5), RAG2 (n = 2), ADA (n = 3), DCLRE1C (n = 2), NHEJ1 (n = 2), CD3E (n = 2), IL2RG (n = 3), JAK3 (n = 4) and IL7R (n = 1). The overall success rate of our custom-made NGS panel was 60% (39.3% for NK+ SCID and 100% for NK- SCID). Incidence of autosomal-recessive inherited genes is more frequently found in our cohort than the previously reported populations probably due to the high consanguineous marriages in Turkey. In conclusion, the custom-made sequencing panel was able to identify and confirm the previously known and novel disease-causing variants with high accuracy.
Primary antibody deficiencies in Turkey: Molecular and clinical aspects (oct, 10.1007/s12026-021-09242-z, 2021)
(Springer, 2021-10-19) Fırtına, Sinem; Ng, Yuk Yin; Ng, Ozden H.; Kiykim, Ayca; Ozek, Esra Yucel; Kara, Manolya; Aydiner, Elif; Nepesov, Serdar; Camcioglu, Yildiz; Sayar, Esra H.; Gungoren, Ezgi Yalcin; Reisli, Ismail; Torun, Selda H.; Haskologlu, Sule; Cogurlu, Tuba; Kaya, Aysenur; Baris, Safa; Ozbek, Ugur; Ozen, Ahmet; Sayitoglu, Muge; Çekiç, Şükrü; ÇEKİÇ, ŞÜKRÜ; Bursa Uludağ Üniversitesi/Tıp Fakültesi.; 0000-0002-9574-1842; L-1933-2017
The original published version of this article contained a mistake in one of the afliations. The correct afliation of author Manolya Kara (7) should read: Istinye University Faculty of Medicine, VM MedicalPark Pendik Hospital, Pediatric Infectious Diseases Clinic, Istanbul, Turkey The original article has been corrected.
Simple measurement of iga predicts immunity and mortality in ataxia-telangiectasia
(Springer/plenum Publishers, 2021-09-03) Zielen, Stefan; Duecker, Ruth Pia; Woelke, Sandra; Donath, Helena; Bakhtiar, Sharhzad; Buecker, Aileen; Kreyenberg, Hermann; Huenecke, Sabine; Bader, Peter; Mahlaoui, Nizar; Ehl, Stephan; El-Helou, Sabine M.; Pietrucha, Barbara; Plebani, Alessandro; van der Flier, Michiel; van Aerde, Koen; Reda, Shereen M.; Kostyuchenko, Larysa; McDermott, Elizabeth; Galal, Nermeen; Pignata, Claudio; Perez, Juan Luis Santos; Laws, Hans-Juergen; Niehues, Tim; Kutukculer, Necil; Seidel, Markus G.; Marques, Laura; Ciznar, Peter; Edgar, John David M.; Soler-Palacin, Pere; von Bernuth, Horst; Krueger, Renate; Meyts, Isabelle; Baumann, Ulrich; Kanariou, Maria; Grimbacher, Bodo; Hauck, Fabian; Graf, Dagmar; Granado, Luis Ignacio Gonzalez; Prader, Seraina; Reisli, Ismail; Slatter, Mary; Rodriguez-Gallego, Carlos; Arkwright, Peter D.; Bethune, Claire; Deripapa, Elena; Sharapova, Svetlana O.; Lehmberg, Kai; Davies, E. Graham; Schuetz, Catharina; Kindle, Gerhard; Schubert, Ralf; Kilic, Sara S.; KILIÇ GÜLTEKİN, SARA ŞEBNEM; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları Anabilim Dalı.
Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naive CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ss repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978)
The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency
(Mosby-Elsevier, 2015-08-01) Engelhardt, Karin R.; Gertz, Michael E.; Keleş, Sevgi; Schaeffer, Alejandro A.; Sigmund, Elena C.; Glocker, Cristina; Saghafi, Shiva; Pourpak, Zahra; Ceja, Ruben; Sassi, Atfa; Graham, Laura E.; Massaad, Michel J.; Mellouli, Fethi; Ben-Mustapha, Imen; Khemiri, Monia; Kılıç, Sara Şebnem; Etzioni, Amos; Freeman, Alexandra F.; Thiel, Jens; Schulze, Ilka; Al-Herz, Waleed; Metin, Ayse; Sanal, Oezden; Tezcan, Ilhan; Yeganeh, Mehdi; Niehues, Tim; Dueckers, Gregor; Weinspach, Sebastian; Patiroglu, Turkan; Ünal, Ekrem; Dasouki, Majed; Yılmaz, Mustafa; Genel, Ferah; Aytekin, Caner; Kütükçüler, Necil; Somer, Ayper; Kılıç, Mehmet; Reisli, Ismail; Camcioğlu, Yıldız; Gennery, Andrew R.; Cant, Andrew J.; Jones, Alison; Gaspar, Bobby H.; Arkwright, Peter D.; Pietrogrande, Maria C.; Baz, Zeina; Al-Tamemi, Salem; Lougaris, Vassilios; Lefranc, Gerard; Megarbane, Andre; Boutros, Jeannette; Galal, Nermeen; Bejaoui, Mohamed; Barbouche, Mohamed-Ridha; Geha, Raif S.; Chatila, Talal A.; Grimbacher, Bodo; KILIÇ GÜLTEKİN, SARA ŞEBNEM; Uludağ Üniversitesi/Tıp Fakültesi/Pediatrik İmmünoloji Anabilim Dalı.; AAH-1658-2021
Background: Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management.Objectives: We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings.Methods: Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations.Results: DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/mu L (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4(+) and CD8(+) T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations.Conclusions: DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures.
The middle east and north africa diagnosis and management guidelines for inborn errors of immunity
(Elsevier, 2023-01-05) Barış, Safa; Abolhassani, Hassan; Massaad, Michel J.; Al-Nesf, Maryam; Chavoshzadeh, Zahra; Keles, Sevgi; Reisli, Ismail; Tahiat, Azzeddine; Shendi, Hiba Mohammad; Abd Elaziz, Dalia; Belaid, Brahim; Al Dhaheri, Fatima; Haskologlu, Sule; Dogu, Figen; Ben-Mustapha, Imen; Sobh, Ali; Galal, Nermeen; Meshaal, Safa; Elhawary, Rabab; El-marsafy, Aisha; Alroqi, Fayhan J.; Al-Saud, Bandar; Al-Ahmad, Mona; Al Farsi, Tariq; AL Sukaiti, Nashat; Al-Tamemi, Salem; Mehawej, Cybel; Dbaibo, Ghassan; ElGhazali, Gehad; Kilic, Sara Sebnem; Genel, Ferah; Kiykim, Ayca; Musabak, Ugur; Artac, Hasibe; Güner, Şükrü Nail; Boukari, Rachida; Djidjik, Reda; Kechout, Nadia; Cagdas, Deniz; El-Sayed, Zeinab Awad; Karakoc-Aydiner, Elif; Alzyoud, Raed; Barbouche, Mohamed Ridha; Adeli, Mehdi; Wakim, Rima Hanna; Reda, Shereen M.; Ikinciogullari, Aydan; Ozen, Ahmet; Bousfiha, Aziz; Al-Mousa, Hamoud; Rezaei, Nima; Al-Herz, Waleed; Geha, Raif S.; KILIÇ GÜLTEKİN, SARA ŞEBNEM; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Çocuk İmmünolojisi ve Romatoloji Anabilim Dalı.; AAH-1658-2021
Human inborn errors of immunity (IEI) are a group of 485 distinct genetic disorders affecting children and adults. Signs and symptoms of IEI are heterogeneous, and accurate diagnosis can be challenging and depends on the available human expertise and laboratory resources. The Middle East and North Africa (MENA) region has an increased prevalence of IEI because of the high rate of consanguinity with a predominance of autosomal recessive disorders. This area also exhibits more severe disease phenotypes compared with other regions, probably due to the delay in diagnosis. The MENA-IEI registry network has designed protocols and guidelines for the diagnosis and treatment of IEI, taking into consideration the variable regional expertise and resources. These guidelines are primarily meant to improve the care of patients within the region, but can also be followed in other regions with similar patient pop-ulations. (c) 2022 American Academy of Allergy, Asthma & Immunology