Browsing by Author "Chatila, Talal A."

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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.
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    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.