Person: AYDINER, ELİF
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AYDINER
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ELİF
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Publication Metadata only Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy(AMER ASSOC ADVANCEMENT SCIENCE, 2015) AYDINER, ELİF; Lo, Bernice; Zhang, Kejian; Lu, Wei; Zheng, Lixin; Zhang, Qian; Kanellopoulou, Chrysi; Zhang, Yu; Liu, Zhiduo; Fritz, Jill M.; Marsh, Rebecca; Husami, Ammar; Kissell, Diane; Nortman, Shannon; Chaturvedi, Vijaya; Haines, Hilary; Young, Lisa R.; Mo, Jun; Filipovich, Alexandra H.; Bleesing, Jack J.; Mustillo, Peter; Stephens, Michael; Rueda, Cesar M.; Chougnet, Claire A.; Hoebe, Kasper; McElwee, Joshua; Hughes, Jason D.; Karakoc-Aydiner, Elif; Matthews, Helen F.; Price, Susan; Su, Helen C.; Rao, V. Koneti; Lenardo, Michael J.; Jordan, Michael B.Mutations in the LRBA gene (encoding the lipopolysaccharide-responsive and beige-like anchor protein) cause a syndrome of autoimmunity, lymphoproliferation, and humoral immune deficiency. The biological role of LRBA in immunologic disease is unknown. We found that patients with LRBA deficiency manifested a dramatic and sustained improvement in response to abatacept, a CTLA4 (cytotoxic T lymphocyte antigen-4)-immunoglobulin fusion drug. Clinical responses and homology of LRBA to proteins controlling intracellular trafficking led us to hypothesize that it regulates CTLA4, a potent inhibitory immune receptor. We found that LRBA colocalized with CTLA4 in endosomal vesicles and that LRBA deficiency or knockdown increased CTLA4 turnover, which resulted in reduced levels of CTLA4 protein in FoxP3(+) regulatory and activated conventional Tcells. In LRBA-deficient cells, inhibition of lysosome degradation with chloroquine prevented CTLA4 loss. These findings elucidate a mechanism for CTLA4 trafficking and control of immune responses and suggest therapies for diseases involving the CTLA4 pathway.Publication Metadata only JAGN1 Deficient Severe Congenital Neutropenia: Two Cases from the Same Family(SPRINGER/PLENUM PUBLISHERS, 2015) ÖZEN, AHMET OĞUZHAN; Baris, S.; Karakoc-Aydiner, E.; Ozen, A.; Delil, K.; Kiykim, A.; Ogulur, I.; Baris, I.; Barlan, I. B.Recently autosomal recessively inherited mutations in the gene encoding Jagunal homolog 1 (JAGN1) was described as a novel disease-causing gene of severe congenital neutropenia (SCN) JAGN1-mutant neutrophils were characterized by abnormality in endoplasmic reticulum structure, absence of granules, abnormal N-glycosylation of proteins and susceptibility to apoptosis. These findings imply the role of JAGN1 in neutrophil survival. Here, we report two siblings with a homozygous mutation in JAGN1 gene, exhibiting multisystemic involvement.Publication Metadata only Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency(WILEY) ÖZEN, AHMET OĞUZHAN; Kolukisa, Burcu; Baser, Dilek; Akcam, Bengu; Danielson, Jeffrey; Eltan, Sevgi Bilgic; Haliloglu, Yesim; Sefer, Asena Pinar; Babayeva, Royale; Akgun, Gamze; Charbonnier, Louis-Marie; Schmitz-Abe, Klaus; Demirkol, Yasemin Kendir; Zhang, Yu; Gonzaga-Jauregui, Claudia; Heredia, Raul Jimenez; Kasap, Nurhan; Kiykim, Ayca; Yucel, Esra Ozek; Gok, Veysel; Unal, Ekrem; Kisaarslan, Aysenur Pac; Nepesov, Serdar; Baysoy, Gokhan; Onal, Zerrin; Yesil, Gozde; Celkan, Tulin Tiraje; Cokugras, Haluk; Camcioglu, Yildiz; Eken, Ahmet; Boztug, Kaan; Lo, Bernice; Karakoc-Aydiner, Elif; Su, Helen C.; Ozen, Ahmet; Chatila, Talal A.; Baris, SafaBackground Biallelic loss-of-function mutations in CARMIL2 cause combined immunodeficiency associated with dermatitis, inflammatory bowel disease (IBD), and EBV-related smooth muscle tumors. Clinical and immunological characterizations of the disease with long-term follow-up and treatment options have not been previously reported in large cohorts. We sought to determine the clinical and immunological features of CARMIL2 deficiency and long-term efficacy of treatment in controlling different disease manifestations. Methods The presenting phenotypes, long-term outcomes, and treatment responses were evaluated prospectively in 15 CARMIL2-deficient patients, including 13 novel cases. Lymphocyte subpopulations, protein expression, regulatory T (Treg), and circulating T follicular helper (cT(FH)) cells were analyzed. Three-dimensional (3D) migration assay was performed to determine T-cell shape. Results Mean age at disease onset was 38 +/- 23 months. Main clinical features were skin manifestations (n = 14, 93%), failure to thrive (n = 10, 67%), recurrent infections (n = 10, 67%), allergic symptoms (n = 8, 53%), chronic diarrhea (n = 4, 27%), and EBV-related leiomyoma (n = 2, 13%). Skin manifestations ranged from atopic and seborrheic dermatitis to psoriasiform rash. Patients had reduced proportions of memory CD4(+) T cells, Treg, and cT(FH) cells. Memory B and NK cells were also decreased. CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix. IBD was the most severe clinical manifestation, leading to growth retardation, requiring multiple interventional treatments. All patients were alive with a median follow-up of 10.8 years (range: 3-17 years). Conclusion This cohort provides clinical and immunological features and long-term follow-up of different manifestations of CARMIL2 deficiency.Publication Metadata only Clinical Heterogeneity of Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked: Pulmonary Involvement as a Non-Classical Disease Manifestation(SPRINGER/PLENUM PUBLISHERS, 2014) ÖZEN, AHMET OĞUZHAN; Baris, Safa; Schulze, Ilka; Ozen, Ahmet; Aydiner, Elif Karakoc; Altuncu, Emel; Karasu, Gulsun Tezcan; Ozturk, Nilufer; Lorenz, Myriam; Schwarz, Klaus; Vraetz, Thomas; Ehl, Stephan; Barlan, Isil B.IPEX (Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked) is a rare X-linked recessive life-threatening disorder characterized by autoimmunity and early death. Pulmonary complication related with IPEX has not been elucidated exactly. Here, we report 4 IPEX patients, 3 of which died from severe pulmonary disease. Clinical data and laboratory findings including autoantibodies, immunoglobulin levels as well as number of T, B and NK cells were evaluated. FOXP3 expression and T reg activity were analyzed. The FOXP3 gene was sequenced and RNA analysis was performed. Patient I (PI) presented with nephrotic syndrome at 3 years of age and then developed autoimmune hepatitis without eczema, enteropathy or high IgE and died at 9 years of age due to acute respiratory distress syndrome (ARDS). Two cousins of PI had the same hypomorphic splice site mutation leading to a deletion of 27 amino acids, but normal FOXP3 protein expression and normal suppressive capacity of T reg in a proliferation inhibition assay. However, they exhibited typical symptoms such as eczema, diabetes and enteropathy with eosinophilia at early age (PII, PIII) and were transplanted in infancy. One of them had severe respiratory distress right after birth (PIII). Patient IV from another family presented with chronic diarrhea without autoimmune manifestations and died due to ARDS. Lung disease related to IPEX syndrome has not been reported before and this entity could be a critical factor in disease outcome.Publication Metadata only Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency(SPRINGER/PLENUM PUBLISHERS, 2022) ÖZEN, AHMET OĞUZHAN; Sefer, Asena Pinar; Abolhassani, Hassan; Ober, Franziska; Kayaoglu, Basak; Eltan, Sevgi Bilgic; Kara, Altan; Erman, Baran; Yilmaz, Naz Surucu; Aydogmus, Cigdem; Aydemir, Sezin; Charbonnier, Louis-Marie; Kolukisa, Burcu; Azizi, Gholamreza; Delavari, Samaneh; Momen, Tooba; Aliyeva, Simuzar; Demirkol, Yasemin Kendir; Tekin, Saban; Kiykim, Ayca; Baser, Omer Faruk; Cokugras, Haluk; Gursel, Mayda; Karakoc-Aydiner, Elif; Ozen, Ahmet; Krappmann, Daniel; Chatila, Talal A.; Rezaei, Nima; Baris, SafaPurpose MALT1 deficiency is a combined immune deficiency characterized by recurrent infections, eczema, chronic diarrhea, and failure to thrive. Clinical and immunological characterizations of the disease have not been previously reported in large cohorts. We sought to determine the clinical, immunological, genetic features, and the natural history of MALT-1 deficiency. Methods The clinical findings and treatment outcomes were evaluated in nine new MALT1-deficient patients. Peripheral lymphocyte subset analyses, cytokine secretion, and proliferation assays were performed. We also analyzed ten previously reported patients to comprehensively evaluate genotype/phenotype correlation. Results The mean age of patients and disease onset were 33 +/- 17 and 1.6 +/- 0.7 months, respectively. The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%). Eosinophilia and high IgE were observed in six (67%) and two (22%) patients, respectively. The majority of patients had normal T and NK cells, while eight (89%) exhibited reduced B cells. Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications. One patient received hematopoietic stem cell transplantation (HSCT) and five patients died as a complication of life-threatening infections. Analyzing this cohort with reported patients revealed overall survival in 58% (11/19), which was higher in patients who underwent HSCT (P = 0.03). Conclusion This cohort provides the largest analysis for clinical and immunological features of MALT1 deficiency. HSCT should be offered as a curative therapeutic option for all patients at the early stage of life.