Person: AYDINER, ELİF
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AYDINER
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ELİF
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Publication Open Access Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study(MOSBY-ELSEVIER, 2018-03) ÖZEN, AHMET OĞUZHAN; Barzaghi, Federica; Hernandez, Laura Cristina Amaya; Neven, Benedicte; Ricci, Silvia; Kucuk, Zeynep Yesim; Bleesing, Jack J.; Nademi, Zohreh; Slatter, Mary Anne; Ulloa, Erlinda Rose; Shcherbina, Anna; Roppelt, Anna; Worth, Austen; Silva, Juliana; Aiuti, Alessandro; Murguia-Favela, Luis; Speckmann, Carsten; Carneiro-Sampaio, Magda; Fernandes, Juliana Folloni; Baris, Safa; Ozen, Ahmet; Karakoc-Aydiner, Elif; Kiykim, Ayca; Schulz, Ansgar; Steinmann, Sandra; Notarangelo, Lucia Dora; Gambineri, Eleonora; Lionetti, Paolo; Shearer, William Thomas; Forbes, Lisa R.; Martinez, Caridad; Moshous, Despina; Blanche, Stephane; Fisher, Alain; Ruemmele, Frank M.; Tissandier, Come; Ouachee-Chardin, Marie; Rieux-Laucat, Frederic; Cavazzana, Marina; Qasim, Waseem; Lucarelli, Barbarella; Albert, Michael H.; Kobayashi, Ichiro; Alonso, Laura; De Heredia, Cristina Diaz; Kanegane, Hirokazu; Lawitschka, Anita; Seo, Jong Jin; Gonzalez-Vicent, Marta; Diaz, Miguel Angel; Goyal, Rakesh Kumar; Sauer, Martin G.; Yesilipek, Akif; Kim, Minsoo; Yilmaz-Demirdag, Yesim; Bhatia, Monica; Khlevner, Julie; Padilla, Erick J. Richmond; Martino, Silvana; Montin, Davide; Neth, Olaf; Molinos-Quintana, Agueda; Valverde-Fernandez, Justo; Broides, Arnon; Pinsk, Vered; Ballauf, Antje; Haerynck, Filomeen; Bordon, Victoria; Dhooge, Catharina; Garcia-Lloret, Maria Laura; Bredius, Robbert G.; Kalwak, Krzysztof; Haddad, Elie; Seidel, Markus Gerhard; Duckers, Gregor; Pai, Sung-Yun; Dvorak, Christopher C.; Ehl, Stephan; Locatelli, Franco; Goldman, Frederick; Gennery, Andrew Richard; Cowan, Mort J.; Roncarolo, Maria-Grazia; Bacchetta, RosaBackground: Immunodysregulation polyendocrinopathy enteropathy x-linked(IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. Methods: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n 5 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. Conclusions: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term.disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.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 Open Access ILC3 deficiency and generalized ILC abnormalities in DOCK8-deficient patients(WILEY, 2020-04) ÖZEN, AHMET OĞUZHAN; Eken, Ahmet; Cansever, Murat; Okus, Fatma Zehra; Erdem, Serife; Nain, Ercan; Azizoglu, Zehra Busra; Haliloglu, Yesim; Karakukcu, Musa; Ozcan, Alper; Devecioglu, Omer; Aksu, Guzide; Arikan Ayyildiz, Zeynep; Topal, Erdem; Karakoc Aydiner, Elif; Kiykim, Ayca; Metin, Ayse; Cipe, Funda; Kaya, Aysenur; Artac, Hasibe; Reisli, Ismail; Guner, Sukru N.; Uygun, Vedat; Karasu, Gulsun; Doenmez Altuntas, Hamiyet; Canatan, Halit; Oukka, Mohamed; Ozen, Ahmet; Chatila, Talal A.; Keles, Sevgi; Baris, Safa; Unal, Ekrem; Patiroglu, TurkanBackgroundDedicator of cytokinesis 8 (DOCK8) deficiency is the main cause of the autosomal recessive hyper-IgE syndrome (HIES). We previously reported the selective loss of group 3 innate lymphoid cell (ILC) number and function in a Dock8-deficient mouse model. In this study, we sought to test whether DOCK8 is required for the function and maintenance of ILC subsets in humans. MethodsPeripheral blood ILC1-3 subsets of 16 DOCK8-deficient patients recruited at the pretransplant stage, and seven patients with autosomal dominant (AD) HIES due to STAT3 mutations, were compared with those of healthy controls or post-transplant DOCK8-deficient patients (n = 12) by flow cytometry and real-time qPCR. Sorted total ILCs from DOCK8- or STAT3-mutant patients and healthy controls were assayed for survival, apoptosis, proliferation, and activation by IL-7, IL-23, and IL-12 by cell culture, flow cytometry, and phospho-flow assays. ResultsDOCK8-deficient but not STAT3-mutant patients exhibited a profound depletion of ILC3s, and to a lesser extent ILC2s, in their peripheral blood. DOCK8-deficient ILC1-3 subsets had defective proliferation, expressed lower levels of IL-7R, responded less to IL-7, IL-12, or IL-23 cytokines, and were more prone to apoptosis compared with those of healthy controls. ConclusionDOCK8 regulates human ILC3 expansion and survival, and more globally ILC cytokine signaling and proliferation. DOCK8 deficiency leads to loss of ILC3 from peripheral blood. ILC3 deficiency may contribute to the susceptibility of DOCK8-deficient patients to infections.Publication Open Access Expanding the clinical and immunological phenotypes and natural history of MALT1 deficiency(2022-04-01) KOLUKISA, BURCU; BARIŞ, SAFA; ÖZEN, AHMET OĞUZHAN; AYDINER, ELİF; Sefer A. P., Abolhassani H., Ober F., KAYAOĞLU B., Eltan S. B., Kara A., ERMAN B., Yilmaz N. S., Aydogmus C., Aydemir S., et al.Purpose 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.Publication Open Access Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency(ELSEVIER SCIENCE BV, 2019-07) ÖZEN, AHMET OĞUZHAN; Farmer, Jocelyn R.; Foldvari, Zsofia; Ujhazi, Boglarka; De Ravin, Suk See; Chen, Karin; Bleesing, Jack J. H.; Schuetz, Catharina; Al-Herz, Waleed; Abraham, Roshini S.; Joshi, Avni Y.; Costa-Carvalho, Beatriz T.; Buchbinder, David; Booth, Claire; Reiff, Andreas; Ferguson, Polly J.; Aghamohammadi, Asghar; Abolhassani, Hassan; Puck, Jennifer M.; Adeli, Mehdi; Cancrini, Caterina; Palma, Paolo; Bertaina, Alice; Locatelli, Franco; Di Matteo, Gigliola; Geha, Raif S.; Kanariou, Maria G.; Lycopoulou, Lilia; Tzanoudaki, Marianna; Sleasman, John W.; Parikh, Suhag; Pinero, Gloria; Fischer, Bernard M.; Dbaibo, Ghassan; Unal, Ekrem; Patiroglu, Turkan; Karakukcu, Musa; Al-Saad, Khulood Khalifa; Dilley, Meredith A.; Pai, Sung-Yun; Dutmer, Cullen M.; Gelfand, Erwin W.; Geier, Christoph B.; Eibl, Martha M.; Wolf, Hermann M.; Henderson, Lauren A.; Hazen, Melissa M.; Bonfim, Carmem; Wolska-Kusnierz, Beata; Butte, Manish J.; Hernandez, Joseph D.; Nicholas, Sarah K.; Stepensky, Polina; Chandrakasan, Shanmuganathan; Miano, Maurizio; Westermann-Clark, Emma; Goda, Vera; Krivan, Gergely; Holland, Steven M.; Fadugba, Olajumoke; Henrickson, Sarah E.; Ozen, Ahmet; Karakoc-Aydiner, Elif; Baris, Safa; Kiykim, Ayca; Bredius, Robbert; Hoeger, Birgit; Boztug, Kaan; Pashchenko, Olga; Neven, Benedicte; Moshous, Despina; de Villartay, Jean-Pierre; Bousfiha, Ahmed Aziz; Hill, Harry R.; Notarangelo, Luigi D.; Walter, Jolan E.BACKGROUND: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/ hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management. (C) 2019 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.Publication Open Access Comparing the levels of CTLA-4-dependent biological defects in patients with LRBA deficiency and CTLA-4 insufficiency(2022-10-01) BARIŞ, SAFA; AYDINER, ELİF; ÖZEN, AHMET OĞUZHAN; Catak M. C., Akcam B., Bilgic Eltan S., Babayeva R., Karakus I. S., Akgun G., Baser D., Bulutoglu A., Bayram F., Kasap N., et al.Background Lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency and cytotoxic T-lymphocyte protein-4 (CTLA-4) insufficiency are recently described disorders that present with susceptibility to infections, autoimmunity, and lymphoproliferation. Clinical and immunological comparisons of the diseases with long-term follow-up have not been previously reported. We sought to compare the clinical and laboratory manifestations of both diseases and investigate the role of flow cytometry in predicting the genetic defect in patients with LRBA deficiency and CTLA-4 insufficiency. Methods Patients were evaluated clinically with laboratory assessments for lymphocyte subsets, T follicular helper cells (T-FH), LRBA expression, and expression of CD25, FOXP3, and CTLA4 in regulatory T cells (Tregs) at baseline and 16 h post-stimulation. Results LRBA-deficient patients (n = 29) showed significantly early age of symptom onset, higher rates of pneumonia, autoimmunity, chronic diarrhea, and failure to thrive compared to CTLA-4 insufficiency (n = 12). In total, 29 patients received abatacept with favorable responses and the overall survival probability was not different between transplanted versus non-transplanted patients in LRBA deficiency. Meanwhile, higher probability of survival was observed in CTLA-4-insufficient patients (p = 0.04). The T-cell subsets showed more deviation to memory cells in CTLA-4-insufficiency, accompanied by low percentages of Treg and dysregulated cT(FH) cells response in both diseases. Cumulative numbers of autoimmunities positively correlated with cT(FH) frequencies. Baseline CTLA-4 expression was significantly diminished in LRBA deficiency and CTLA-4 insufficiency, but significant induction in CTLA-4 was observed after short-term T-cell stimulation in LRBA deficiency and controls, while this elevation was less in CTLA-4 insufficiency, allowing to differentiate this disease from LRBA deficiency with high sensitivity (87.5%) and specificity (90%). Conclusion This cohort provided detailed clinical and laboratory comparisons for LRBA deficiency and CTLA-4 insufficiency. The flow cytometric approach is useful in predicting the defective gene; thus, targeted sequencing can be conducted to provide rapid diagnosis and treatment for these diseases impacting the CTLA-4 pathway.Publication Open Access Diagnostic Usage of Intracellular Protein Staining by Flow Cytometer in Primary Immune Deficiencies; Marmara Experience(BILIMSEL TIP YAYINEVI, 2018-01-10) ÖZEN, AHMET OĞUZHAN; Ogulur, Ismail; Baris, Safa; Ozen, Ahmet; Nain, Ercan; Kiykim, Ayca; Karakoc-Aydiner, ElifObjective: The aim of our study was the optimization and standardization of intracellular dedicator of cytokinesis 8 (DOCK8), LPS-responsive beige-like anchor protein (LRBA), SH2D1A/SLAM-ssociated protein (SAP) and X-linked inhibitor of apoptosis protein (XIAP) protein expressions in healthy controls with a single flow cytometer protocol and to concomitantly evaluate the possible use of this method for diagnosis. Materials and Methods: Peripheral blood mononuclear cells were isolated from heparinized blood samples. Protein expressions were analyzed as mean fluorescein intensity difference (Delta MFI) according to the isotype. Results: Delta MFI values obtained by DOCK8 antibody staining were 21.3 +/- 4 in CD3+ T cells and 25 +/- 3.3 in CD20+ T cells in healthy controls. These values in patients with DOCK8 deficiency were either very low or completely absent. Delta MFI values obtained by LRBA protein antibody staining were 36 +/- 7.7 in healthy controls, while they were at the very low levels of 5.9 +/- 1.8 in the LRBA protein deficiency patients. The values obtained by SAP and XIAP antibody staining were 30.2 +/- 3 in CD8+ T cells for SAP, 13.9 +/- 3.2 in CD3+ T and 14.6 +/- 3.5 in CD20+ B cells for XIAP. Since the SAP and XIAP results were not confirmed by gene sequencing, the results were not compared to healthy controls. Conclusion: Due to its rapid and reliable results in clinically relevant cases for DOCK8 and LRBA deficiencies, analysis of protein expression is primarily suitable to evaluate intracellular staining protocol by flow cytometer. In addition, this particular method could be suitable for patients considered to be SAP and XIAP deficient.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 Open Access Abatacept as a Long-Term Targeted Therapy for LRBA Deficiency(ELSEVIER, 2019-11) ÖZEN, AHMET OĞUZHAN; Kiykim, Ayca; Ogulur, Ismail; Dursun, Esra; Charbonnier, Louis Marie; Nain, Ercan; Cekic, Sukru; 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; Kilic, Sara S.; Yilmaz, Mustafa; Karakoc-Aydiner, Elif; Lo, Bernice; Ozen, Ahmet; Chatila, Talal A.; Baris, SafaBACKGROUND: 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. (C) 2019 American Academy of Allergy, Asthma & ImmunologyPublication 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.