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1. Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency.

Author

Yu, David, Miller, Corey, Feng, Yi, Guichard, Audrey, Béziat, Vivien, Bustamante, Jacinta, Pan-Hammarström, Qiang, Zhang, Yu, Rosen, Lindsey, Holland, Steve, Bosticardo, Marita, Kenney, Heather, Castagnoli, Riccardo, Slade, Charlotte, Boztuğ, Kaan, Mahlaoui, Nizar, Latour, Sylvain, Abraham, Roshini, Lougaris, Vassilios, Hauck, Fabian, Sediva, Anna, Atschekzei, Faranaz, Sogkas, Georgios, Poli, M, Slatter, Mary, Palterer, Boaz, Keller, Michael, Pinzon-Charry, Alberto, Sullivan, Anna, Droney, Luke, Suan, Daniel, Wong, Melanie, Kane, Alisa, Hu, Hannah, Ma, Cindy, Grombiříková, Hana, Ciznar, Peter, Dalal, Ilan, Aladjidi, Nathalie, Hie, Miguel, Lazaro, Estibaliz, Franco, Jose, Keles, Sevgi, Malphettes, Marion, Pasquet, Marlene, Maccari, Maria, Meinhardt, Andrea, Ikinciogullari, Aydan, Shahrooei, Mohammad, Celmeli, Fatih, Frosk, Patrick, Goodnow, Christopher, Gray, Paul, Belot, Alexandre, Kuehn, Hye, Rosenzweig, Sergio, Miyara, Makoto, Licciardi, Francesco, Servettaz, Amélie, Barlogis, Vincent, Le Guenno, Guillaume, Herrmann, Vera-Maria, Kuijpers, Taco, Ducoux, Grégoire, Sarrot-Reynauld, Françoise, Schuetz, Catharina, Cunningham-Rundles, Charlotte, Rieux-Laucat, Frédéric, Tangye, Stuart, Sobacchi, Cristina, Doffinger, Rainer, Warnatz, Klaus, Grimbacher, Bodo, Fieschi, Claire, Berteloot, Laureline, Bryant, Vanessa, Trouillet Assant, Sophie, Su, Helen, Neven, Benedicte, Abel, Laurent, Zhang, Qian, Boisson, Bertrand, Cobat, Aurélie, Jouanguy, Emmanuelle, Kampe, Olle, Bastard, Paul, Roifman, Chaim, Landegren, Nils, Notarangelo, Luigi, Le Voyer, Tom, Parent, Audrey, Liu, Xian, Cederholm, Axel, Gervais, Adrian, Rosain, Jérémie, Nguyen, Tina, Perez Lorenzo, Malena, Rackaityte, Elze, Rinchai, Darawan, and Zhang, Peng

Subjects
Humans, Autoantibodies, COVID-19, Gain of Function Mutation, Genetic Predisposition to Disease, Heterozygote, I-kappa B Proteins, Interferon Type I, Loss of Function Mutation, NF-kappa B, NF-kappa B p52 Subunit, Pneumonia, Viral, Thymus Gland, Thyroid Epithelial Cells
Abstract

Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.

Published
2023

2. Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.

Author

Béziat, Vivien, Tavernier, Simon J, Chen, Yin-Huai, Ma, Cindy S, Materna, Marie, Laurence, Arian, Staal, Jens, Aschenbrenner, Dominik, Roels, Lisa, Worley, Lisa, Claes, Kathleen, Gartner, Lisa, Kohn, Lisa A, De Bruyne, Marieke, Schmitz-Abe, Klaus, Charbonnier, Louis-Marie, Keles, Sevgi, Nammour, Justine, Vladikine, Natasha, Maglorius Renkilaraj, Majistor Raj Luxman, Seeleuthner, Yoann, Migaud, Mélanie, Rosain, Jérémie, Jeljeli, Mohamed, Boisson, Bertrand, Van Braeckel, Eva, Rosenfeld, Jill A, Dai, Hongzheng, Burrage, Lindsay C, Murdock, David R, Lambrecht, Bart N, Avettand-Fenoel, Véronique, Vogel, Tiphanie P, Undiagnosed Diseases Network, Esther, Charles R, Haskologlu, Sule, Dogu, Figen, Ciznar, Peter, Boutboul, David, Ouachée-Chardin, Marie, Amourette, Jean, Lebras, Marie-Noëlle, Gauvain, Clément, Tcherakian, Colas, Ikinciogullari, Aydan, Beyaert, Rudi, Abel, Laurent, Milner, Joshua D, Grimbacher, Bodo, Couderc, Louis-Jean, Butte, Manish J, Freeman, Alexandra F, Catherinot, Émilie, Fieschi, Claire, Chatila, Talal A, Tangye, Stuart G, Uhlig, Holm H, Haerynck, Filomeen, Casanova, Jean-Laurent, and Puel, Anne

Subjects
Undiagnosed Diseases Network, Th2 Cells, Cells, Cultured, Cell Membrane, Fibroblasts, Humans, C-Reactive Protein, Cytokines, Pedigree, Genetics, Population, Up-Regulation, Kinetics, Genes, Dominant, Phenotype, Mutation, Alleles, Models, Biological, Adolescent, Middle Aged, Child, Female, Male, Cytokine Receptor gp130, Young Adult, HEK293 Cells, Job Syndrome, Loss of Function Mutation, Cells, Cultured, Genetics, Population, Genes, Dominant, Models, Biological, Medical and Health Sciences, Immunology
Abstract

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

Published
2020

3. Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

Author

Lévy, Romain, Okada, Satoshi, Béziat, Vivien, Moriya, Kunihiko, Liu, Caini, Chai, Louis Yi Ann, Migaud, Mélanie, Hauck, Fabian, Al Ali, Amein, Cyrus, Cyril, Vatte, Chittibabu, Patiroglu, Turkan, Unal, Ekrem, Ferneiny, Marie, Hyakuna, Nobuyuki, Nepesov, Serdar, Oleastro, Matias, Ikinciogullari, Aydan, Dogu, Figen, Asano, Takaki, Ohara, Osamu, Yun, Ling, Della Mina, Erika, Bronnimann, Didier, Itan, Yuval, Gothe, Florian, Bustamante, Jacinta, Boisson-Dupuis, Stéphanie, Tahuil, Natalia, Aytekin, Caner, Salhi, Aicha, Al Muhsen, Saleh, Kobayashi, Masao, Toubiana, Julie, Abel, Laurent, Li, Xiaoxia, Camcioglu, Yildiz, Celmeli, Fatih, Klein, Christoph, AlKhater, Suzan A, Casanova, Jean-Laurent, and Puel, Anne

Subjects
Pediatric, Genetics, Clinical Research, Infectious Diseases, Rare Diseases, Emerging Infectious Diseases, Aetiology, 2.1 Biological and endogenous factors, Infection, Good Health and Well Being, Alleles, Bacterial Infections, Candida, Candidiasis, Cell Membrane, Child, Child, Preschool, Family Health, Female, Fibroblasts, Genes, Recessive, Genome-Wide Association Study, HEK293 Cells, Homozygote, Humans, Immunophenotyping, Infant, Infant, Newborn, Interleukin-17, Male, Mutation, Mycoses, Open Reading Frames, Pedigree, Receptors, Interleukin-17, Skin, T-Lymphocytes, genetics, immunodeficiency, candidiasis
Abstract

Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensal Candida species. The first genetic etiology of isolated CMC-autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency-was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity to Candida and Staphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.

Published
2016

4. BCG vaccination in patients with severe combined immunodeficiency: complications, risks, and vaccination policies.

Author

Marciano, Beatriz, Huang, Chiung-Yu, Joshi, Gyan, Rezaei, Nima, Carvalho, Beatriz, Allwood, Zoe, Ikinciogullari, Aydan, Reda, Shereen, Gennery, Andrew, Thon, Vojtech, Espinosa-Rosales, Francisco, Al-Herz, Waleed, Porras, Oscar, Shcherbina, Anna, Szaflarska, Anna, Kiliç, Şebnem, Franco, Jose, Gómez Raccio, Andrea, Roxo, Persio, Esteves, Isabel, Galal, Nermeen, Grumach, Anete, Al-Tamemi, Salem, Yildiran, Alisan, Orellana, Julio, Yamada, Masafumi, Morio, Tomohiro, Liberatore, Diana, Ohtsuka, Yoshitoshi, Lau, Yu-Lung, Nishikomori, Ryuta, Torres-Lozano, Carlos, Mazzucchelli, Juliana, Vilela, Maria, Tavares, Fabiola, Cunha, Luciana, Pinto, Jorge, Espinosa-Padilla, Sara, Hernandez-Nieto, Leticia, Elfeky, Reem, Ariga, Tadashi, Toshio, Heike, Dogu, Figen, Cipe, Funda, Formankova, Renata, Nuñez-Nuñez, M, Bezrodnik, Liliana, Marques, Jose, Pereira, María, Listello, Viviana, Slatter, Mary, Nademi, Zohreh, Kowalczyk, Danuta, Fleisher, Thomas, Davies, Graham, Neven, Bénédicte, and Rosenzweig, Sergio

Subjects
BCG, Primary immunodeficiency, hematopoietic stem cell transplant, immune reconstitution syndrome, mycobacteria, newborn screening, severe combined immunodeficiency, vaccine, BCG Vaccine, Child, Preschool, Comorbidity, Female, Hematopoietic Stem Cell Transplantation, Humans, Infant, Infant, Newborn, Kaplan-Meier Estimate, Male, Prevalence, Retrospective Studies, Risk, Severe Combined Immunodeficiency, Vaccination
Abstract

BACKGROUND: Severe combined immunodeficiency (SCID) is a syndrome characterized by profound T-cell deficiency. BCG vaccine is contraindicated in patients with SCID. Because most countries encourage BCG vaccination at birth, a high percentage of patients with SCID are vaccinated before their immune defect is detected. OBJECTIVES: We sought to describe the complications and risks associated with BCG vaccination in patients with SCID. METHODS: An extensive standardized questionnaire evaluating complications, therapeutics, and outcomes regarding BCG vaccination in patients given a diagnosis of SCID was widely distributed. Summary statistics and association analysis was performed. RESULTS: Data on 349 BCG-vaccinated patients with SCID from 28 centers in 17 countries were analyzed. Fifty-one percent of the patients had BCG-associated complications, 34% disseminated and 17% localized (a 33,000- and 400-fold increase, respectively, over the general population). Patients receiving early vaccination (≤1 month) showed an increased prevalence of complications (P = .006) and death caused by BCG-associated complications (P < .0001). The odds of experiencing complications among patients with T-cell numbers of 250/μL or less at diagnosis was 2.1 times higher (95% CI, 1.4-3.4 times higher; P = .001) than among those with T-cell numbers of greater than 250/μL. BCG-associated complications were reported in 2 of 78 patients who received antimycobacterial therapy while asymptomatic, and no deaths caused by BCG-associated complications occurred in this group. In contrast, 46 BCG-associated deaths were reported among 160 patients treated with antimycobacterial therapy for a symptomatic BCG infection (P < .0001). CONCLUSIONS: BCG vaccine has a very high rate of complications in patients with SCID, which increase morbidity and mortality rates. Until safer and more efficient antituberculosis vaccines become available, delay in BCG vaccination should be considered to protect highly vulnerable populations from preventable complications.

Published
2014

5. Impaired respiratory burst contributes to infections in PKC-deficient patients

Author

Paul A. Brogan, Alexandre Belot, Tom Le Voyer, Jacinta Bustamante, Mélanie Migaud, Marion Roderick, Gulbu Uzel, Figen Dogu, Jean-Laurent Casanova, Anna Lena Neehus, Jamel El-Benna, Ahmet Ozen, Laurent Abel, Erdal Ince, Mohammad Shahrooei, Engin Altundag, Elif Karakoc-Aydiner, Gonca Hancioglu, Anne Puel, Aydan Ikinciogullari, Manon Roynard, Kunihiko Moriya, Kaan Boztug, Karim Dorgham, Romain Lévy, Kathrin Haake, Alisan Yildiran, Sule Haskologlu, Nico Lachmann, Safa Baris, Guy Gorochov, Nima Parvaneh, Alejandro Nieto-Patlán, Hassan Abolhassani, Ayca Kiykim, Neehus, Anna-Lena, Moriya, Kunihiko, Nieto-Patlan, Alejandro, Le Voyer, Tom, Levy, Romain, Ozen, Ahmet, Karakoc-Aydiner, Elif, Baris, Safa, Yildiran, Alisan, Altundag, Engin, Roynard, Manon, Haake, Kathrin, Migaud, Melanie, Dorgham, Karim, Gorochov, Guy, Abel, Laurent, Lachmann, Nico, Dogu, Figen, Haskologlu, Sule, Ince, Erdal, El-Benna, Jamel, Uzel, Gulbu, Kiykim, Ayca, Boztug, Kaan, Roderick, Marion R., Shahrooei, Mohammad, Brogan, Paul A., Abolhassani, Hassan, Hancioglu, Gonca, Parvaneh, Nima, Belot, Alexandre, Ikinciogullari, Aydan, Casanova, Jean-Laurent, Puel, Anne, Bustamante, Jacinta, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
Male, 0301 basic medicine, Nadph Oxidase, Phagocyte, CELL-SURVIVAL, P47(Phox) Phosphorylation, medicine.disease_cause, Autoimmunity, 0302 clinical medicine, Chronic granulomatous disease, NADPH oxidase complex, Lymphoproliferative Syndrome, NADPH OXIDASE, Protein Isoforms, Immunology and Allergy, CRYSTAL-STRUCTURE, Phosphorylation, SYSTEMIC-LUPUS-ERYTHEMATOSUS, Respiratory Burst, chemistry.chemical_classification, B-Lymphocytes, TYROSINE PHOSPHORYLATION, NADPH oxidase, Chronic Granulomatous-Disease, biology, Pedigree, 3. Good health, Respiratory burst, Cell-Survival, Protein Kinase C-delta, CHRONIC GRANULOMATOUS-DISEASE, medicine.anatomical_structure, LYMPHOPROLIFERATIVE SYNDROME, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Tyrosine Phosphorylation, Immunology, Infections, 03 medical and health sciences, Phagocytosis, P47(PHOX) PHOSPHORYLATION, medicine, THREONINE 154, Humans, PROTEIN-KINASE-C, Protein-Kinase-C, Crystal-Structure, Reactive oxygen species, business.industry, Infant, NADPH Oxidases, Threonine 154, Neutrophil extracellular traps, medicine.disease, Systemic-Lupus-Erythematosus, 030104 developmental biology, chemistry, biology.protein, business, 030215 immunology
Abstract

Patients with autosomal recessive protein kinase C delta (PKC delta) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack of reactive oxygen species (ROS) production. We studied an international cohort of 17 PKC delta-deficient patients and found that their EBV-B cells and monocyte-derived phagocytes produced only small amounts of ROS and did not phosphorylate p40(phox) normally after PMA or opsonized Staphylococcus aureus stimulation. Moreover, the patients' circulating phagocytes displayed abnormally low levels of ROS production and markedly reduced neutrophil extracellular trap formation, altogether suggesting a role for PKC delta in activation of the NADPH oxidase complex. Our findings thus show that patients with PKC delta deficiency have impaired NADPH oxidase activity in various myeloid subsets, which may contribute to their CGD-like infectious phenotype. Yale Center for Mendelian Genomics - National Human Genome Research Institute [UM1HG006504]; National Institute of Allergy and Infectious DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [5R01AI089970, 5R37AI095983, R01AI127564-01]; National Center for Research ResourcesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR); National Center for Advancing Translational Sciences of the National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS) [8UL1TR001866]; Rockefeller University; St. Giles Foundation; INSERMInstitut National de la Sante et de la Recherche Medicale (Inserm)European Commission; University of Paris; French Foundation for Medical ResearchFondation pour la Recherche Medicale [EQU201903007798]; Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10-LABX-62-IBEID]; SCOR Corporate Foundation for Science; French National Research Agency (ANR) under the Investments for the future programFrench National Research Agency (ANR) [ANR-10-IAHU-01]; ANR-IFNPHOX [ANR-13-ISV3-0001-01]; ANR-GENMSMDFrench National Research Agency (ANR) [ANR-16-CE17-0005-01]; ANR-GENCMCD [ANR-11-BSV3-005-01]; ANR-HGDIFDFrench National Research Agency (ANR) [ANR-14-CE15-0006-01]; Bettencourt Schueller Foundation; International PhD program of the Imagine Institute; Japanese Foundation; EURO-CMC project [ANR-14-RARE-0005-02]; Societe Nationale Francaise de Medecine Interne (Bourse Marcel Simon); INSERM PhD program for medical doctors (poste d'accueil INSERM); Fulbright grant (Franco-American commission); MD-PhD program of Imagine Institute; Consejo Nacional de Ciencia y Tecnologa National PhD Fellowship Program; National Institute for Health Research Biomedical Research CentreNational Institute for Health Research (NIHR); Great Ormond Street Hospital Charity; Deutsche Forschungsgemeinschaft under Germany's Excellence StrategyGerman Research Foundation (DFG) [EXC 2155, 390874280]; REBIRTH Center for Translational Regenerative Medicine through the State of Lower Saxony [MWK: ZN3440] This paper is dedicated to the memory of Prof. Asghar Agha-mohammadi, who passed away in November 2020, and made immense contributions to the understanding and treatment of primary immunodeficiencies. We thank all patients, their relatives, and the treatment teams for their cooperation in this study. We thank all the members of the Laboratory of Human Genetics of Infectious Diseases for helpful discussions. We also thank Christine Rivalain, Cecile Pa-tissier, Lazaro Lorenzo-Diaz, Dominick Papandrea, Dana Liu, and Yelena Nemirovskaya for administrative assistance and Gaspard Kerner for statistical advice. We thank the Necker Institute Imaging Facility for technical advice. The graphical abstract was created with BioRender.com under subscription. This research was supported by the Yale Center for Mendelian Genomics funded by the National Human Genome Research Insti-tute (UM1HG006504) . The Howard Hughes Medical Institute lab-oratory was funded in part by the National Institute of Allergy and Infectious Diseases (grants 5R01AI089970, 5R37AI095983, and R01AI127564-01) , the National Center for Research Resources, and the National Center for Advancing Translational Sciences of the National Institutes of Health (grant 8UL1TR001866 for J-L. Casa-nova) , the Rockefeller University, the St. Giles Foundation, INSERM, the University of Paris, the French Foundation for MedicalResearch (EQU201903007798) , the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID) , the SCOR Corporate Foundation for Science, and the French National Research Agency (ANR) under the Investments for the future program (grant ANR-10-IAHU-01) , ANR-IFNPHOX (grant ANR-13-ISV3-0001-01 for J. Bustamante) , ANR-GENMSMD (grant ANR-16-CE17-0005-01 for J. Bustamante) , ANR-GENCMCD (grant ANR-11-BSV3-005-01 for A. Puel) , and ANR-HGDIFD (grant ANR-14-CE15-0006-01 for J. Bustamante) . A-L. Neehus was sup-ported by the Bettencourt Schueller Foundation and the Interna-tional PhD program of the Imagine Institute, K. Moriya by a Japanese Foundation for Pediatric Research fellowship grant and EURO-CMC project (grant ANR-14-RARE-0005-02 for J. Bustamante) , R. Levy by the Societe Nationale Francaise de Medecine Interne (Bourse Marcel Simon) , the INSERM PhD program for medical doctors (poste d'accueil INSERM) , and the Fulbright grant (Franco-American commission) , T. Le Voyer by the Bettencourt Schueller Foundation and the MD-PhD program of Imagine Institute, and A. Nieto-Patlan by the Consejo Nacional de Ciencia y Tecnologa Na-tional PhD Fellowship Program. All research at the Great Ormond Street Hospital National Health Service Foundation Trust is sup-ported by the National Institute for Health Research Biomedical Research Centre. P.A. Brogan also acknowledges support from the Great Ormond Street Hospital Charity. N. Lachmann acknowledges support from the Deutsche Forschungsgemeinschaft under Ger-many's Excellence Strategy-EXC 2155-project number 390874280 and the REBIRTH Center for Translational Regenerative Medicine funded through the State of Lower Saxony (MWK: ZN3440) . Author contributions: A-L. Neehus, J-L. Casanova, A. Puel, and J. Bustamante conceived and designed the study. A-L. Neehus, K. Moriya, T. Le Voyer, A. Nieto-Patlan, R. Levy, M. Roynard, K. Haake, M. Migaud, and K. Dorgham performed the experiments. A. ozen, E. Karakoc-Aydiner, S. Baris, A. Yildiran, E. Altundag, F. Dogu, S. Has-kologlu, E. Ince, G. Uzel, A. Kiykim, K. Boztug, M.R. Roderick, M. Shahrooei, P.A. Brogan, H. Abolhassani, G. Hancioglu, N. Parvaneh, A.; Belot, and A. Ikinciogullari were the treating physicians respon-sible for clinical diagnosis, deep phenotyping, sample collection, and patient follow-up. G. Gorochov, L. Abel, N. Lachmann, J. El-Benna, and A. Belot provided conceptual advice. A-L. Neehus, J-L. Casanova, A. Puel, and J. Bustamante analyzed the results and wrote the man-uscript. All authors revised the manuscript and approved the final manuscript as submitted. Disclosures: P.A. Brogan reported personal fees from Sobi, No-vartis, Roche, and GSK, and grants from Sobi outside the sub-mitted work. No other disclosures were reported.

Published
2021

6. Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score

Author

Bella Shadur, Andrew R. Gennery, Nurcicek Padem, Anna Mukhina, Polina Stepensky, Svetlana O. Sharapova, Sara Sebnem Kilic, Magdalena Avbelj Stefanija, Luis I. Gonzales-Granado, Isabelle Meyts, Jacques G. Rivière, Filomeen Haerynck, Joachim Zobel, Benoit Florkin, Laura Gamez, Vedat Uygun, Nicolette Moes, Neslihan Edeer Karaca, Lennart Hammarström, Anke M.J. Peters, Bodo Grimbacher, Sevgi Köstel Bal, Aydan Ikinciogullari, Zahra Chavoshzadeh, Joris M. van Montfrans, Sule Haskologlu, Hassan Abolhassani, Necil Kutukculer, Safa Baris, Yuliya Mareika, Juan Luis Santos Perez, Elif Karakoc-Aydiner, Asghar Aghamohammadi, Mehdi Adeli, Antonio Marzollo, Hermann J. Girschick, Sevgi Keles, Amer Khojah, Shahrzad Bakhtiar, Victoria Katharina Tesch, Anna Shcherbina, Antonios G.A. Kolios, Marie Meeths, Mikko Seppänen, Austen Worth, Marina Garcia-Prat, Figen Dogu, Arjan C. Lankester, Markus G. Seidel, European Soc Blood, European Soc Immunodeficiencies, University of Zurich, Tesch, Victoria Katharina, Abolhassani, Hassan, Shadur, Bella, Zobel, Joachim, Mareika, Yuliya, Sharapova, Svetlana, Karakoc-Aydiner, Elif, Riviere, Jacques G., Garcia-Prat, Marina, Moes, Nicolette, Haerynck, Filomeen, Gonzales-Granado, Luis I., Santos Perez, Juan Luis, Mukhina, Anna, Shcherbina, Anna, Aghamohammadi, Asghar, Hammarstrom, Lennart, Dogu, Figen, Haskologlu, Sule, Ikinciogullari, Aydan I., Bal, Sevgi Kostel, Baris, Safa, Kilic, Sara Sebnem, Karaca, Neslihan Edeer, Kutukculer, Necil, Girschick, Hermann, Kolios, Antonios, Keles, Sevgi, Uygun, Vedat, Stepensky, Polina, Worth, Austen, van Montfrans, Joris M., Peters, Anke M. J., Meyts, Isabelle, Adeli, Mehdi, Marzollo, Antonio, Padem, Nurcicek, Khojah, Amer M., Chavoshzadeh, Zahra, Stefanija, Magdalena Avbelj, Bakhtiar, Shahrzad, Florkin, Benoit, Meeths, Marie, Gamez, Laura, Grimbacher, Bodo, Seppanen, Mikko R. J., Lankester, Arjan, Gennery, Andrew R., Seidel, Markus G., Ege Üniversitesi, Bursa Uludağ Üniversitesi/Tıp Fakültesi/Çocuk İmmünoloji., Kılıç, Sara Şebnem, AAH-1658-2021, Children's Hospital, HUS Children and Adolescents, Clinicum, Department of Medicine, TRIMM - Translational Immunology Research Program, Research Programs Unit, University of Helsinki, and HUS Inflammation Center

Subjects
Male, Neurologic disease, medicine.medical_treatment, Autoimmunity, Hematopoietic stem cell transplantation, Treatment response, Eye disease, 0302 clinical medicine, Thrombotic thrombocytopenic purpura, Azathioprine, combined immunodeficiency, Disease activity, Treatment outcome, Disease course, Child, Inborn error of immunity (IEI), Immunodeficiency, combined, Hematopoietic Stem Cell Transplantation, combined immunodeficiency (CID), hematopoietic stem cell transplantation (HSCT), Tocilizumab, Signal transducing, Multicenter study, Immunologic deficiency syndromes, 3. Good health, Clinical trial, Retrospective study, sirolimus, Child, Preschool, Cyclosporine, 2723 Immunology and Allergy, Graft failure, Lung infection, hematopoietic stem, Cohort analysis, Longitudinal study, Rituximab, Infection, Human, Hepatomegaly, medicine.medical_specialty, Genotype, Immunology, Cause of death, Major clinical study, Article, 03 medical and health sciences, Signal transducing adaptor protein, Humans, Lipopolysaccharide responsive beige like anchor protein deficiency, cell transplantation, Aged, 2403 Immunology, MUTATIONS, Abatacept, Immunologic Deficiency Syndromes, Adalimumab, Failure to thrive, Follow up, Survival analysis, Immune dysregulation, medicine.disease, Survival Analysis, 030104 developmental biology, Disease activity score, Splenomegaly, 10033 Clinic for Immunology, School child, Human medicine, immunodeficiency, 0301 basic medicine, Thyroiditis, Allergy, Unclassified drug, Immune deficiency, Lipopolysaccharide responsive beige like anchor protein, Respiratory failure, Skin manifestation, medicine.disease_cause, Lymphocyte proliferation, Medicine and Health Sciences, Immunology and Allergy, Overall survival, Middle aged, performance scale, Interstitial pneumonia, Priority journal, CTLA4, Mycophenolate mofetil, Chloroquine, clinical score, Immunosuppression, Disease burden, Transplant-Related Mortality, Middle Aged, Acute graft versus host disease, Hospitalization, Immune deficiency and dysregulation activity score, Treatment Outcome, Phenotype, surgical procedures, operative, primary immunodeficiency disorder (PID), hematopoietic stem cell transplantation, Female, medicine.drug, Adult, dysregulation, Malabsorption, abatacept, Adolescent, Child, preschool, Pemission, Interstitial lung disease, 610 Medicine & health, LRBA, Young Adult, immune dysregulation, Internal medicine, Adaptor proteins, medicine, primary immunodeficiency disorder, Mycophenolic acid, Rapamycin, Mortality, Disease severity, Adaptor Proteins, Signal Transducing, Inborn error of immunity, Chimera, business.industry, Protein, Retrospective cohort study, LRBA protein, Multiple organ failure, Infliximab, Immunosuppressive treatment, Young adult, Preschool child, 3121 General medicine, internal medicine and other clinical medicine, Common Variable Immunodeficiency, Immunoglobulin Deficiency, immune, business, 030215 immunology
Abstract

Background: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant. Objective: This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant. Method: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices. Results: of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. the overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). in contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome. Conclusion: the lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT., Styrian Children's Cancer Aid Foundation; Slovenian Research AgencySlovenian Research Agency - Slovenia [P3-0343]; Jonas S_oderquist Foundation; Scientific and Technological Research Council of TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [217S847, 318S202]; Deutsche Forschungsgemeinschaft under Germany's Excellence StrategyGerman Research Foundation (DFG) [390939984, 39087428]; E-Rare program of the European Union by the Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [GR1617/14-1/iPAD]; Netzwerke Seltener Erkrankungen of the German Ministry of Education and Research [GAIN_ 01GM1910A]; Finnish Foundation for Pediatric Research and Pediatric Research Center, HUS Helsinki University Hospital; Graduate Research Training Scholarship of the Australian government; Hadassah Australia; ERN-RITA network [739543], M.G. Seidel and the Research Unit for Pediatric Hematology and Immunology are supported in part by the Styrian Children's Cancer Aid Foundation. M. Avbeli Stefanija was supported by the Slovenian Research Agency (grant P3-0343). H. Abolhassani was supported by the Jonas S_oderquist Foundation. S. Baris was supported by the Scientific and Technological Research Council of Turkey for the diagnosis of patients with LRBA deficiency (grants 217S847 and 318S202). B. Grimbacher receives support through the Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy (CIBSS-EXC-2189-Project ID 390939984 and RESIST-EXC 2155-Project ID 39087428); through the E-Rare program of the European Union, managed by the Deutsche Forschungsgemeinschaft (grant GR1617/14-1/iPAD); and through the Netzwerke Seltener Erkrankungen of the German Ministry of Education and Research (grant GAIN_ 01GM1910A). M.R.J. Sepp_anen was supported by the Finnish Foundation for Pediatric Research and Pediatric Research Center, HUS Helsinki University Hospital. I. Meyts is a member of the ERN-RITA network (project identification number 739543). B. Shadur is supported by a Graduate Research Training Scholarship of the Australian government and by Hadassah Australia.

Published
2020

7. Defects along the TH17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome

Author

Anupama Rambhatla, Ismail Reisli, Mutlu Yüksek, Mustafa Yilmaz, Ercan Kucukosmanoglu, Nerin N. Bahceciler, Derek W. Nickerson, Shadi Al Khatib, Haluk Cokugras, Hasibe Artac, Maria Garcia-Lloret, Sevgi Keles, Necil Kutukculer, Ferah Genel, Aydan Ikinciogullari, Elif Karakoc-Aydiner, Sean A. McGhee, Olcay Yegin, Ali Baki, Isil Barlan, Ayper Somer, Yildiz Camcioglu, Talal A. Chatila, Çukurova Üniversitesi, Selçuk Üniversitesi, Al Khatib, Shadi, Keles, Sevgi, Garcia-Lioret, Maria, Koc-Aydiner, Elif Kara, Reisli, Ismail, Artac, Hasibe, Camcioglu, Yildiz, Cokugras, Haluk, Somer, Ayper, Kutukculer, Necil, Yilmaz, Mustafa, Ikinciogullari, Aydan, Yegin, Olcay, Yueksek, Mutlu, Genel, Ferah, Kucukosmanoglu, Ercan, Baki, Ali, Bahceciler, Nerin N., Rambhatla, Anupama, Nickerson, Derek W., McGhee, Sean, Barlan, Isil B., Chatila, Talal, and Ege Üniversitesi

Subjects
Male, Receptors, Retinoic Acid, Immunoglobulin E, Interleukin-23, Cohort Studies, STAT3, Interleukin 21, BINDING, IL-21, Immunology and Allergy, STAT1, TH17, Child, PHOSPHORYLATION, CELL-DIFFERENTIATION, Receptors, Thyroid Hormone, ROLES, biology, Interleukin-17, Cell Differentiation, T-Lymphocytes, Helper-Inducer, Nuclear Receptor Subfamily 1, Group F, Member 3, Interleukin-12, DEFICIENCY, STAT1 Transcription Factor, Tyrosine kinase 2, Job Syndrome, Child, Preschool, ROR?t, Female, Interleukin 17, Antibody, STAT3 Transcription Factor, medicine.medical_specialty, Adolescent, DEFENSE, Immunology, INNATE, Article, Interferon-gamma, Internal medicine, medicine, Humans, IL-6, Interleukin-6, MUTATIONS, Interleukins, T(H)17, Infant, Interferon-alpha, ROR gamma t, UNPHOSPHORYLATED STAT3, Endocrinology, Mutation, biology.protein, STAT protein, Hyper IgE syndrome, Interleukin-1, GENERATION
Abstract

WOS: 000268860400023, PubMed ID: 19577286, Background: The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE, and diminished inflammatory responses. It exists as autosomal-dominant and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)-3 and impaired T(H)17 differentiation. Objective: To elucidate mechanisms underlying different forms of HIES. Methods: A cohort of 25 Turkish children diagnosed with HIES were examined for STAT3 mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-alpha was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. T(H)17 and T(H)1 cell differentiation was assessed by measuring the production of IL-17 and IFN-gamma, respectively. Results: Six subjects had STAT3 mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired TH17 responses, but whereas STAT3 mutations abrogated early steps in TH17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps. Conclusion: In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired TH17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome. (J Allergy Clin Immunol 2009;124:342-8.), National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [5R01AI065617], Supported by National Institutes of Health grant 5R01AI065617 (T.C.).

Published
2009

8. Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency

Author

Emily S.J. Edwards, Safa Baris, Asghar Aghamohammadi, Hubert Kogler, Emma Gostick, Baran Erman, Geetha Rao, Ekrem Unal, Musa Karakukcu, Funda Erol Cipe, Kaan Boztug, Michael Paulussen, Sule Haskologlu, Sevgi Köstel Bal, Renate Krüger, Bénédicte Neven, David Price, Ruy Perez Becker, Joris M. van Montfrans, Stuart G. Tangye, Sylvain Latour, Tim Niehues, Elif Karakoc-Aydiner, Maura Faraci, Fabian Hauck, Dagmar Berghuis, Elisabeth Salzer, Roland Meisel, Theresa Cole, Yu Zhang, Arjan C. Lankester, Raúl Jiménez Heredia, Austen Worth, Ayse Metin, Emma C. Morris, Tooba Momen, Lennart Hammarström, Bethany Pillay, Claudia Gonzaga-Jauregui, Figen Dogu, Andy I. M. Hoepelman, Ebru Yilmaz, Cindy S. Ma, Sharon Choo, Horst von Bernuth, Ahmet Ozen, Dirk Holzinger, Helen C. Su, Nima Rezaei, Pieter L. A. Fraaij, Samaneh Zoghi, Andrew J. Oler, Aditya Gupta, Candan Islamoglu, Marco Gattorno, Sujal Ghosh, Leo Kager, Ebmt, Prasad T. Oommen, Aydan Ikinciogullari, Gregor Dückers, Inci Ilhan, Michael J. Lenardo, Hassan Abolhassani, Serdar Ceylaner, Qiang Pan-Hammarström, Siobhan O. Burns, Kubra Baskin, E. Graham Davies, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Pediatrics, Virology, Ghosh, Sujal, Bal, Sevgi Koestel, Edwards, Emily S. J., Pillay, Bethany, Heredia, Raul Jimenez, Cipe, Funda Erol, Rao, Geetha, Salzer, Elisabeth, Zoghi, Samaneh, Abolhassani, Hassan, Momen, Tooba, Gostick, Emma, Price, David A., Zhang, Yu, Oler, Andrew J., Gonzaga-Jauregui, Claudia, Erman, Baran, Metin, Ayse, Ilhan, Inci, Haskologlu, Sule, Islamoglu, Candan, Baskin, Kubra, Ceylaner, Serdar, Yilmaz, Ebru, Unal, Ekrem, Karakukcu, Musa, Berghuis, Dagmar, Cole, Theresa, Gupta, Aditya K., Hauck, Fabian, Kogler, Hubert, Hoepelman, Andy I. M., Baris, Safa, Karakoc-Aydiner, Elif, Ozen, Ahmet, Kager, Leo, Holzinger, Dirk, Paulussen, Michael, Krueger, Renate, Meisel, Roland, Oommen, Prasad T., Morris, Emma, Neven, Benedicte, Worth, Austen, van Montfrans, Joris, Fraaij, Pieter L. A., Choo, Sharon, Dogu, Figen, Davies, E. Graham, Burns, Siobhan, Duckers, Gregor, Becker, Ruy Perez, von Bernuth, Horst, Latour, Sylvain, Faraci, Maura, Gattorno, Marco, Su, Helen C., Pan-Hammarstroem, Qiang, Hammarstroem, Lennart, Lenardo, Michael J., Ma, Cindy S., Niehues, Tim, Aghamohammadi, Asghar, Rezaei, Nima, Ikinciogullari, Aydan, Tangye, Stuart G., Lankester, Arjan C., Boztug, Kaan, İstinye Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, and Erol Cipe, Funda

Subjects
Male, Mononucleosis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Medizin, CHILDREN, Hematopoietic stem cell transplantation, T-CELL, medicine.disease_cause, Biochemistry, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, MEMORY B-CELLS, EPSTEIN-BARR-VIRUS, Child, 0303 health sciences, Hematology, Hematopoietic Stem Cell Transplantation, Allografts, 3. Good health, Survival Rate, 030220 oncology & carcinogenesis, Child, Preschool, Female, Adult, medicine.medical_specialty, Adolescent, Immunology, chemical and pharmacologic phenomena, IMMUNITY, Disease-Free Survival, 03 medical and health sciences, Immune system, EBV, Internal medicine, medicine, Humans, 030304 developmental biology, Retrospective Studies, Hemophagocytic lymphohistiocytosis, business.industry, Genetic Diseases, Inborn, Immunologic Deficiency Syndromes, Infant, STEM-CELL TRANSPLANTATION, Cell Biology, Immune dysregulation, COMBINED IMMUNODEFICIENCY, medicine.disease, REFERENCE VALUES, Lymphoma, Tumor Necrosis Factor Receptor Superfamily, Member 7, business, CD8, GENERATION, CD27 Ligand
Abstract

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV+ at diagnosis, but only ∼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.

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