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1. Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency

Author

Oda, Hirotsugu, Manthiram, Kalpana, Chavan, Pallavi Pimpale, Rieser, Eva, Veli, Önay, Kaya, Öykü, Rauch, Charles, Nakabo, Shuichiro, Kuehn, Hye Sun, Swart, Mariël, Wang, Yanli, Çelik, Nisa Ilgim, Molitor, Anne, Ziaee, Vahid, Movahedi, Nasim, Shahrooei, Mohammad, Parvaneh, Nima, Alipour-olyei, Nasrin, Carapito, Raphael, Xu, Qin, Preite, Silvia, Beck, David B., Chae, Jae Jin, Nehrebecky, Michele, Ombrello, Amanda K., Hoffmann, Patrycja, Romeo, Tina, Deuitch, Natalie T., Matthíasardóttir, Brynja, Mullikin, James, Komarow, Hirsh, Stoddard, Jennifer, Niemela, Julie, Dobbs, Kerry, Sweeney, Colin L., Anderton, Holly, Lawlor, Kate E., Yoshitomi, Hiroyuki, Yang, Dan, Boehm, Manfred, Davis, Jeremy, Mudd, Pamela, Randazzo, Davide, Tsai, Wanxia Li, Gadina, Massimo, Kaplan, Mariana J., Toguchida, Junya, Mayer, Christian T., Rosenzweig, Sergio D., Notarangelo, Luigi D., Iwai, Kazuhiro, Silke, John, Schwartzberg, Pamela L., Boisson, Bertrand, Casanova, Jean-Laurent, Bahram, Seiamak, Rao, Anand Prahalad, Peltzer, Nieves, Walczak, Henning, Lalaoui, Najoua, Aksentijevich, Ivona, and Kastner, Daniel L.

Published
2024
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2. Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease

Author

Sharma, Mehul, Leung, Daniel, Momenilandi, Mana, Jones, Lauren CW, Pacillo, Lucia, James, Alyssa E, Murrell, Jill R, Delafontaine, Selket, Maimaris, Jesmeen, Vaseghi-Shanjani, Maryam, Del Bel, Kate L, Lu, Henry Y, Chua, Gilbert T, Di Cesare, Silvia, Fornes, Oriol, Liu, Zhongyi, Di Matteo, Gigliola, Fu, Maggie P, Amodio, Donato, San Tam, Issan Yee, Chan, Gavin Shueng Wai, Sharma, Ashish A, Dalmann, Joshua, van der Lee, Robin, Blanchard-Rohner, Géraldine, Lin, Susan, Philippot, Quentin, Richmond, Phillip A, Lee, Jessica J, Matthews, Allison, Seear, Michael, Turvey, Alexandra K, Philips, Rachael L, Brown-Whitehorn, Terri F, Gray, Christopher J, Izumi, Kosuke, Treat, James R, Wood, Kathleen H, Lack, Justin, Khleborodova, Asya, Niemela, Julie E, Yang, Xingtian, Liang, Rui, Kui, Lin, Wong, Christina Sze Man, Poon, Grace Wing Kit, Hoischen, Alexander, van der Made, Caspar I, Yang, Jing, Chan, Koon Wing, Da Rosa Duque, Jaime Sou, Lee, Pamela Pui Wah, Ho, Marco Hok Kung, Chung, Brian Hon Yin, Le, Huong Thi Minh, Yang, Wanling, Rohani, Pejman, Fouladvand, Ali, Rokni-Zadeh, Hassan, Changi-Ashtiani, Majid, Miryounesi, Mohammad, Puel, Anne, Shahrooei, Mohammad, Finocchi, Andrea, Rossi, Paolo, Rivalta, Beatrice, Cifaldi, Cristina, Novelli, Antonio, Passarelli, Chiara, Arasi, Stefania, Bullens, Dominique, Sauer, Kate, Claeys, Tania, Biggs, Catherine M, Morris, Emma C, Rosenzweig, Sergio D, O’Shea, John J, Wasserman, Wyeth W, Bedford, H Melanie, van Karnebeek, Clara DM, Palma, Paolo, Burns, Siobhan O, Meyts, Isabelle, Casanova, Jean-Laurent, Lyons, Jonathan J, Parvaneh, Nima, Van Nguyen, Anh Thi, Cancrini, Caterina, Heimall, Jennifer, Ahmed, Hanan, McKinnon, Margaret L, Lau, Yu Lung, Béziat, Vivien, and Turvey, Stuart E

Subjects
Genetics, Rare Diseases, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Humans, STAT6 Transcription Factor, Gain of Function Mutation, Asthma, Food Hypersensitivity, Immunoglobulin E, Medical and Health Sciences, Immunology
Abstract

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

Published
2023

3. Immunogenetics associated with severe coccidioidomycosis

Author

Hsu, Amy P, Korzeniowska, Agnieszka, Aguilar, Cynthia C, Gu, Jingwen, Karlins, Eric, Oler, Andrew J, Chen, Gang, Reynoso, Glennys V, Davis, Joie, Chaput, Alexandria, Peng, Tao, Sun, Ling, Lack, Justin B, Bays, Derek J, Stewart, Ethan R, Waldman, Sarah E, Powell, Daniel A, Donovan, Fariba M, Desai, Jigar V, Pouladi, Nima, Priel, Debra A Long, Yamanaka, Daisuke, Rosenzweig, Sergio D, Niemela, Julie E, Stoddard, Jennifer, Freeman, Alexandra F, Zerbe, Christa S, Kuhns, Douglas B, Lussier, Yves A, Olivier, Kenneth N, Boucher, Richard C, Hickman, Heather D, Frelinger, Jeffrey, Fierer, Joshua, Shubitz, Lisa F, Leto, Thomas L, Thompson, George R, Galgiani, John N, Lionakis, Michail S, and Holland, Steven M

Subjects
Rare Diseases, Prevention, Vaccine Related, Biodefense, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Humans, Tumor Necrosis Factor-alpha, Hydrogen Peroxide, Coccidioidomycosis, Coccidioides, beta-Glucans, Fungal infections, Genetics, Infectious disease, Innate immunity, Population genetics
Abstract

Disseminated coccidioidomycosis (DCM) is caused by Coccidioides, pathogenic fungi endemic to the southwestern United States and Mexico. Illness occurs in approximately 30% of those infected, less than 1% of whom develop disseminated disease. To address why some individuals allow dissemination, we enrolled patients with DCM and performed whole-exome sequencing. In an exploratory set of 67 patients with DCM, 2 had haploinsufficient STAT3 mutations, and defects in β-glucan sensing and response were seen in 34 of 67 cases. Damaging CLEC7A and PLCG2 variants were associated with impaired production of β-glucan-stimulated TNF-α from PBMCs compared with healthy controls. Using ancestry-matched controls, damaging CLEC7A and PLCG2 variants were overrepresented in DCM, including CLEC7A Y238* and PLCG2 R268W. A validation cohort of 111 patients with DCM confirmed the PLCG2 R268W, CLEC7A I223S, and CLEC7A Y238* variants. Stimulation with a DECTIN-1 agonist induced DUOX1/DUOXA1-derived hydrogen peroxide [H2O2] in transfected cells. Heterozygous DUOX1 or DUOXA1 variants that impaired H2O2 production were overrepresented in discovery and validation cohorts. Patients with DCM have impaired β-glucan sensing or response affecting TNF-α and H2O2 production. Impaired Coccidioides recognition and decreased cellular response are associated with disseminated coccidioidomycosis.

Published
2022

4. Cushing syndrome and glucocorticoids: T-cell lymphopenia, apoptosis, and rescue by IL-21.

Author

Hwang, SuJin, Tatsi, Christina, Kuehn, Hye, Niemela, Julie, Stoddard, Jennifer, Su, Yan, Lodish, Maya, Uzel, Gulbu, Spolski, Rosanne, Leonard, Warren, Holland, Steven, Fleisher, Thomas, Stratakis, Constantine, and Rosenzweig, Sergio

Subjects
BCL2, NF-κB, PI3K, cytokines, infections, interleukins, Adolescent, Apoptosis, Child, Cushing Syndrome, Cytokines, Female, Glucocorticoids, Humans, Leukocyte Count, Lymphopenia, Male, T-Lymphocytes
Abstract

BACKGROUND: Pediatric endogenous Cushing syndrome (eCs) is mainly caused by pituitary corticotropin-producing adenomas, and most glucocorticoid-dependent effects progressively regress upon tumor removal. eCs reproduces long-term, high-dose glucocorticoid therapy, representing a clean, natural, and unbiased model in which to study glucocorticoid bona fide effects on immunity. OBJECTIVE: We performed extensive immunologic studies in otherwise healthy pediatric patients with eCs before and 6 to 13 months after tumor resection, as well as in in vitro glucocorticoid-treated control cells. METHODS: Flow cytometry, immunoblotting, enzyme-linked immunosorbent assay, real-time quantitative PCR, and RNA-Seq techniques were used to characterize patients and in vitro glucocorticoid treated cells. RESULTS: Reduced thymic output, decreased naive T cells, diminished proliferation, and increased T-cell apoptosis were detected before surgery; all these defects eventually normalized after tumor removal in patients. In vitro studies also showed increased T-cell apoptosis, with correspondingly diminished NF-κB signaling and IL-21 levels. In this setting, IL-21 addition upregulated antiapoptotic BCL2 expression and rescued T-cell apoptosis in a PI3K pathway-dependent manner. Similar and reproducible findings were confirmed in eCs patient cells as well. CONCLUSIONS: We identified decreased thymic output and lymphocyte proliferation, together with increased apoptosis, as the underlying causes to T-cell lymphopenia in eCs patients. IL-21 was decreased in both natural and in vitro long-term, high-dose glucocorticoid environments, and in vitro addition of IL-21 counteracted the proapoptotic effects of glucocorticoid therapy. Thus, our results suggest that administration of IL-21 in patients receiving long-term, high-dose glucocorticoid therapy may contribute to ameliorate lymphopenia and the complications associated to it.

Published
2022

5. Inherited ARPC5 mutations cause an actinopathy impairing cell motility and disrupting cytokine signaling

Author

Nunes-Santos, Cristiane J., Kuehn, HyeSun, Boast, Brigette, Hwang, SuJin, Kuhns, Douglas B., Stoddard, Jennifer, Niemela, Julie E., Fink, Danielle L., Pittaluga, Stefania, Abu-Asab, Mones, Davies, John S., Barr, Valarie A., Kawai, Tomoki, Delmonte, Ottavia M., Bosticardo, Marita, Garofalo, Mary, Carneiro-Sampaio, Magda, Somech, Raz, Gharagozlou, Mohammad, Parvaneh, Nima, Samelson, Lawrence E., Fleisher, Thomas A., Puel, Anne, Notarangelo, Luigi D., Boisson, Bertrand, Casanova, Jean-Laurent, Derfalvi, Beata, and Rosenzweig, Sergio D.

Published
2023
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6. Disease-associated AIOLOS variants lead to immune deficiency/dysregulation by haploinsufficiency and redefine AIOLOS functional domains

Author

Kuehn, Hye Sun, Sakovich, Inga S., Niemela, Julie E., Silva, Agustin A. Gil, Stoddard, Jennifer L., Polyakova, Ekaterina A., Sole, Ana Esteve, Aleshkevich, Svetlana N., Uglova, Tatjana A., Belevtsev, Mikhail V., Vertelko, Vladislav R., Shman, Tatsiana V., Kupchinskaya, Aleksandra N., Walter, Jolan E., Fleisher, Thomas A., Notarangelo, Luigi D., Peng, Xiao P., Delmonte, Ottavia M., Sharapova, Svetlana O., and Rosenzweig, Sergio D.

Subjects
United States. National Institutes of Health, Thermo Fisher Scientific Inc., Becton, Dickinson and Co., Scientific equipment and supplies industry, DNA-ligand interactions, Omalizumab, Medical test kit industry, Autoimmunity, Allergic reaction, B cells, Medical equipment and supplies industry, Allergy, DNA binding proteins, Health care industry
Abstract

AIOLOS, also known as IKZF3, is a transcription factor that is highly expressed in the lymphoid lineage and is critical for lymphocyte differentiation and development. Here, we report on 9 individuals from 3 unrelated families carrying AIOLOS variants Q402* or E82K, which led to AIOLOS haploinsufficiency through different mechanisms of action. Nonsense mutant Q402* displayed abnormal DNA binding, pericentromeric targeting, posttranscriptional modification, and transcriptome regulation. Structurally, the mutant lacked the AIOLOS zinc finger (ZF) 5-6 dimerization domain, but was still able to homodimerize with WT AIOLOS and negatively regulate DNA binding through ZF1, a previously unrecognized function for this domain. Missense mutant E82K showed overall normal AIOLOS functions; however, by affecting a redefined AIOLOS protein stability domain, it also led to haploinsufficiency. Patients with AIOLOS haploinsufficiency showed hypogammaglobulinemia, recurrent infections, autoimmunity, and allergy, but with incomplete clinical penetrance. Altogether, these data redefine the AIOLOS structure-function relationship and expand the spectrum of AIOLOS- associated diseases., Introduction The IKAROS family members consist of 5 zinc-finger (ZF) transcription factors encoded by IKZF1 to IKZF5. IKAROS (IKZF1), HELIOS (IKZF2), and AIOLOS (IKZF3) are highly expressed in the lymphoid [...]

Published
2024
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7. Natural history study of patients with familial platelet disorder with associated myeloid malignancy

Author

Cunningham, Lea, Merguerian, Matthew, Calvo, Katherine R., Davis, Joie, Deuitch, Natalie T., Dulau-Florea, Alina, Patel, Nisha, Yu, Kai, Sacco, Keith, Bhattacharya, Sumona, Passi, Monica, Ozkaya, Neval, De Leon, Seila, Chong, Shawn, Craft, Kathleen, Diemer, Jamie, Bresciani, Erica, O’Brien, Kevin, Andrews, Elizabeth J., Park, Nguyen, Hathaway, Londa, Cowen, Edward W., Heller, Theo, Ryan, Kerry, Barochia, Amisha, Nghiem, Khanh, Niemela, Julie, Rosenzweig, Sergio, Young, David J., Frischmeyer-Guerrerio, Pamela A., Braylan, Raul, and Liu, Paul P.

Published
2023
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8. TCF3 haploinsufficiency defined by immune, clinical, gene-dosage, and murine studies

Author

Boast, Brigette, Goel, Shubham, González-Granado, Luis I., Niemela, Julie, Stoddard, Jennifer, Edwards, Emily S.J., Seneviratne, Sandali, Spensberger, Dominik, Quesada-Espinosa, Juan F., Allende, Luis M., McDonnell, John, Haseley, Alexandria, Lesmana, Harry, Walkiewicz, Magdalena A., Muhammad, Emad, Bosco, Julian J., Fleisher, Thomas A., Cohen, Shai, Holland, Steven M., van Zelm, Menno C., Enders, Anselm, Kuehn, Hye Sun, and Rosenzweig, Sergio D.

Published
2023
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10. 103 Biallelic OSMR deficiency causes a novel primary atopic disorder

Author

Samra, Simran, primary, Sharma, Mehul, additional, Bel, Kate L. Del, additional, Liu, Yihui, additional, James, Alyssa E., additional, Rosenzweig, Sergio, additional, Niemela, Julie, additional, Patil, Siddaramappa J., additional, Bayer, Diana K., additional, Lyons, Jonathan J., additional, and Turvey, Stuart E., additional

Published
2024
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11. Clinical Manifestations, Mutational Analysis, and Immunological Phenotype in Patients with RAG1/2 Mutations: First Cases Series from Mexico and Description of Two Novel Mutations

Author

Lugo-Reyes, Saul Oswaldo, Pastor, Nina, González-Serrano, Edith, Yamazaki-Nakashimada, Marco Antonio, Scheffler-Mendoza, Selma, Berron-Ruiz, Laura, Wakida, Guillermo, Nuñez-Nuñez, Maria Enriqueta, Macias-Robles, Ana Paola, Staines-Boone, Aide Tamara, Venegas-Montoya, Edna, Alaez-Verson, Carmen, Molina-Garay, Carolina, Flores-Lagunes, Luis Leonardo, Carrillo-Sanchez, Karol, Niemela, Julie, Rosenzweig, Sergio D., Gaytan, Paul, Yañez, Jorge A., Martinez-Duncker, Ivan, Notarangelo, Luigi D., Espinosa-Padilla, Sara, and Cruz-Munoz, Mario Ernesto

Published
2021
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12. Germline IKAROS dimerization haploinsufficiency causes hematologic cytopenias and malignancies

Author

Kuehn, Hye Sun, Niemela, Julie E., Stoddard, Jennifer, Mannurita, Sara Ciullini, Shahin, Tala, Goel, Shubham, Hintermeyer, Mary, Heredia, Raul Jimenez, Garofalo, Mary, Lucas, Laura, Singh, Smriti, Tondo, Annalisa, Jacobs, Zachary, Gahl, William A., Latour, Sylvain, Verbsky, James, Routes, John, Cunningham-Rundles, Charlotte, Boztug, Kaan, Gambineri, Eleonora, Fleisher, Thomas A., Chandrakasan, Shanmuganathan, and Rosenzweig, Sergio D.

Published
2021
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13. Flow cytometry-based diagnostic approach for inborn errors of immunity: experience from Algeria.

Author

Tahiat, Azzeddine, Belbouab, Reda, Yagoubi, Abdelghani, Hakem, Saliha, Fernini, Faiza, Keddari, Malika, Belhadj, Hayet, Touri, Souad, Aggoune, Samira, Stoddard, Jennifer, Niemela, Julie, Zerifi, Farida, Melzi, Souhila, Aboura, Rawda, Saad-Djaballah, Amina, Ferhani, Yacine, Ketfi, Abdalbasset, Messaoudi, Hassen, Madani, Tahar Bencharif, and Benhacine, Zouleikha

Subjects
JOB'S syndrome, LYMPHOCYTE subsets, LOW-income countries, GENETIC testing, HEMOPHAGOCYTIC lymphohistiocytosis, SEVERE combined immunodeficiency
Abstract

Purpose: In this study, we retrospectively reviewed the use of flow cytometry (FCM) in the diagnosis of inborn errors of immunity (IEIs) at a single center in Algeria. Sharing insights into our practical experience, we present FCM based diagnostic approaches adapted to different clinical scenarios. Methods: Between May 2017 and February 2024, pediatric and adult patients presenting with clinical features suggestive of immunodeficiency were subjected to FCM evaluation, including lymphocyte subset analysis, detection of specific surface or intracellular proteins, and functional analysis of immune cells. Results: Over a nearly seven-year period, our laboratory diagnosed a total of 670 patients (372 (55.5%) males and 298 (44.5%) females), distributed into 70 different IEIs belonging to 9 different categories of the International Union of Immunological Societies classification. FCM was used to diagnose and categorize IEI in 514 patients (76.7%). It provided direct diagnostic insights for IEIs such as severe combined immunodeficiency, Omenn syndrome, MHC class II deficiency, familial hemophagocytic lymphohistiocytosis, and CD55 deficiency. For certain IEIs, including hyper-IgE syndrome, STAT1-gain of function, autoimmune lymphoproliferative syndrome, and activated PI3K delta syndrome, FCM offered suggestive evidence, necessitating subsequent genetic testing for confirmation. Protein expression and functional assays played a crucial role in establishing definitive diagnoses for various disorders. To setup such diagnostic assays at high and reproducible quality, high level of expertise is required; in house reference values need to be determined and the parallel testing of healthy controls is highly recommended. Conclusion: Flow cytometry has emerged as a highly valuable and cost-effective tool for diagnosing and studying most IEIs, particularly in low-income countries where access to genetic testing can be limited. FCM analysis could provide direct diagnostic insights for most common IEIs, offer clues to the underlying genetic defects, and/or aid in narrowing the list of putative genes to be analyzed. [ABSTRACT FROM AUTHOR]

Published
2024
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16. A Nonsense N –Terminus NFKB2 Mutation Leading to Haploinsufficiency in a Patient with a Predominantly Antibody Deficiency

Author

Kuehn, Hye Sun, Bernasconi, Andrea, Niemela, Julie E., Almejun, Maria Belen, Gallego, William Alexander Franco, Goel, Shubham, Stoddard, Jennifer L., Sánchez, Ronald Guillermo Peláez, Franco, Carlos Andrés Arango, Oleastro, Matías, Grunebaum, Eyal, Ballas, Zuhair, Cunningham-Rundles, Charlotte, Fleisher, Thomas A., Franco, José Luis, Danielian, Silvia, and Rosenzweig, Sergio D.

Published
2020
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17. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations

Author

Price, Susan, Shaw, Pamela A, Seitz, Amy, Joshi, Gyan, Davis, Joie, Niemela, Julie E, Perkins, Katie, Hornung, Ronald L, Folio, Les, Rosenberg, Philip S, Puck, Jennifer M, Hsu, Amy P, Lo, Bernice, Pittaluga, Stefania, Jaffe, Elaine S, Fleisher, Thomas A, Rao, V Koneti, and Lenardo, Michael J

Subjects
Cancer, Lymphoma, Brain Disorders, Rare Diseases, Genetics, Clinical Research, Hematology, Autoimmune Disease, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Adult, Autoimmune Lymphoproliferative Syndrome, Cell Proliferation, Child, Disease Progression, Female, Follow-Up Studies, Humans, Lymphocytes, Male, Middle Aged, Mutation, Penetrance, Young Adult, fas Receptor, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Paediatrics and Reproductive Medicine, Immunology
Abstract

Autoimmune lymphoproliferative syndrome (ALPS) presents in childhood with nonmalignant lymphadenopathy and splenomegaly associated with a characteristic expansion of mature CD4 and CD8 negative or double negative T-cell receptor αβ(+) T lymphocytes. Patients often present with chronic multilineage cytopenias due to autoimmune peripheral destruction and/or splenic sequestration of blood cells and have an increased risk of B-cell lymphoma. Deleterious heterozygous mutations in the FAS gene are the most common cause of this condition, which is termed ALPS-FAS. We report the natural history and pathophysiology of 150 ALPS-FAS patients and 63 healthy mutation-positive relatives evaluated in our institution over the last 2 decades. Our principal findings are that FAS mutations have a clinical penetrance of

Published
2014

18. Mulibrey nanism and immunological complications: a comprehensive case report and literature review

Author

Gazzin, Andrea, primary, Pala, Francesca, additional, Bosticardo, Marita, additional, Niemela, Julie, additional, Stoddard, Jennifer, additional, Biasin, Eleonora, additional, Quarello, Paola, additional, Carli, Diana, additional, Ferroni, Francesca, additional, Delmonte, Ottavia M., additional, Montin, Davide, additional, Rosenzweig, Sergio D., additional, Licciardi, Francesco, additional, and Notarangelo, Luigi D., additional

Published
2023
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19. Disease-associated AIOLOS variants lead to immune deficiency/dysregulation by haploinsufficiency and redefine AIOLOS functional domains

Author

Kuehn, Hye Sun, primary, Sakovich, Inga S., additional, Niemela, Julie E., additional, Gil Silva, Agustin A., additional, Stoddard, Jennifer L., additional, Polyakova, Ekaterina A., additional, Esteve-Sole, Ana, additional, Aleshkevich, Svetlana N., additional, Uglova, Tatjana A., additional, Belevtsev, Mikhail V., additional, Vertelko, Vladislav R., additional, Shman, Tatsiana V., additional, Kupchinskaya, Aleksandra N., additional, Walter, Jolan E., additional, Fleisher, Thomas A., additional, Notarangelo, Luigi D., additional, Peng, Xiao P., additional, Delmonte, Ottavia Maria, additional, Sharapova, Svetlana O., additional, and Rosenzweig, Sergio D., additional

Published
2023
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21. 213 IKAROS negatively regulate memory T cell formation in humans

Author

Tagirasa, Ravichandra, Kueh, HyeSun, Bosticardo, Marita, Pala, Francesca, Amini, Kayla, Anaya, Eduardo, Stoddard, Jennifer, Niemela, Julie, Alsina, Laia, Seoane, Mario Framil, Dimitrova, Dimana, Oleastro, Matias, Bouso, Carolina, LWasserman, Richard, Notarangelo, Luigi, and Rosenzweig, Sergio

Published
2024
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22. 211 Biallelic null mutations in PPM1D cause a novel combined immunodeficiency with severe neurodevelopmental defects

Author

Sole, Ana Esteve, González-Granado, Luis Ignacio, Boast, Brigette, Niemela, Julie E., Stoddart, Jennifer L., Silva, Agustin G., Pias, Leticia, Bolasell, Merce, Marin, Ana V., Regueiro, Jose R, Alsina, Laia, Martine, Pierre, Brown, Kate, Apella, Ettore, Quesada, Juan Francisco, Sweeney, Colin L, Malech, Harry, Haigh, Cathryn L, Kueh, HyeSun, and Rosenzweig, Sergio

Published
2024
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23. Identification of eight novel proteasome variants in five unrelated cases of proteasome-associated autoinflammatory syndromes (PRAAS)

Author

Papendorf, Jonas Johannes, primary, Ebstein, Frédéric, additional, Alehashemi, Sara, additional, Piotto, Daniela Gerent Petry, additional, Kozlova, Anna, additional, Terreri, Maria Teresa, additional, Shcherbina, Anna, additional, Rastegar, Andre, additional, Rodrigues, Marta, additional, Pereira, Renan, additional, Park, Sophia, additional, Lin, Bin, additional, Uss, Kat, additional, Möller, Sophie, additional, da Silva Pina, Ana Flávia, additional, Sztajnbok, Flavio, additional, Torreggiani, Sofia, additional, Niemela, Julie, additional, Stoddard, Jennifer, additional, Rosenzweig, Sergio D., additional, Oler, Andrew J., additional, McNinch, Colton, additional, de Guzman, Marietta M., additional, Fonseca, Adriana, additional, Micheloni, Nicole, additional, Fraga, Melissa Mariti, additional, Perazzio, Sandro Félix, additional, Goldbach-Mansky, Raphaela, additional, de Jesus, Adriana A., additional, and Krüger, Elke, additional

Published
2023
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24. Subcutaneous panniculitis-like T-cell lymphoma in two unrelated individuals with BENTA disease

Author

Bauman, Bradly M., primary, Dorjbal, Batsukh, additional, Pittaluga, Stefania, additional, Zhang, Yu, additional, Niemela, Julie E., additional, Stoddard, Jennifer L., additional, Rosenzweig, Sergio D., additional, Anderson, Ronald, additional, Guilcher, Gregory M.T., additional, Auer, Iwona, additional, Perrier, Renee, additional, Campbell, Martin, additional, Bhandal, Samarjeet K., additional, Alba, Camille, additional, Sukumar, Gautham, additional, Dalgard, Clifton L., additional, Schelotto, Magdalena, additional, Wright, Nicola A.M., additional, Su, Helen C., additional, and Snow, Andrew L., additional

Published
2023
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26. Correction to: Clinical Manifestations, Mutational Analysis, and Immunological Phenotype in Patients with RAG1/2 Mutations: First Cases Series from Mexico and Description of Two Novel Mutations

Author

Lugo-Reyes, Saul Oswaldo, Pastor, Nina, González-Serrano, Edith, Yamazaki-Nakashimada, Marco Antonio, Scheffler-Mendoza, Selma, Berron-Ruiz, Laura, Wakida, Guillermo, Nuñez-Nuñez, Maria Enriqueta, Macias-Robles, Ana Paola, Staines-Boone, Aide Tamara, Venegas-Montoya, Edna, Alaez-Verson, Carmen, Molina-Garay, Carolina, Flores-Lagunes, Luis Leonardo, Carrillo-Sanchez, Karol, Niemela, Julie, Rosenzweig, Sergio D., Gaytan, Paul, Yañez, Jorge A., Martinez-Duncker, Ivan, Notarangelo, Luigi D., Espinosa-Padilla, Sara, and Cruz-Munoz, Mario Ernesto

Published
2021
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27. Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency

Author

Boutboul, David, Kuehn, Hye Sun, Wyngaert, Zoe Van de, Niemela, Julie E., Callebaut, Isabelle, Stoddard, Jennifer, Lenoir, Christelle, Barlogis, Vincent, Farnarier, Catherine, Vely, Frederic, Yoshida, Nao, Kojima, Seiji, Kanegane, Hirokazu, Hoshino, Akihiro, Hauck, Fabian, Lhermitte, Ludovic, Asnafi, Vahid, Roehrs, Philip, Chen, Shaoying, Verbsky, James W., Calvo, Katherine R., Husami, Ammar, Zhang, Kejian, Roberts, Joseph, Amrol, David, Sleaseman, John, Hsu, Amy P., Holland, Steven M., Marsh, Rebecca, Fischer, Alain, Fleisher, Thomas A., Picard, Capucine, Latour, Sylvain, and Rosenzweig, Sergio D.

Subjects
Hematopoiesis -- Research -- Genetic aspects, Gene mutation -- Research, Transcription factors -- Research -- Physiological aspects -- Properties, Acute lymphocytic leukemia -- Research -- Risk factors -- Genetic aspects, Health care industry
Abstract

Ikaros/IKZF1 is an essential transcription factor expressed throughout hematopoiesis. IKZF1 is implicated in lymphocyte and myeloid differentiation and negative regulation of cell proliferation. In humans, somatic mutations in IKZF1 have been linked to the development of B cell acute lymphoblastic leukemia (ALL) in children and adults. Recently, heterozygous germline IKZF1 mutations have been identified in patients with a B cell immune deficiency mimicking common variable immunodeficiency. These mutations demonstrated incomplete penetrance and led to haploinsufficiency. Herein, we report 7 unrelated patients with a novel early-onset combined immunodeficiency associated with de novo germline IKZF1 heterozygous mutations affecting amino acid N159 located in the DNA-binding domain of IKZF1. Different bacterial and viral infections were diagnosed, but Pneumocystis jirovecii pneumonia was reported in all patients. One patient developed a T cell ALL. This immunodeficiency was characterized by innate and adaptive immune defects, including low numbers of B cells, neutrophils, eosinophils, and myeloid dendritic cells, as well as T cell and monocyte dysfunctions. Notably, most T cells exhibited a naive phenotype and were unable to evolve into effector memory cells. Functional studies indicated these mutations act as dominant negative. This defect expands the clinical spectrum of human IKZF1- associated diseases from somatic to germline, from haploinsufficient to dominant negative., Introduction IKAROS, a transcription factor encoded by IKZF1, is expressed during hematopoiesis (1, 2). It has been involved in positive regulation of lymphocyte differentiation and negative regulation of cell proliferation [...]

Published
2018
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28. NF-kappa-B essential modulator (NEMO) gene polymorphism in an adult woman with systemic lupus erythematosus and recurrent non-tuberculous mycobacterial disseminated infections

Author

Thomas, Konstantinos, primary, Tsioulos, Georgios, additional, Kotsogianni, Christina, additional, Banos, Agellos, additional, Niemela, Julie E., additional, Cheng, Aristine, additional, DiMaggio, Tom, additional, Holland, Steven, additional, Rosenzweig, Sergio D., additional, Tziolos, Nikolaos, additional, Papadopoulos, Antonios, additional, Lionakis, Michail S., additional, and Boumpas, Dimitrios T., additional

Published
2023
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29. Biallelic human SHARPINloss of function induces autoinflammation and immunodeficiency

Author

Oda, Hirotsugu, Manthiram, Kalpana, Chavan, Pallavi Pimpale, Rieser, Eva, Veli, Önay, Kaya, Öykü, Rauch, Charles, Nakabo, Shuichiro, Kuehn, Hye Sun, Swart, Mariël, Wang, Yanli, Çelik, Nisa Ilgim, Molitor, Anne, Ziaee, Vahid, Movahedi, Nasim, Shahrooei, Mohammad, Parvaneh, Nima, Alipour-olyei, Nasrin, Carapito, Raphael, Xu, Qin, Preite, Silvia, Beck, David B., Chae, Jae Jin, Nehrebecky, Michele, Ombrello, Amanda K., Hoffmann, Patrycja, Romeo, Tina, Deuitch, Natalie T., Matthíasardóttir, Brynja, Mullikin, James, Komarow, Hirsh, Stoddard, Jennifer, Niemela, Julie, Dobbs, Kerry, Sweeney, Colin L., Anderton, Holly, Lawlor, Kate E., Yoshitomi, Hiroyuki, Yang, Dan, Boehm, Manfred, Davis, Jeremy, Mudd, Pamela, Randazzo, Davide, Tsai, Wanxia Li, Gadina, Massimo, Kaplan, Mariana J., Toguchida, Junya, Mayer, Christian T., Rosenzweig, Sergio D., Notarangelo, Luigi D., Iwai, Kazuhiro, Silke, John, Schwartzberg, Pamela L., Boisson, Bertrand, Casanova, Jean-Laurent, Bahram, Seiamak, Rao, Anand Prahalad, Peltzer, Nieves, Walczak, Henning, Lalaoui, Najoua, Aksentijevich, Ivona, and Kastner, Daniel L.

Abstract

The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpinleads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical function of the LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.

Published
2024
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30. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations

Author

Milner, Joshua D., Vogel, Tiphanie P., Forbes, Lisa, Ma, Chi A., Stray-Pedersen, Asbjørg, Niemela, Julie E., Lyons, Jonathan J., Engelhardt, Karin R., Zhang, Yu, Topcagic, Nermina, Roberson, Elisha D.O., Matthews, Helen, Verbsky, James W., Dasu, Trivikram, Vargas-Hernandez, Alexander, Varghese, Nidhy, McClain, Kenneth L., Karam, Lina B., Nahmod, Karen, Makedonas, George, Mace, Emily M., Sorte, Hanne S., Perminow, Gøri, Rao, V. Koneti, O’Connell, Michael P., Price, Susan, Su, Helen C., Butrick, Morgan, McElwee, Joshua, Hughes, Jason D., Willet, Joseph, Swan, David, Xu, Yaobo, Santibanez-Koref, Mauro, Slowik, Voytek, Dinwiddie, Darrell L., Ciaccio, Christina E., Saunders, Carol J., Septer, Seth, Kingsmore, Stephen F., White, Andrew J., Cant, Andrew J., Hambleton, Sophie, and Cooper, Megan A.

Published
2015
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31. Correction to: A Nonsense N –Terminus NFKB2 Mutation Leading to Haploinsufficiency in a Patient with a Predominantly Antibody Deficiency

Author

Kuehn, Hye Sun, Bernasconi, Andrea, Niemela, Julie E., Almejun, Maria Belen, Gallego, William Alexander Franco, Goel, Shubham, Stoddard, Jennifer L., Sánchez, Ronald Guillermo Peláez, Franco, Carlos Andrés Arango, Oleastro, Matías, Grunebaum, Eyal, Ballas, Zuhair, Cunningham-Rundles, Charlotte, Fleisher, Thomas A., Franco, José Luis, Danielian, Silvia, and Rosenzweig, Sergio D.

Published
2020
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32. Human LUBAC deficiency leads to autoinflammation and immunodeficiency by dysregulation in TNF-mediated cell death

Author

Oda, Hirotsugu, primary, Manthiram, Kalpana, additional, Chavan, Pallavi Pimpale, additional, Nakabo, Shuichiro, additional, Kuehn, Hye Sun, additional, Beck, David B., additional, Chae, Jae Jin, additional, Nehrebecky, Michele, additional, Ombrello, Amanda K., additional, Romeo, Tina, additional, Deuitch, Natalie, additional, Matthíasardóttir, Brynja, additional, Mullikin, Jim, additional, Stoddard, Jennifer, additional, Niemela, Julie, additional, Anderton, Holly, additional, Lawlor, Kate E., additional, Yoshitomi, Hiroyuki, additional, Yang, Dan, additional, Boehm, Manfred, additional, Davis, Jeremy, additional, Mudd, Pamela, additional, Randazzo, Davide, additional, Tsai, Wanxia Li, additional, Gadina, Massimo, additional, Kaplan, Mariana J., additional, Toguchida, Junya, additional, Mayer, Christian, additional, Rosenzweig, Sergio D., additional, Iwai, Kazuhiro, additional, Silke, John, additional, Boisson, Bertrand, additional, Casanova, Jean-Laurent, additional, Rao, Anand, additional, Lalaoui, Najoua, additional, Aksentijevich, Ivona, additional, and Kastner, Daniel L., additional

Published
2022
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33. Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations

Author

Similuk, Morgan N., primary, Yan, Jia, additional, Ghosh, Rajarshi, additional, Oler, Andrew J., additional, Franco, Luis M., additional, Setzer, Michael R., additional, Kamen, Michael, additional, Jodarski, Colleen, additional, DiMaggio, Thomas, additional, Davis, Joie, additional, Gore, Rachel, additional, Jamal, Leila, additional, Borges, Adrienne, additional, Gentile, Nicole, additional, Niemela, Julie, additional, Lowe, Chenery, additional, Jevtich, Kathleen, additional, Yu, Yunting, additional, Hullfish, Haley, additional, Hsu, Amy P., additional, Hong, Celine, additional, Littel, Patricia, additional, Seifert, Bryce A., additional, Milner, Joshua, additional, Johnston, Jennifer J., additional, Cheng, Xi, additional, Li, Zhiwen, additional, Veltri, Daniel, additional, Huang, Ke, additional, Kaladi, Krishnaveni, additional, Barnett, Jason, additional, Zhang, Lingwen, additional, Vlasenko, Nikita, additional, Fan, Yongjie, additional, Karlins, Eric, additional, Ganakammal, Satishkumar Ranganathan, additional, Gilmore, Robert, additional, Tran, Emily, additional, Yun, Alvin, additional, Mackey, Joseph, additional, Yazhuk, Svetlana, additional, Lack, Justin, additional, Kuram, Vasudev, additional, Cao, Wenjia, additional, Huse, Susan, additional, Frank, Karen, additional, Fahle, Gary, additional, Rosenzweig, Sergio, additional, Su, Yan, additional, Hwang, SuJin, additional, Bi, Weimin, additional, Bennett, John, additional, Myles, Ian A., additional, De Ravin, Suk See, additional, Fuss, Ivan, additional, Strober, Warren, additional, Bielekova, Bibiana, additional, Almeida de Jesus, Adriana, additional, Goldbach-Mansky, Raphaela, additional, Williamson, Peter, additional, Kumar, Kelly, additional, Dempsy, Caeden, additional, Frischmeyer-Guerrerio, Pamela, additional, Fisch, Robin, additional, Bolan, Hyejeong, additional, Metcalfe, Dean D., additional, Komarow, Hirsh, additional, Carter, Melody, additional, Druey, Kirk M., additional, Sereti, Irini, additional, Dropulic, Lesia, additional, Klion, Amy D., additional, Khoury, Paneez, additional, O' Connell, Elise M., additional, Holland-Thomas, Nicole C., additional, Brown, Thomas, additional, McDermott, David H., additional, Murphy, Philip M., additional, Bundy, Vanessa, additional, Keller, Michael D., additional, Peng, Christine, additional, Kim, Helen, additional, Norman, Stephanie, additional, Delmonte, Ottavia M., additional, Kang, Elizabeth, additional, Su, Helen C., additional, Malech, Harry, additional, Freeman, Alexandra, additional, Zerbe, Christa, additional, Uzel, Gulbu, additional, Bergerson, Jenna R.E., additional, Rao, V. Koneti, additional, Olivier, Kenneth N., additional, Lyons, Jonathan J., additional, Lisco, Andrea, additional, Cohen, Jeffrey I., additional, Lionakis, Michail S., additional, Biesecker, Leslie G., additional, Xirasagar, Sandhya, additional, Notarangelo, Luigi D., additional, Holland, Steven M., additional, and Walkiewicz, Magdalena A., additional

Published
2022
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34. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4

Author

Sun Kuehn, Hye, Ouyang, Weiming, Lo, Bernice, Deenick, Elissa K., Niemela, Julie E., Avery, Danielle T., Schickel, Jean-Nicolas, Tran, Dat Q., Stoddard, Jennifer, Zhang, Yu, Frucht, David M., Dumitriu, Bogdan, Scheinberg, Phillip, Folio, Les R., Frein, Cathleen A., Price, Susan, Koh, Christopher, Heller, Theo, Seroogy, Christine M., Huttenlocher, Anna, Rao, V. Koneti, Su, Helen C., Kleiner, David, Notarangelo, Luigi D., Rampertaap, Yajesh, Olivier, Kenneth N., McElwee, Joshua, Hughes, Jason, Pittaluga, Stefania, Oliveira, Joao B., Meffre, Eric, Fleisher, Thomas A., Holland, Steven M., Lenardo, Michael J., Tangye, Stuart G., and Uzel, Gulbu

Published
2014

35. Identification of eight novel proteasome variants in five unrelated cases of proteasomeassociated autoinflammatory syndromes (PRAAS).

Author

Papendorf, Jonas Johannes, Ebstein, Frédéric, Alehashemi, Sara, Petry Piotto, Daniela Gerent, Kozlova, Anna, Terreri, Maria Teresa, Shcherbina, Anna, Rastegar, Andre, Rodrigues, Marta, Pereira, Renan, Park, Sophia, Bin Lin, Uss, Kat, Möller, Sophie, da Silva Pina, Ana Flávia, Sztajnbok, Flavio, Torreggiani, Sofia, Niemela, Julie, Stoddard, Jennifer, and Rosenzweig, Sergio D.

Subjects
TYPE I interferons, GENETIC variation, GENETIC counseling, PYODERMA gangrenosum, HIGH temperatures, MOLECULAR diagnosis
Abstract

Mutations in genes coding for proteasome subunits and/or proteasome assembly helpers typically cause recurring autoinflammation referred to as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE) or proteasome-associated autoinflammatory syndrome (PRAAS). Patients with CANDLE/PRAAS present with mostly chronically elevated type I interferon scores that emerge as a consequence of increased proteotoxic stress by mechanisms that are not fully understood. Here, we report on five unrelated patients with CANDLE/ PRAAS carrying novel inherited proteasome missense and/or nonsense variants. Four patients were compound heterozygous for novel pathogenic variants in the known CANDLE/PRAAS associated genes, PSMB8 and PSMB10, whereas one patient showed additive loss-of-function mutations in PSMB8. Variants in two previously not associated proteasome genes, PSMA5 and PSMC5, were found in a patient who also carried the PSMB8 founder mutation, p.T75M. All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes. Our observations expand the spectrum of PRAAS-associated genetic variants and improve a molecular diagnosis and genetic counseling of patients with sterile autoinflammation. [ABSTRACT FROM AUTHOR]

Published
2023
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42. Digenic Inheritance of Dominant TRAF6 and Recessive OSMR Pathogenic Variants Associated with Short Stature, Atopy, and Eosinophilic Inflammation

Author

James, Alyssa, primary, Liu, Yihui, additional, Wolfe, Lynne, additional, Chovanec, Jack, additional, O’Connell, Michael, additional, Lee, Kate, additional, Niemela, Julie, additional, Ferreira, Carlos, additional, DiMaggio, Thomas, additional, Makri, Angeliki, additional, Boehnke, Michael, additional, Weixel, Tara, additional, Kinnunen, Leena, additional, Oler, Andrew, additional, Connelly, James, additional, Dulek, Daniel, additional, Khan, Yasmin, additional, Delaney, Angela, additional, Jee, Youn Hee, additional, Rosenzweig, Sergio, additional, Milner, Joshua, additional, Koistinen, Heikki, additional, Macnamara, Ellen, additional, Adams, David, additional, Gahl, William, additional, and Lyons, Jonathan, additional

Published
2022
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43. Loss of B Cells in Patients with Heterozygous Mutations in IKAROS

Author

Kuehn, Hye Sun, Boisson, Bertrand, Cunningham-Rundles, Charlotte, Reichenbach, Janine, Stray-Pedersen, Asbjørg, Gelfand, Erwin W., Maffucci, Patrick, Pierce, Keith R., Abbott, Jordan K., Voelkerding, Karl V., South, Sarah T., Augustine, Nancy H., Bush, Jeana S., Dolen, William K., Wray, Betty B., Itan, Yuval, Cobat, Aurelie, Sorte, Hanne Sørmo, Ganesan, Sundar, Prader, Seraina, Martins, Thomas B., Lawrence, Monica G., Orange, Jordan S., Calvo, Katherine R., Niemela, Julie E., Casanova, Jean-Laurent, Fleisher, Thomas A., Hill, Harry R., Kumánovics, Attila, Conley, Mary Ellen, and Rosenzweig, Sergio D.

Published
2016
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44. Hypomorphic Rag mutations can cause destructive midline granulomatous disease

Author

De Ravin, Suk See, Cowen, Edward W., Zarember, Kol A., Whiting-Theobald, Narda L., Kuhns, Douglas B., Sandler, Netanya G., Douek, Daniel C., Pittaluga, Stefania, Poliani, Pietro L., Lee, Yu Nee, Notarangelo, Luigi D., Wang, Lei, Alt, Frederick W., Kang, Elizabeth M., Milner, Joshua D., Niemela, Julie E., Fontana-Penn, Mary, Sinal, Sara H., and Malech, Harry L.

Published
2010
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46. Paciente adulto portador de una mutación con ganancia de función en el gen STAT3

Author

López, Ana Laura, Niemela, Julie, Stoddard, Jennifer, Paolini, María Virginia, Rosenzweig, Sergio, and Fernández Romero, Diego S.

Subjects
Ganancia de función, Signal transducer and activator of transcription 3, Lung disease, Transductor de señales y activador de la transcripción 3, Gain of func tion, Enfermedad pulmonar, Common variable immunodeficiency, Inmunodeficiencia común variable
Abstract

Germline gain-of-function (GOF) mutation of the signal transducer and activator of transcription 3 (STAT3) gene causes a disease clinically characterized by a significant lymphoproliferation, includ ing lymphadenopathy and/or hepatosplenomegaly, as well as childhood onset autoimmunity. Here we present an adult patient who, during his early years of life, presented recurrent infections, autoimmune hemolytic anemia and benign lymphoproliferative disease, characterized by hepatosplenomegaly and lymphadenopathy, being diagnosed with common variable immunodeficiency (CVID) at 13 years of age. He was diagnosed with lymphocytic interstitial pneumonia at the age of 20. When he was 40 years old, after a diagnostic review, it was decided to perform genetic studies. A heterozygous mutation in STAT3 NM_003150 c.2141C>T, p.P714L was detected by whole exome sequencing and validated by Sanger. Previously published functional studies performed in two siblings showed that this mutation resulted in gain-of-function. They were initially diagnosed with autoimmune lymphoproliferative syndrome, and later with STAT3 GOF as a second genetic defect. Our patient developed severe pulmonary disease and died, without access to treatment targeted to his molecular defect due to the advanced nature of his pulmonary involvement and the fact that many of the therapies were still in develop ment at that time. The diagnosis of STAT3 GOF mutations should be suspected in patients with early-onset of lymphoproliferative disease, autoimmunity and hypogammaglobulinemia. This must be considered especially in the group of CVID patients with these characteristics, in order to allow the implementation of treatments target ing the molecular defect (JAK inhibitors and Il-6 receptor antagonists) that could modify the disease evolution. Resumen Mutaciones en línea germinal con ganancia de función (GOF) del gen transductor de señales y acti vador de la transcripción 3 (STAT3) provocan una enfermedad caracterizada por importante linfoproliferación, incluyendo linfadenopatías y/o hepatoesplenomegalia, así como autoinmunidad de inicio en la infancia. Presen tamos un paciente adulto que, durante sus primeros años de vida, presentó infecciones recurrentes, anemia hemolítica autoinmune y enfermedad linfoproliferativa benigna, caracterizada inicialmente por hepatoespleno megalia y linfoadenopatías, diagnosticado de inmunodeficiencia común variable (IDCV) a los 13 años. A los 20 años, al ser estudiado por compromiso pulmonar, se diagnosticó neumonía intersticial linfocítica. A los 40 años, tras revisión diagnóstica se decidió realizar estudios genéticos. Por secuenciación del exoma completo se detectó una mutación heterocigota en STAT3 NM_003150 c.2141C>T, p.P714L, que se validó por Sanger. Estudios funcionales previamente publicados realizados en dos hermanos con diagnóstico inicial de síndrome linfoproliferativo autoinmune, mostraron que esta mutación daba lugar a una ganancia de función. Nuestro pa ciente desarrolló enfermedad pulmonar grave y falleció a los 41 años, sin posibilidad de acceder a tratamiento dirigido a su defecto molecular por lo avanzado de su compromiso pulmonar y a que muchas de las terapias se encontraban en ese momento en desarrollo. El diagnóstico de mutaciones STAT3 GOF debe sospecharse en pacientes con enfermedad linfoproliferativa temprana, autoinmunidad e hipogammaglobulinemia. Esto debe ser considerado especialmente en pacientes con IDCV con estas características, para permitir la implementación de tratamientos dirigidos al defecto molecular (inhibidores de JAK y antagonistas del receptor de Il-6) que podrían modificar la evolución de la enfermedad.

Published
2021

47. CARD9 Expression Pattern, Gene Dosage, and Immunodeficiency Phenotype Revisited

Author

Goel, Shubham, primary, Kuehn, Hye Sun, additional, Chinen, Javier, additional, Niemela, Julie, additional, Stoddard, Jennifer, additional, Yamanaka, Daisuke, additional, Garofalo, Mary, additional, Samir, Sophia, additional, Migaud, Melanie, additional, Oikonomou, Vasileios, additional, Fleisher, Thomas, additional, Puel, Anne, additional, Lionakis, Michail S., additional, and Rosenzweig, Sergio D., additional

Published
2021
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48. T and B cell abnormalities, pneumocystis pneumonia, and chronic lymphocytic leukemia associated with an AIOLOS defect in patients

Author

Kuehn, Hye Sun, primary, Chang, Jingjie, additional, Yamashita, Motoi, additional, Niemela, Julie E., additional, Zou, Chengcheng, additional, Okuyama, Kazuki, additional, Harada, Junji, additional, Stoddard, Jennifer L., additional, Nunes-Santos, Cristiane J., additional, Boast, Brigette, additional, Baxter, Ryan M., additional, Hsieh, Elena W.Y., additional, Garofalo, Mary, additional, Fleisher, Thomas A., additional, Morio, Tomohiro, additional, Taniuchi, Ichiro, additional, Dutmer, Cullen M., additional, and Rosenzweig, Sergio D., additional

Published
2021
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