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1. RelB-deficient autoinflammatory pathology presents as interferonopathy, but in mice is interferon-independent.

Author

Navarro, Héctor, Liu, Yi, Fraser, Anna, Lefaudeux, Diane, Chia, Jennifer, Vong, Linda, Roifman, Chaim, and Hoffmann, Alexander

Subjects
RelB, autoimmunity, dendritic cells, inflammation, interferonopathy, relopathy, Animals, Humans, Mice, Autoimmune Diseases, Interferons, Mice, Knockout, NF-kappa B, Signal Transduction, Transcription Factor RelB
Abstract

BACKGROUND: Autoimmune diseases are leading causes of ill health and morbidity and have diverse etiology. Two signaling pathways are key drivers of autoimmune pathology, interferon and nuclear factor-κB (NF-κB)/RelA, defining the 2 broad labels of interferonopathies and relopathies. Prior work has established that genetic loss of function of the NF-κB subunit RelB leads to autoimmune and inflammatory pathology in mice and humans. OBJECTIVE: We sought to characterize RelB-deficient autoimmunity by unbiased profiling of the responses of immune sentinel cells to stimulus and to determine the functional role of dysregulated gene programs in the RelB-deficient pathology. METHODS: Transcriptomic profiling was performed on fibroblasts and dendritic cells derived from patients with RelB deficiency and knockout mice, and transcriptomic responses and pathology were assessed in mice deficient in both RelB and the type I interferon receptor. RESULTS: We found that loss of RelB in patient-derived fibroblasts and mouse myeloid cells results in elevated induction of hundreds of interferon-stimulated genes. Removing hyperexpression of the interferon-stimulated gene program did not ameliorate the autoimmune pathology of RelB knockout mice. Instead, we found that RelB suppresses a different set of inflammatory response genes in a manner that is independent of interferon signaling but associated with NF-κB binding motifs. CONCLUSION: Although transcriptomic profiling would describe RelB-deficient autoimmune disease as an interferonopathy, the genetic evidence indicates that the pathology in mice is interferon-independent.

Published
2023

2. 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

3. NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.

Author

Sharfe, Nigel, Dalal, Ilan, Naghdi, Zahra, Lefaudeux, Diane, Vong, Linda, Dadi, Harjit, Navarro, Hector, Tasher, Diana, Ovadia, Adi, Zangen, Tzili, Ater, Dorit, Ngan, Bo, Hoffmann, Alexander, and Roifman, Chaim

Subjects
Autoimmunity, Combined immunodeficiency, Memory B cells, NFκB pathway, Naïve T cells, RelB, Humans, Transcription Factor RelB, NF-kappa B, Signal Transduction, Gene Expression Regulation, Autoimmune Diseases
Abstract

BACKGROUND: Genetic aberrations in the NFκB pathway lead to primary immunodeficiencies with various degrees of severity. We previously demonstrated that complete ablation of the RelB transcription factor, a key component of the alternative pathway, results in an early manifested combined immunodeficiency requiring stem cell transplantation. OBJECTIVE: To study the molecular basis of a progressive severe autoimmunity and immunodeficiency in three patients. METHODS: Whole exome sequencing was performed to identify the genetic defect. Molecular and cellular techniques were utilized to assess the variant impact on NFκB signaling, canonical and alternative pathway crosstalk, as well as the resultant effects on immune function. RESULTS: Patients presented with multiple autoimmune progressive severe manifestations encompassing the liver, gut, lung, and skin, becoming debilitating in the second decade of life. This was accompanied by a deterioration of the immune system, demonstrating an age-related decline in naïve T cells and responses to mitogens, accompanied by a gradual loss of all circulating CD19+ cells. Whole exome sequencing identified a novel homozygous c. C1091T (P364L) transition in RELB. The P364L RelB protein was unstable, with extremely low expression, but retained some function and could be transiently and partially upregulated following Toll-like receptor stimulation. Stimulation of P364L patient fibroblasts resulted in a marked rise in a cluster of pro-inflammatory hyper-expressed transcripts consistent with the removal of RelB inhibitory effect on RelA function. This is likely the main driver of autoimmune manifestations in these patients. CONCLUSION: Incomplete loss of RelB provided a unique opportunity to gain insights into NFκBs pathway interactions as well as the pathogenesis of autoimmunity. The P364L RelB mutation leads to gradual decline in immune function with progression of severe debilitating autoimmunity.

Published
2023

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

Author

Le Voyer, Tom, Parent, Audrey V., Liu, Xian, Cederholm, Axel, Gervais, Adrian, Rosain, Jérémie, Nguyen, Tina, Perez Lorenzo, Malena, Rackaityte, Elze, Rinchai, Darawan, Zhang, Peng, Bizien, Lucy, Hancioglu, Gonca, Ghillani-Dalbin, Pascale, Charuel, Jean-Luc, Philippot, Quentin, Gueye, Mame Sokhna, Maglorius Renkilaraj, Majistor Raj Luxman, Ogishi, Masato, Soudée, Camille, Migaud, Mélanie, Rozenberg, Flore, Momenilandi, Mana, Riller, Quentin, Imberti, Luisa, Delmonte, Ottavia M., Müller, Gabriele, Keller, Baerbel, Orrego, Julio, Franco Gallego, William Alexander, Rubin, Tamar, Emiroglu, Melike, Parvaneh, Nima, Eriksson, Daniel, Aranda-Guillen, Maribel, Berrios, David I., Vong, Linda, Katelaris, Constance H., Mustillo, Peter, Raedler, Johannes, Bohlen, Jonathan, Bengi Celik, Jale, Astudillo, Camila, Winter, Sarah, McLean, Catriona, Guffroy, Aurélien, DeRisi, Joseph L., Yu, David, Miller, Corey, Feng, Yi, Guichard, Audrey, Béziat, Vivien, Bustamante, Jacinta, Pan-Hammarström, Qiang, Zhang, Yu, Rosen, Lindsey B., Holland, Steve M., Bosticardo, Marita, Kenney, Heather, Castagnoli, Riccardo, Slade, Charlotte A., Boztuğ, Kaan, Mahlaoui, Nizar, Latour, Sylvain, Abraham, Roshini S., Lougaris, Vassilios, Hauck, Fabian, Sediva, Anna, Atschekzei, Faranaz, Sogkas, Georgios, Poli, M. Cecilia, Slatter, Mary A., Palterer, Boaz, Keller, Michael D., 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 Elena, Meinhardt, Andrea, Ikinciogullari, Aydan, Shahrooei, Mohammad, Celmeli, Fatih, Frosk, Patrick, Goodnow, Christopher C., Gray, Paul E., Belot, Alexandre, Kuehn, Hye Sun, Rosenzweig, Sergio D., 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 G., Sobacchi, Cristina, Doffinger, Rainer, Warnatz, Klaus, Grimbacher, Bodo, Fieschi, Claire, Berteloot, Laureline, Bryant, Vanessa L., Trouillet Assant, Sophie, Su, Helen, Neven, Benedicte, Abel, Laurent, Zhang, Qian, Boisson, Bertrand, Cobat, Aurélie, Jouanguy, Emmanuelle, Kampe, Olle, Bastard, Paul, Roifman, Chaim M., Landegren, Nils, Notarangelo, Luigi D., Anderson, Mark S., Casanova, Jean-Laurent, and Puel, Anne

Published
2023
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9. Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.

Author

de la Morena, M Teresa, Leonard, David, Torgerson, Troy R, Cabral-Marques, Otavio, Slatter, Mary, Aghamohammadi, Asghar, Chandra, Sharat, Murguia-Favela, Luis, Bonilla, Francisco A, Kanariou, Maria, Damrongwatanasuk, Rongras, Kuo, Caroline Y, Dvorak, Christopher C, Meyts, Isabelle, Chen, Karin, Kobrynski, Lisa, Kapoor, Neena, Richter, Darko, DiGiovanni, Daniela, Dhalla, Fatima, Farmaki, Evangelia, Speckmann, Carsten, Español, Teresa, Shcherbina, Anna, Hanson, Imelda Celine, Litzman, Jiri, Routes, John M, Wong, Melanie, Fuleihan, Ramsay, Seneviratne, Suranjith L, Small, Trudy N, Janda, Ales, Bezrodnik, Liliana, Seger, Reinhard, Raccio, Andrea Gomez, Edgar, J David M, Chou, Janet, Abbott, Jordan K, van Montfrans, Joris, González-Granado, Luis Ignacio, Bunin, Nancy, Kutukculer, Necil, Gray, Paul, Seminario, Gisela, Pasic, Srdjan, Aquino, Victor, Wysocki, Christian, Abolhassani, Hassan, Dorsey, Morna, Cunningham-Rundles, Charlotte, Knutsen, Alan P, Sleasman, John, Costa Carvalho, Beatriz Tavares, Condino-Neto, Antonio, Grunebaum, Eyal, Chapel, Helen, Ochs, Hans D, Filipovich, Alexandra, Cowan, Mort, Gennery, Andrew, Cant, Andrew, Notarangelo, Luigi D, and Roifman, Chaim M

Subjects
Humans, Hematopoietic Stem Cell Transplantation, Proportional Hazards Models, Retrospective Studies, Cohort Studies, Follow-Up Studies, Time, Adolescent, Adult, Middle Aged, Child, Child, Preschool, Infant, Female, Male, Hyper-IgM Immunodeficiency Syndrome, Young Adult, Kaplan-Meier Estimate, CD40 ligand, Karnofsky/Lansky scores, X-linked hyper-IgM syndrome, defects in class-switch recombination, hematopoietic cell transplantation, long-term outcomes, primary immunodeficiency, Pediatric, Clinical Research, Transplantation, Inflammatory and immune system, Good Health and Well Being, Immunology, Allergy
Abstract

BackgroundX-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients.ObjectivesWe sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT.MethodsPhysicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression.ResultsTwenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 ± 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P

Published
2017

11. Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations

Author

Adhya, Zoe, Alachkar, Hana, Anantharachagan, Ariharan, Antrobus, Richard, Arumugakani, Gururaj, Ashford, Sofie, Astle, William J., Attwood, Anthony, Bacchelli, Chiara, Batista, Joana, Baxendale, Helen E., Bethune, Claire, Bibi, Shahnaz, Bleda, Marta, Boardman, Barbara, Booth, Claire, Bradley, John R., Breen, Gerome, Brown, Matthew, Browning, Michael J., Brownlie, Mary, Buckland, Matthew S., Burns, Siobhan O., Burren, Oliver S., Carss, Keren, Chambers, John, Chandra, Anita, Brod, Naomi Clements, Clifford, Hayley, Cooper, Nichola, Daugherty, Louise C., Davies, E.G., Davies, Sophie, Davis, John, Deacock, Sarah, Deevi, Sri V.V., Dempster, John, Devlin, Lisa A., Dewhurst, Eleanor F., Downes, Kate, Drewe, Elizabeth, Duarte, Daniel, Edgar, J. David M., Edwards, Karen, Egner, William, El-Shanawany, Tariq, Erwood, Marie, Fletcher, Debra, Fox, James, Frary, Amy J., Frontini, Mattia, Furnell, Abigail, Gaspar, H. Bobby, Ghurye, Rohit, Gilmour, Kimberly C., Gleadall, Nicholas S., Goddard, Sarah, Gordins, Pavels, Gräf, Stefan, Grassi, Luigi, Greene, Daniel, Grigoriadou, Sofia, Hackett, Scott, Hague, Rosie, Haimel, Matthias, Harper, Lorraine, Hayman, Grant, Herwadkar, Archana, Hu, Fengyuan, Hughes, Stephen, Huissoon, Aarnoud P., James, Roger, Jolles, Stephen, Jolley, Jennifer, Jones, Julie, Karim, Yousuf, Kasanicki, Mary A., Kelleher, Peter, Kempster, Carly, Kiani, Sorena, Kingston, Nathalie, Klein, Nigel, Kostadima, Myrto, Kreuzhuber, Roman, Kuijpers, Taco W., Kumararatne, Dinakantha, Laffan, James, Allen, Hana Lango, Lear, Sara E., Linger, Rachel, Longhurst, Hilary, Lorenzo, Lorena E., Lyons, Paul A., Maimaris, Jesmeen, Manson, Ania, Mapeta, Rutendo, Martin, Jennifer, McCarthy, Mark I., McDermott, Elizabeth M., McKinney, Harriet, Meacham, Stuart, Megy, Karyn, Millar, Hazel, Mistry, Anoop, Morrisson, Valerie, Murng, Sai H.K., Nasir, Iman, Nejentsev, Sergey, Noorani, Sadia, Oksenhendler, Eric, Ouwehand, Willem H., Papadia, Sofia, Penkett, Christopher J., Petersen, Romina, Ponsford, Mark J., Qasim, Waseem, Quinn, Ellen, Quinti, Isabella, Raymond, F. Lucy, Rayner-Matthews, Paula J., Richter, Alex, Samani, Nilesh, Samarghitean, Crina, Sanchis-Juan, Alba, Sargur, Ravishankar B., Savic, Sinisa, Seneviratne, Suranjith L., Sewell, W.A. Carrock, Seyres, Denis, Shackley, Fiona, Shamardina, Olga, Simeoni, Ilenia, Simpson, Michael A., Smith, Kenneth G.C., Staines, Simon, Staples, Emily, Stark, Hannah, Stauss, Hans, Steele, Cathal L., Stephens, Jonathan, Stirrups, Kathleen E., Thaventhiran, James E., Thomas, David, Thomas, Moira J., Thomas, Patrick, Thrasher, Adrian J., Tilly, Tobias, Titterton, Catherine, Treadaway, Paul, Tuna, Salih, Turro, Ernest, Urniaz, Rafal, von Ziegenweidt, Julie, Walker, Neil, Watt, Christopher, Welch, Steven B., Whitehorn, Deborah, Willcocks, Lisa, Wood, Nicholas, Wood, Yvette, Workman, Sarita, Worth, Austen, Yates, Katherine, Yeatman, Nigel, Yong, Patrick F.K., Young, Timothy, Yu, Ping, Zlamalova, Eliska, Lorenzini, Tiziana, Fliegauf, Manfred, Klammer, Nils, Frede, Natalie, Proietti, Michele, Bulashevska, Alla, Camacho-Ordonez, Nadezhda, Varjosalo, Markku, Kinnunen, Matias, de Vries, Esther, van der Meer, Jos W.M., Ameratunga, Rohan, Roifman, Chaim M., Schejter, Yael D., Kobbe, Robin, Hautala, Timo, Atschekzei, Faranaz, Schmidt, Reinhold E., Schröder, Claudia, Stepensky, Polina, Shadur, Bella, Pedroza, Luis A., van der Flier, Michiel, Martínez-Gallo, Mónica, Gonzalez-Granado, Luis Ignacio, Allende, Luis M., Shcherbina, Anna, Kuzmenko, Natalia, Zakharova, Victoria, Neves, João Farela, Svec, Peter, Fischer, Ute, Ip, Winnie, Bartsch, Oliver, Barış, Safa, Klein, Christoph, Geha, Raif, Chou, Janet, Alosaimi, Mohammed, Weintraub, Lauren, Boztug, Kaan, Hirschmugl, Tatjana, Dos Santos Vilela, Maria Marluce, Holzinger, Dirk, Seidl, Maximilian, Lougaris, Vassilios, Plebani, Alessandro, Alsina, Laia, Piquer-Gibert, Monica, Deyà-Martínez, Angela, Slade, Charlotte A., Aghamohammadi, Asghar, Abolhassani, Hassan, Hammarström, Lennart, Kuismin, Outi, Helminen, Merja, Freeman, Alexandra F., Cook, Matthew, Bakhtiar, Shahrzad, Christiansen, Mette, Cunningham-Rundles, Charlotte, Patel, Niraj C., Rae, William, Niehues, Tim, Brauer, Nina, Syrjänen, Jaana, Seppänen, Mikko R.J., Tuijnenburg, Paul, Warnatz, Klaus, and Grimbacher, Bodo

Published
2020
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12. Prevalence and Clinical Features of Inflammatory Bowel Diseases Associated With Monogenic Variants, Identified by Whole-Exome Sequencing in 1000 Children at a Single Center

Author

Crowley, Eileen, Warner, Neil, Pan, Jie, Khalouei, Sam, Elkadri, Abdul, Fiedler, Karoline, Foong, Justin, Turinsky, Andrei L., Bronte-Tinkew, Dana, Zhang, Shiqi, Hu, Jamie, Tian, David, Li, Dalin, Horowitz, Julie, Siddiqui, Iram, Upton, Julia, Roifman, Chaim M., Church, Peter C., Wall, Donna A., Ramani, Arun K., Kotlarz, Daniel, Klein, Christoph, Uhlig, Holm, Snapper, Scott B., Gonzaga-Jauregui, Claudia, Paterson, Andrew D., McGovern, Dermot P.B., Brudno, Michael, Walters, Thomas D., Griffiths, Anne M., and Muise, Aleixo M.

Published
2020
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13. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency.

Author

Walter, Jolan E, Rosen, Lindsey B, Csomos, Krisztian, Rosenberg, Jacob M, Mathew, Divij, Keszei, Marton, Ujhazi, Boglarka, Chen, Karin, Lee, Yu Nee, Tirosh, Irit, Dobbs, Kerry, Al-Herz, Waleed, Cowan, Morton J, Puck, Jennifer, Bleesing, Jack J, Grimley, Michael S, Malech, Harry, De Ravin, Suk See, Gennery, Andrew R, Abraham, Roshini S, Joshi, Avni Y, Boyce, Thomas G, Butte, Manish J, Nadeau, Kari C, Balboni, Imelda, Sullivan, Kathleen E, Akhter, Javeed, Adeli, Mehdi, El-Feky, Reem A, El-Ghoneimy, Dalia H, Dbaibo, Ghassan, Wakim, Rima, Azzari, Chiara, Palma, Paolo, Cancrini, Caterina, Capuder, Kelly, Condino-Neto, Antonio, Costa-Carvalho, Beatriz T, Oliveira, Joao Bosco, Roifman, Chaim, Buchbinder, David, Kumanovics, Attila, Franco, Jose Luis, Niehues, Tim, Schuetz, Catharina, Kuijpers, Taco, Yee, Christina, Chou, Janet, Masaad, Michel J, Geha, Raif, Uzel, Gulbu, Gelman, Rebecca, Holland, Steven M, Recher, Mike, Utz, Paul J, Browne, Sarah K, and Notarangelo, Luigi D

Subjects
Animals, Mice, Inbred Strains, Humans, Mice, Virus Diseases, Granulomatous Disease, Chronic, Severe Combined Immunodeficiency, Autoimmune Diseases, Disease Models, Animal, DNA-Binding Proteins, Homeodomain Proteins, Nuclear Proteins, Autoantibodies, Autoantigens, Cytokines, Antibody Specificity, Adolescent, Adult, Child, Child, Preschool, Infant, Female, Male, Toll-Like Receptors, DEAD-box RNA Helicases, Young Adult, Antibodies, Neutralizing, Interferon-Induced Helicase, IFIH1, Autoimmune Disease, Genetics, Biotechnology, Infectious Diseases, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Medical and Health Sciences, Immunology
Abstract

Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-α or anti-IFN-ω antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1S723C/S723C mice, which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations.

Published
2015

17. A Unique Comprehensive Model to Screen Newborns for Severe Combined Immunodeficiency—An Ontario Single-Centre Experience Spanning 2013–2023.

Author

Al Ghamdi, Abdulrahman, Pachul, Jessica Willett, Al Shaqaq, Azhar, Fraser, Meghan, Watts-Dickens, Abby, Yang, Nicole, Vong, Linda, Kim, Vy H. D., Siu, Victoria Mok, Pham-Huy, Anne, Brager, Rae, Reid, Brenda, and Roifman, Chaim M.

Subjects
SEVERE combined immunodeficiency, T cell receptors, PRIMARY immunodeficiency diseases, NEWBORN screening, BIOMARKERS, T cells
Abstract

Background: Severe combined immunodeficiency (SCID) is a life-threatening genetic disorder caused by critical defects of the immune system. Almost all cases are lethal if not treated within the first two years of life. Early diagnosis and intervention are thus essential for improving patient outcomes. In 2013, Ontario became the first Canadian province to perform newborn screening (NBS) for SCID by T cell receptor excision circles (TRECs) analysis, a surrogate marker of thymic function and lymphocyte maturation. Methods: This retrospective study reports on nearly 10 years of NBS for SCID at a quaternary referral centre. Results: From August 2013 to April 2023, our centre's densely populated catchment area flagged 162 newborns with low TRECs levels, including 10 cases with SCID. Follow-up revealed other causes of low TRECs, including non-SCID T cell lymphopenia (secondary/reversible or idiopathic causes, and syndromic conditions) and prematurity. A small number of cases with normal repeat TRECs levels and/or T cell subsets were also flagged. Province-wide data from around this period revealed at least 24 diagnosed cases of SCID or Leaky SCID. Conclusions: This is the first report of NBS outcomes in a Canadian province describing the causative genetic defects, and the non-SCID causes of a positive NBS for SCID. [ABSTRACT FROM AUTHOR]

Published
2024
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21. A Phenotypic Approach for IUIS PID Classification and Diagnosis: Guidelines for Clinicians at the Bedside

Author

Bousfiha, Ahmed Aziz, Jeddane, Leïla, Ailal, Fatima, Al Herz, Waleed, Conley, Mary Ellen, Cunningham-Rundles, Charlotte, Etzioni, Amos, Fischer, Alain, Franco, Jose Luis, Geha, Raif S, Hammarström, Lennart, Nonoyama, Shigeaki, Ochs, Hans D, Roifman, Chaim M, Seger, Reinhard, Tang, Mimi LK, Puck, Jennifer M, Chapel, Helen, Notarangelo, Luigi D, and Casanova, Jean-Laurent

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Pediatric, Clinical Research, Algorithms, Diagnosis, Differential, Diagnostic Tests, Routine, Genotype, Humans, Immunologic Deficiency Syndromes, Immunologic Tests, Phenotype, Practice Guidelines as Topic, Primary immunodeficiency, classification, IUIS, diagnosis tool, Immunology
Abstract

The number of genetically defined Primary Immunodeficiency Diseases (PID) has increased exponentially, especially in the past decade. The biennial classification published by the IUIS PID expert committee is therefore quickly expanding, providing valuable information regarding the disease-causing genotypes, the immunological anomalies, and the associated clinical features of PIDs. These are grouped in eight, somewhat overlapping, categories of immune dysfunction. However, based on this immunological classification, the diagnosis of a specific PID from the clinician's observation of an individual clinical and/or immunological phenotype remains difficult, especially for non-PID specialists. The purpose of this work is to suggest a phenotypic classification that forms the basis for diagnostic trees, leading the physician to particular groups of PIDs, starting from clinical features and combining routine immunological investigations along the way. We present 8 colored diagnostic figures that correspond to the 8 PID groups in the IUIS Classification, including all the PIDs cited in the 2011 update of the IUIS classification and most of those reported since.

Published
2013

22. Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations

Author

Leiding, Jennifer W., Okada, Satoshi, Hagin, David, Abinun, Mario, Shcherbina, Anna, Balashov, Dmitry N., Kim, Vy H.D., Ovadia, Adi, Guthery, Stephen L., Pulsipher, Michael, Lilic, Desa, Devlin, Lisa A., Christie, Sharon, Depner, Mark, Fuchs, Sebastian, van Royen-Kerkhof, Annet, Lindemans, Caroline, Petrovic, Aleksandra, Sullivan, Kathleen E., Bunin, Nancy, Kilic, Sara Sebnem, Arpaci, Fikret, Calle-Martin, Oscar de la, Martinez-Martinez, Laura, Aldave, Juan Carlos, Kobayashi, Masao, Ohkawa, Teppei, Imai, Kohsuke, Iguchi, Akihiro, Roifman, Chaim M., Gennery, Andrew R., Slatter, Mary, Ochs, Hans D., Morio, Tomohiro, and Torgerson, Troy R.

Published
2018
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23. Primary Immunodeficiency Diseases: An Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency

Author

Al-Herz, Waleed, Bousfiha, Aziz, Casanova, Jean-Laurent, Chapel, Helen, Conley, Mary Ellen, Cunningham-Rundles, Charlotte, Etzioni, Amos, Fischer, Alain, Franco, Jose Luis, Geha, Raif S, Hammarström, Lennart, Nonoyama, Shigeaki, Notarangelo, Luigi Daniele, Ochs, Hans Dieter, Puck, Jennifer M, Roifman, Chaim M, Seger, Reinhard, and Tang, Mimi LK

Subjects
Biomedical and Clinical Sciences, Immunology, Rare Diseases, Good Health and Well Being, primary immunodeficiency diseases, Medical Microbiology, Biochemistry and cell biology, Genetics
Abstract

We report the updated classification of primary immunodeficiency diseases, compiled by the ad hoc Expert Committee of the International Union of Immunological Societies. As compared to the previous edition, more than 15 novel disease entities have been added in the updated version. For each disorders, the key clinical and laboratory features are provided. This updated classification is meant to help in the diagnostic approach to patients with these diseases.

Published
2011

24. Combined T- and B-Cell Immunodeficiencies

Author

Le Deist, Françoise, Moshous, Despina, Villa, Anna, Al-Herz, Waleed, Roifman, Chaim M., Fischer, Alain, Notarangelo, Luigi D., Rezaei, Nima, editor, Aghamohammadi, Asghar, editor, and Notarangelo, Luigi D., editor

Published
2017
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29. Variants in TRIM22 That Affect NOD2 Signaling Are Associated With Very-Early-Onset Inflammatory Bowel Disease

Author

Li, Qi, Lee, Cheng Hiang, Peters, Lauren A., Mastropaolo, Lucas A., Thoeni, Cornelia, Elkadri, Abdul, Schwerd, Tobias, Zhu, Jun, Zhang, Bin, Zhao, Yongzhong, Hao, Ke, Dinarzo, Antonio, Hoffman, Gabriel, Kidd, Brian A., Murchie, Ryan, Al Adham, Ziad, Guo, Conghui, Kotlarz, Daniel, Cutz, Ernest, Walters, Thomas D., Shouval, Dror S., Curran, Mark, Dobrin, Radu, Brodmerkel, Carrie, Snapper, Scott B., Klein, Christoph, Brumell, John H., Hu, Mingjing, Nanan, Ralph, Snanter-Nanan, Brigitte, Wong, Melanie, Le Deist, Francoise, Haddad, Elie, Roifman, Chaim M., Deslandres, Colette, Griffiths, Anne M., Gaskin, Kevin J., Uhlig, Holm H., Schadt, Eric E., and Muise, Aleixo M.

Published
2016
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31. List of Contributors

Author

Abraham, Roshini Sarah, primary, Albanesi, Cristina, additional, Alevizos, Ilias, additional, Anguita, Juan, additional, Antiochos, Brendan, additional, Aranow, Cynthia, additional, Atkinson, John P., additional, Austin, Howard A., additional, Babu, Subash, additional, Ballow, Mark C., additional, Balow, James E., additional, Belmont, John W., additional, Berek, Claudia, additional, Beukelman, Timothy, additional, Bhavsar, Tapan, additional, Bird, J. Andrew, additional, Blutt, Sarah E., additional, Boguniewicz, Mark, additional, Bonamichi-Santos, Rafael, additional, Boisson, Bertrand, additional, Borzova, Elena, additional, Boyaka, Prosper N., additional, Boyce, Joshua, additional, Browne, Sarah K., additional, Burks, Wesley, additional, Bustamante, Jacinta, additional, Calder, Virginia L., additional, Campbell, Matthew, additional, Cardones, Adela Rambi G., additional, Casanova, Jean-Laurent, additional, Castells, Mariana, additional, Cavacini, Lisa A., additional, Chan, Edwin S.L., additional, Chaplin, David D., additional, Chatham, W. Winn, additional, Chen, Edward S., additional, Chinen, Javier, additional, Christopher-Stine, Lisa, additional, Ciancanelli, Michael, additional, Cope, Andrew P., additional, Corry, David B., additional, Crea, Filippo, additional, Cron, Randy Q., additional, Cuellar-Rodriguez, Jennifer M., additional, Dalakas, Marinos C., additional, Dann, Sara M., additional, Diamond, Betty, additional, Du, Terry W., additional, Dupuis-Boisson, Stéphanie, additional, Eagar, Todd N., additional, Elmets, Craig A., additional, Erkan, Doruk, additional, Fanning, Laura, additional, Fikrig, Erol, additional, Flego, Davide, additional, Fleisher, Thomas A., additional, Fonacier, Luz, additional, Fontenot, Andrew P., additional, Freeman, Alexandra F., additional, Frew, Anthony J., additional, Fujihashi, Kohtaro, additional, Gadina, Massimo, additional, Gatt, Moshe E., additional, Gershwin, M. Eric, additional, Gillespie, Susan L., additional, Goronzy, Jörg J., additional, Goswami, Sangeeta, additional, Grattan, Clive E.H., additional, Greenspan, Neil S., additional, Gupta, Sarthak, additional, Gustafson, Claire E., additional, Hall, Russell P., additional, Hamilton, Robert G., additional, Harrington, Laurie E., additional, Harrison, Leonard C., additional, Hasni, Sarfaraz A., additional, Helbling, Arthur, additional, Hester, Joanna, additional, Holland, Steven M., additional, Hourcade, Dennis, additional, Huntington, Nicholas D., additional, Hwangpo, Tracy, additional, Imboden, John B., additional, Issa, Fadi, additional, Izraeli, Shai, additional, Jaffe, Elaine S., additional, Jalkanen, Sirpa, additional, Jones, Stacie, additional, Jouanguy, Emmanuelle, additional, Kabbani, Sarah, additional, Kaufmann, Stefan H.E., additional, Kheradmand, Farrah, additional, Kohn, Donald B., additional, Korngold, Robert, additional, Kovalszki, Anna, additional, Kuhns, Douglas B., additional, Kulkarni, Hrishikesh, additional, Kuo, Caroline Y., additional, Lahouti, Arash, additional, Landgren, C. Ola, additional, Laurence, Arian, additional, Lee, Joyce S., additional, Lemière, Catherine, additional, Leung, Donald Y.M., additional, Levinson, Arnold I., additional, Levy, Ofer, additional, Lewis, Dorothy E., additional, Lin, Phoebe, additional, Linkermann, Andreas, additional, Liuzzo, Giovanna, additional, Lockshin, Michael D., additional, Lord, Allison K., additional, Lozier, Jay N., additional, Luong, Amber, additional, Luqmani, Raashid, additional, Mackay, Meggan, additional, Maltzman, Jonathan S., additional, Mannon, Peter J., additional, Manns, Michael P., additional, Martin, James G., additional, Maynard, Craig L., additional, McCash, Samual, additional, McDonald, Douglas R., additional, Melby, Peter C., additional, Miller, Stephen D., additional, Mitchell, Anna L., additional, Mohd-Zaki, Amirah, additional, Mold, Carolyn, additional, Moller, David R., additional, Monos, Dimitrios S., additional, Mueller, Scott N., additional, Mulders-Manders, Catharina M., additional, Mulligan, Mark J., additional, Müller, Ulrich R., additional, Munshi, Pashna N., additional, Murata, Kazunori, additional, Murphy, Philip M., additional, Navasa, Nicolás, additional, Noel, Pierre, additional, Notarangelo, Luigi D., additional, Nussbaum, Robert L., additional, Nutman, Thomas B., additional, Nutt, Stephen L., additional, Oliveira, João B., additional, Ortel, Thomas L., additional, O'Shea, John J., additional, Pai, Sung-Yun, additional, Pandit, Lavannya, additional, Paul, Mary E., additional, Pearce, Simon H.S., additional, Pedicino, Daniela, additional, Peterson, Erik J., additional, Picard, Capucine, additional, Pittaluga, Stefania, additional, Priel, Debra Long, additional, Puck, Jennifer, additional, Puel, Anne, additional, Radbruch, Andreas, additional, Reece, Stephen T., additional, Reveille, John D., additional, Rich, Robert R., additional, Roifman, Chaim M., additional, Rosen, Antony, additional, Rosenbaum, James T., additional, Rosenzweig, Sergio D., additional, Rouse, Barry T., additional, Rowley, Scott D., additional, Sakaguchi, Shimon, additional, Salmi, Marko, additional, Sant, Andrea J., additional, Satola, Sarah W., additional, Saw, Valerie, additional, Schechter, Marcos C., additional, Schroeder, Harry W., additional, Segal, Benjamin M., additional, Selmi, Carlo, additional, Shankar, Sushma, additional, Sharma, Anu, additional, Sharma, Padmanee, additional, Shearer, William T., additional, Siegel, Richard M., additional, Simon, Anna, additional, Smith, Gideon P., additional, Stephens, David S., additional, Stephens, Robin, additional, Straumann, Alex, additional, Teos, Leyla Y., additional, Timares, Laura, additional, Tonnus, Wulf, additional, Torres, Raul M., additional, Uzel, Gülbü, additional, van der Hilst, Jeroen C.H., additional, van der Meer, Jos W.M., additional, Varga, John, additional, Vyas, Jatin M., additional, Waldman, Meryl, additional, Weiser, Peter, additional, Weller, Peter F., additional, Weyand, Cornelia M., additional, Wigley, Fredrick M., additional, Winchester, Robert J., additional, Wing, James B., additional, Wood, Kathryn J., additional, Wu, Xiaobo, additional, Xu, Hui, additional, Yee, Cassian, additional, and Zhang, Shen-Ying, additional

Published
2019
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34. NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity

Author

Sharfe, Nigel, primary, Dalal, Ilan, additional, Naghdi, Zahra, additional, Lefaudeux, Diane, additional, Vong, Linda, additional, Dadi, Harjit, additional, Navarro, Hector, additional, Tasher, Diana, additional, Ovadia, Adi, additional, Zangen, Tzili, additional, Ater, Dorit, additional, Ngan, Bo, additional, Hoffmann, Alexander, additional, and Roifman, Chaim M., additional

Published
2023
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42. Novel immunodeficiency caused by homozygous mutation in SLC19A1 encoding the reduced folate carrier

Author

Shiraishi, Akira, primary, Uygun, Vedat, additional, Sharfe, Nigel, additional, Beldar, Serap, additional, Sun, Mark George Ford, additional, Dadi, Harjit, additional, Vong, Linda, additional, Maxson, Michelle, additional, Karaca, Neslihan E., additional, Mevlitoğlu, Süleyman, additional, Grinstein, Sergio, additional, Artan, Reha, additional, Merico, Daniele, additional, and Roifman, Chaim M, additional

Published
2023
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43. Impaired thymic AIRE expression underlies autoantibodies against type I IFNs in humans with inborn errors of the alternative NF-kB pathway

Author

Voyer, Tom Le, primary, Gervais, Adrian, additional, Rosain, Jérémie, additional, Parent, Audrey, additional, Cederholm, Axel, additional, Rinchai, Darawan, additional, Bizien, Lucy, additional, Hancioglu, Gonca, additional, Philippot, Quentin, additional, Gueye, Mame Sokhna, additional, Luxman, Majistor Raj, additional, Renkilaraj, Maglorius, additional, Ogishi, Masato, additional, Soudée, Camille, additional, Migaud, Mélanie, additional, Rozenberg, Flore, additional, Momenilandi, Mana, additional, Riller, Quentin, additional, Imberti, Luisa, additional, Delmonte, Ottavia, additional, Müller, Gabriele, additional, Keller, Bärbel, additional, Orrego, Julio, additional, Gallego, William Alexander, additional, Rubin, Tamar, additional, Emiroglu, Melike, additional, Parvaneh, Nima, additional, Eriksson, Daniel, additional, Aranda-Guillen, Maribel, additional, Berrios, David I, additional, Vong, Linda, additional, Katelaris, Connie H, additional, Mustillo, Peter, additional, Rädler, Johannes, additional, Bohlen, Jonathan, additional, Celik, Jale Bengi, additional, Astudillo, Camila, additional, Winter, Sarah, additional, Guichard, Audrey, additional, Béziat, Vivien, additional, Bustamante, Jacinta, additional, Pan-Hammarström, Qiang, additional, Zhang, Yu, additional, Rosen, Lindsey B, additional, Holland, Steve M, additional, Kenney, Heather, additional, Boztuğ, Kaan, additional, Mahlaoui, Nizar, additional, Latour, Sylvain, additional, Abraham, Roshini, additional, Lougaris, Vassilios, additional, Hauck, Fabian, additional, Sediva, Anna, additional, Atschekzei, Faranaz, additional, Poli, M Cecilia, additional, Slatter, Mary A, additional, Palterer, Boaz, additional, Keller, Michael D, additional, Pinzon-Charry, Alberto, additional, Sullivan, Anna, additional, Droney, Luke, additional, Suan, Daniel, additional, Aladjidi, Nathalie, additional, Hie, Miguel, additional, Lazaro, Estibaliz, additional, Franco, Jose, additional, Keles, Sevgi, additional, Malphette, Marion, additional, Pasquet, Marlene, additional, Maccari, Maria Elena, additional, Meinhardt, Andrea, additional, Ikinciogullari, Aydan, additional, Shahrooei, Mohammad, additional, Celmeli, Fatih, additional, Frosk, Patrick, additional, Goodnow, Christopher C, additional, Gray, Paul E, additional, Belot, Alexandre, additional, Kuehn, Hye Sun, additional, Rosenzweig, Sergio D, additional, Licciardi, Francesco, additional, Servettaz, Amélie, additional, Barlogis, Vincent, additional, Guenno, Guillaume Le, additional, Herrmann, Vera-Maria, additional, Kuijpers, Taco, additional, Ducoux, Grégoire, additional, Sarrot-Reynauld, Françoise, additional, Schuetz, Catharina, additional, Cunningham-Rundles, Charlotte, additional, Rieux-Laucat, Frédéric, additional, Tangye, Stuart G, additional, Sobacchi, Cristina, additional, Doffinger, Rainer, additional, Warnatz, Klaus, additional, Grimbacher, Bodo, additional, Fieschi, Claire, additional, Berteloot, Laureline, additional, Bryant, Vanessa, additional, Assant, Sophie Trouillet, additional, Notarangelo, Luigi D, additional, Su, Helen, additional, Neven, Benedicte, additional, Abel, Laurent, additional, Zhang, Qian, additional, Boisson, Bertrand, additional, Cobat, Aurélie, additional, Jouanguy, Emmanuelle, additional, Kampe, Olle, additional, Bastard, Paul, additional, Roifman, Chaim, additional, Landegren, Nils, additional, Anderson, Mark S, additional, Casanova, Jean-Laurent, additional, and Puel, Anne, additional

Published
2023
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47. Combined T and B Cell Immunodeficiencies

Author

Le Deist, Françoise, Moshous, Despina, Howe, Steven J., Nahum, Amit, Kavadas, Fotini D., Lavine, Elana, Roifman, Chaim M., Fischer, Alain, Rezaei, Nima, editor, Aghamohammadi, Asghar, editor, and Notarangelo, Luigi D., editor

Published
2008
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49. Newborn screening for severe combined immunodeficiency: a primer for clinicians

Author

Biggs, Catherine M., Haddad, Elie, Issekutz, Thomas B., Roifman, Chaim M., and Turvey, Stuart E.

Subjects
Diagnosis, Care and treatment, Usage, Research, Health screening -- Usage, Severe combined immunodeficiency -- Diagnosis -- Care and treatment, Gene therapy -- Usage, Hematopoietic stem cell transplantation -- Usage, T cells -- Research
Abstract

Severe combined immunodeficiency is caused by genetic defects that profoundly impair development of the immune system. (1,2) The condition is fatal early in life if affected infants do not receive [...]

Published
2017
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