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1. Intestinal microbiome and metabolome signatures in patients with chronic granulomatous disease.

Author

Chandrasekaran, Prabha, Han, Yu, Zerbe, Christa, Heller, Theo, DeRavin, Suk, Kreuzberg, Samantha, Marciano, Beatriz, Siu, Yik, Jones, Drew, Abraham, Roshini, Stephens, Michael, Tsou, Amy, Snapper, Scott, Conlan, Sean, Subramanian, Poorani, Quinones, Mariam, Grou, Caroline, Calderon, Virginie, Deming, Clayton, Leiding, Jennifer, Arnold, Danielle, Logan, Brent, Griffith, Linda, Petrovic, Aleksandra, Mousallem, Talal, Kapoor, Neena, Heimall, Jennifer, Barnum, Jessie, Kapadia, Malika, Wright, Nicola, Rayes, Ahmad, Chandra, Sharat, Broglie, Larisa, Chellapandian, Deepak, Deal, Christin, Grunebaum, Eyal, Lim, Stephanie, Mallhi, Kanwaldeep, Marsh, Rebecca, Murguia-Favela, Luis, Parikh, Suhag, Touzot, Fabien, Cowan, Morton, Dvorak, Christopher, Haddad, Elie, Kohn, Donald, Notarangelo, Luigi, Pai, Sung-Yun, Puck, Jennifer, Pulsipher, Michael, Torgerson, Troy, Kang, Elizabeth, Malech, Harry, Segre, Julia, Bryant, Clare, Holland, Steven, and Falcone, Emilia

Subjects
CGD, Chronic granulomatous disease, IBD, NADPH oxidase, dysbiosis, inborn errors of immunity, inflammatory bowel disease, intestinal inflammation, metabolome, microbiome, primary immune deficiency, Humans, Granulomatous Disease, Chronic, Gastrointestinal Microbiome, NADPH Oxidases, Cross-Sectional Studies, Inflammatory Bowel Diseases
Abstract

BACKGROUND: Chronic granulomatous disease (CGD) is caused by defects in any 1 of the 6 subunits forming the nicotinamide adenine dinucleotide phosphate oxidase complex 2 (NOX2), leading to severely reduced or absent phagocyte-derived reactive oxygen species production. Almost 50% of patients with CGD have inflammatory bowel disease (CGD-IBD). While conventional IBD therapies can treat CGD-IBD, their benefits must be weighed against the risk of infection. Understanding the impact of NOX2 defects on the intestinal microbiota may lead to the identification of novel CGD-IBD treatments. OBJECTIVE: We sought to identify microbiome and metabolome signatures that can distinguish individuals with CGD and CGD-IBD. METHODS: We conducted a cross-sectional observational study of 79 patients with CGD, 8 pathogenic variant carriers, and 19 healthy controls followed at the National Institutes of Health Clinical Center. We profiled the intestinal microbiome (amplicon sequencing) and stool metabolome, and validated our findings in a second cohort of 36 patients with CGD recruited through the Primary Immune Deficiency Treatment Consortium. RESULTS: We identified distinct intestinal microbiome and metabolome profiles in patients with CGD compared to healthy individuals. We observed enrichment for Erysipelatoclostridium spp, Sellimonas spp, and Lachnoclostridium spp in CGD stool samples. Despite differences in bacterial alpha and beta diversity between the 2 cohorts, several taxa correlated significantly between both cohorts. We further demonstrated that patients with CGD-IBD have a distinct microbiome and metabolome profile compared to patients without CGD-IBD. CONCLUSION: Intestinal microbiome and metabolome signatures distinguished patients with CGD and CGD-IBD, and identified potential biomarkers and therapeutic targets.

Published
2023

2. Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome.

Author

Rensing-Ehl, Anne, Neven, Bénédicte, Hadjadj, Jérôme, Hambleton, Sophie, Ronan Leahy, Timothy, Meesilpavikai, Kornvalee, Cunningham-Rundles, Charlotte, Dutmer, Cullen, Sharapova, Svetlana, Taskinen, Mervi, Chua, Ignatius, Hague, Rosie, Klemann, Christian, Kostyuchenko, Larysa, Morio, Tomohiro, Thatayatikom, Akaluck, Ozen, Ahmet, Scherbina, Anna, Bauer, Cindy, Flanagan, Sarah, Gambineri, Eleonora, Giovannini-Chami, Lisa, Heimall, Jennifer, Sullivan, Kathleen, Allenspach, Eric, Romberg, Neil, Deane, Sean, Prince, Benjamin, Rose, Melissa, Bohnsack, John, Mousallem, Talal, Jesudas, Rohith, Santos Vilela, Maria, OSullivan, Michael, Pachlopnik Schmid, Jana, Průhová, Štěpánka, Klocperk, Adam, Rees, Matthew, Su, Helen, Bahna, Sami, Baris, Safa, Bartnikas, Lisa, Chang Berger, Amy, Briggs, Tracy, Brothers, Shannon, Bundy, Vanessa, Grunebaum, Eyal, Haapaniemi, Emma, Hämäläinen, Sari, Heiskanen, Kaarina, Heiskanen-Kosma, Tarja, Hoffman, Hal, Gonzalez-Granado, Luis, Guerrerio, Anthony, Kainulainen, Leena, Kumar, Ashish, Lawrence, Monica, Levin, Carina, Martelius, Timi, Neth, Olaf, Olbrich, Peter, Palma, Alejandro, Patel, Niraj, Pozos, Tamara, Preece, Kahn, Lugo Reyes, Saúl, Russell, Mark, Schejter, Yael, Seroogy, Christine, Sinclair, Jan, Skevofilax, Effie, Suan, Daniel, Suez, Daniel, Szabolcs, Paul, Velasco, Helena, Warnatz, Klaus, Walkovich, Kelly, Worth, Austen, Seppänen, Mikko, Torgerson, Troy, Sogkas, Georgios, Ehl, Stephan, Tangye, Stuart, Cooper, Megan, Milner, Joshua, Forbes Satter, Lisa, Leiding, Jennifer, Vogel, Tiphanie, Santarlas, Valentine, Mhaskar, Rahul, Smith, Madison, Carisey, Alexandre, Vargas-Hernández, Alexander, Silva-Carmona, Manuel, Chandrakasan, Shanmuganathan, Christiansen, Mette, Cole, Theresa, Cook, Matthew, Desai, Mukesh, and Fischer, Ute

Subjects
STAT3, autoimmunity, cytopenia, gain of function, immune dysregulation, immunodeficiency, lymphoproliferation, precision medicine, Child, Humans, Autoimmunity, Cohort Studies, Gain of Function Mutation, Immune System Diseases, Immunologic Deficiency Syndromes, Mutation, STAT3 Transcription Factor, Cell Proliferation, Lymphocytes
Abstract

BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

Published
2023

4. Allogeneic hematopoietic cell transplantation is effective for p47phox chronic granulomatous disease: A Primary Immune Deficiency Treatment Consortium study

Author

Grunebaum, Eyal, Arnold, Danielle E., Logan, Brent, Parikh, Suhag, Marsh, Rebecca A., Griffith, Linda M., Mallhi, Kanwaldeep, Chellapandian, Deepak, Lim, Stephanie Si, Deal, Christin L., Kapoor, Neena, Murguía-Favela, Luis, Falcone, Emilia Liana, Prasad, Vinod K., Touzot, Fabien, Bleesing, Jack J., Chandrakasan, Shanmuganathan, Heimall, Jennifer R., Bednarski, Jeffrey J., Broglie, Larisa A., Chong, Hey Jin, Kapadia, Malika, Prockop, Susan, Dávila Saldaña, Blachy J., Schaefer, Edo, Bauchat, Andrea L., Teira, Pierre, Chandra, Sharat, Parta, Mark, Cowan, Morton J., Dvorak, Christopher C., Haddad, Elie, Kohn, Donald B., Notarangelo, Luigi D., Pai, Sung-Yun, Puck, Jennifer M., Pulsipher, Michael A., Torgerson, Troy R., Malech, Harry L., Kang, Elizabeth M., and Leiding, Jennifer W.

Published
2024
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6. Genotype, oxidase status, and preceding infection or autoinflammation do not affect allogeneic HCT outcomes for CGD

Author

Leiding, Jennifer W., Arnold, Danielle E., Parikh, Suhag, Logan, Brent, Marsh, Rebecca A., Griffith, Linda M., Wu, Ruizhe, Kidd, Sharon, Mallhi, Kanwaldeep, Chellapandian, Deepak, Si Lim, Stephanie J., Grunebaum, Eyal, Falcone, E. Liana, Murguia-Favela, Luis, Grossman, Debbi, Prasad, Vinod K., Heimall, Jennifer R., Touzot, Fabien, Burroughs, Lauri M., Bleesing, Jack, Kapoor, Neena, Dara, Jasmeen, Williams, Olatundun, Kapadia, Malika, Oshrine, Benjamin R., Bednarski, Jeffrey J., Rayes, Ahmad, Chong, Hey, Cuvelier, Geoffrey D. E., Forbes Satter, Lisa R., Martinez, Caridad, Vander Lugt, Mark T., Yu, Lolie C., Chandrakasan, Shanmuganathan, Joshi, Avni, Prockop, Susan E., Dávila Saldaña, Blachy J., Aquino, Victor, Broglie, Larisa A., Ebens, Christen L., Madden, Lisa M., DeSantes, Kenneth, Milner, Jordan, Rangarajan, Hemalatha G., Shah, Ami J., Gillio, Alfred P., Knutsen, Alan P., Miller, Holly K., Moore, Theodore B., Graham, Pamela, Bauchat, Andrea, Bunin, Nancy J., Teira, Pierre, Petrovic, Aleksandra, Chandra, Sharat, Abdel-Azim, Hisham, Dorsey, Morna J., Birbrayer, Olga, Cowan, Morton J., Dvorak, Christopher C., Haddad, Elie, Kohn, Donald B., Notarangelo, Luigi D., Pai, Sung-Yun, Puck, Jennifer M., Pulsipher, Michael A., Torgerson, Troy R., Malech, Harry L., and Kang, Elizabeth M.

Published
2023
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9. Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients

Author

Geier, Christoph B., Ellison, Maryssa, Cruz, Rachel, Pawar, Sumit, Leiss-Piller, Alexander, Zmajkovicova, Katarina, McNulty, Shannon M, Yilmaz, Melis, Evans, 2nd, Martin Oman, Gordon, Sumai, Ujhazi, Boglarka, Wiest, Ivana, Abolhassani, Hassan, Aghamohammadi, Asghar, Barmettler, Sara, Bhar, Saleh, Bondarenko, Anastasia, Bolyard, Audrey Anna, Buchbinder, David, Cada, Michaela, Cavieres, Mirta, Connelly, James A., Dale, David C., Deordieva, Ekaterina, Dorsey, Morna J., Drysdale, Simon B., Ehl, Stephan, Elfeky, Reem, Fioredda, Francesca, Firkin, Frank, Förster-Waldl, Elizabeth, Geng, Bob, Goda, Vera, Gonzalez-Granado, Luis, Grunebaum, Eyal, Grzesk, Elzbieta, Henrickson, Sarah E., Hilfanova, Anna, Hiwatari, Mitsuteru, Imai, Chihaya, Ip, Winnie, Jyonouchi, Soma, Kanegane, Hirokazu, Kawahara, Yuta, Khojah, Amer M., Kim, Vy Hong-Diep, Kojić, Marina, Kołtan, Sylwia, Krivan, Gergely, Langguth, Daman, Lau, Yu-Lung, Leung, Daniel, Miano, Maurizio, Mersyanova, Irina, Mousallem, Talal, Muskat, Mica, Naoum, Flavio A., Noronha, Suzie A., Ouederni, Monia, Ozono, Shuichi, Richmond, G. Wendell, Sakovich, Inga, Salzer, Ulrich, Schuetz, Catharina, Seeborg, Filiz Odabasi, Sharapova, Svetlana O., Sockel, Katja, Volokha, Alla, von Bonin, Malte, Warnatz, Klaus, Wegehaupt, Oliver, Weinberg, Geoffrey A., Wong, Ke-Juin, Worth, Austen, Yu, Huang, Zharankova, Yulia, Zhao, Xiaodong, Devlin, Lisa, Badarau, Adriana, Csomos, Krisztian, Keszei, Marton, Pereira, Joao, Taveras, Arthur G, Beaussant-Cohen, Sarah L., Ong, Mei-Sing, Shcherbina, Anna, and Walter, Jolan E.

Published
2022
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10. Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome

Author

Aleshkevich, Svetlana, Allende, Luis M., Atkinson, T. Prescott, Atschekzei, Faranaz, Aydemir, Sezin, Aygunes, Utku, Barlogis, Vincent, Baumann, Ulrich, Belko, John, Bezrodnik, Liliana, Biebl, Ariane, Broderick, Lori, Bunin, Nancy J., Caldirola, Maria Soledad, Castelle, Martin, Celmeli, Fatih, Charbonnier, Louis-Marie, Chatila, Talal A., Chellapandian, Deepak, Cokugras, Haluk, Conlon, Niall, Cox, Fionnuala, Crickx, Etienne, Dalgic, Buket, ASH Dalm, Virgil, Danielian, Silvia, Dominguez-Pinilla, Nerea, Dujovny, Tal, Ebbo, Mikael, Eken, Ahmet, Esty, Brittany, Fabre, Alexandre, Fischer, Alain, Hannibal, Mark, Huppert, Laura, Ikeda, Marc D., Jolles, Stephen, Jolly, Kent W., Jones, Neil, Kanariou, Maria, Karakoc-Aydiner, Elif, Karamantziani, Theoni, Kelaidi, Charikleia, Keogan, Mary, Pac Kisaarslan, Ayşenur, Kiykim, Ayca, Klocperk, Adam, Kotsonis, Kosmas, Kuzmenko, Natalia, Leroy, Sylvie, Lianou, Dimitra, Longhurst, Hilary, Lorenz, Myriam Ricarda, Maffucci, Patrick, Manson, Ania, Marchal, Sarah, Malphettes, Marion, Marega, Lia Furlaneto, Mauracher, Andrea A., Meesilpavikai, Kornvalee, Miller, Holly, Mombourquette, Joy, Morgan, Noel G., Mukhina, Anna, Nathalie, Aladjidi, Nelken, Brigitte, Nolan, David, Norlin, Anna-Carin, Oleastro, Matias, Ozcan, Alper, Pasquet, Marlene, Pegler, José Roberto, Picard, Capucine, Polychronopoulou, Sophia, Quartier, Pierre, Quesada, Juan Francisco, Ramakers, Jan, Randall, Katrina L., Rao, V. Koneti, Remiker, Allison, Resin, Geraldine, Richmond, Peter, Rieux-Laucat, Frederic, Rodina, Yulia, Rohrlich, Pierre, Sachs, Johnathan, Sakovich, Inga, Santarlas, Christopher, Sari, Sinan, Sawicki, Gregory, Schauer, Uwe, Scheffler Mendoza, Selma C., Schvetz, Oksana, Schmidt, Reinhold Ernst, Schwarz, Klaus, Sediva, Anna, Sinclair, Kyle, Slatter, Mary, Sleasman, John, Stergiou, Katerina, Suratannon, Narissara, Tanita, Kay, Thompson, Grace, Travis, Stephen, Trojan, Timothy, Tsinti, Maria, Unal, Ekrem, Urdinez, Luciano, Vazquez-Gomez, Felisa, Villa, Mariana, Weinrich, Michael, Weiss, Mitchell J., Wright, Benjamin, Yilmaz, Ebru, Zachova, Radana, Zhang, Yu, Leiding, Jennifer W., Vogel, Tiphanie P., Santarlas, Valentine G.J., Mhaskar, Rahul, Smith, Madison R., Carisey, Alexandre, Vargas-Hernández, Alexander, Silva-Carmona, Manuel, Heeg, Maximilian, Rensing-Ehl, Anne, Neven, Bénédicte, Hadjadj, Jérôme, Hambleton, Sophie, Ronan Leahy, Timothy, Cunningham-Rundles, Charlotte, Dutmer, Cullen M., Sharapova, Svetlana O., Taskinen, Mervi, Chua, Ignatius, Hague, Rosie, Klemann, Christian, Kostyuchenko, Larysa, Morio, Tomohiro, Thatayatikom, Akaluck, Ozen, Ahmet, Scherbina, Anna, Bauer, Cindy S., Flanagan, Sarah E., Gambineri, Eleonora, Giovannini-Chami, Lisa, Heimall, Jennifer, Sullivan, Kathleen E., Allenspach, Eric, Romberg, Neil, Deane, Sean G., Prince, Benjamin T., Rose, Melissa J., Bohnsack, John, Mousallem, Talal, Jesudas, Rohith, Santos Vilela, Maria Marluce Dos, O’Sullivan, Michael, Pachlopnik Schmid, Jana, Průhová, Štěpánka, Rees, Matthew, Su, Helen, Bahna, Sami, Baris, Safa, Bartnikas, Lisa M., Chang Berger, Amy, Briggs, Tracy A., Brothers, Shannon, Bundy, Vanessa, Chan, Alice Y., Chandrakasan, Shanmuganathan, Christiansen, Mette, Cole, Theresa, Cook, Matthew C., Desai, Mukesh M., Fischer, Ute, Fulcher, David A., Gallo, Silvanna, Gauthier, Amelie, Gennery, Andrew R., Gonçalo Marques, José, Gottrand, Frédéric, Grimbacher, Bodo, Grunebaum, Eyal, Haapaniemi, Emma, Hämäläinen, Sari, Heiskanen, Kaarina, Heiskanen-Kosma, Tarja, Hoffman, Hal M., Gonzalez-Granado, Luis Ignacio, Guerrerio, Anthony L., Kainulainen, Leena, Kumar, Ashish, Lawrence, Monica G., Levin, Carina, Martelius, Timi, Neth, Olaf, Olbrich, Peter, Palma, Alejandro, Patel, Niraj C., Pozos, Tamara, Preece, Kahn, Lugo Reyes, Saúl Oswaldo, Russell, Mark A., Schejter, Yael, Seroogy, Christine, Sinclair, Jan, Skevofilax, Effie, Suan, Daniel, Suez, Daniel, Szabolcs, Paul, Velasco, Helena, Warnatz, Klaus, Walkovich, Kelly, Worth, Austen, Seppänen, Mikko R.J., Torgerson, Troy R., Sogkas, Georgios, Ehl, Stephan, Tangye, Stuart G., Cooper, Megan A., Milner, Joshua D., and Forbes Satter, Lisa R.

Published
2023
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11. Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation

Author

Narula, Mansi, Lakshmanan, Uma, Borna, Simon, Schulze, Janika J., Holmes, Tyson H., Harre, Nicholas, Kirkey, Matthew, Ramachandran, Akshaya, Tagi, Veronica Maria, Barzaghi, Federica, Grunebaum, Eyal, Upton, Julia E.M., Hong-Diep Kim, Vy, Wysocki, Christian, Dimitriades, Victoria R., Weinberg, Kenneth, Weinacht, Katja G., Gernez, Yael, Sathi, Bindu K., Schelotto, Magdalena, Johnson, Matthew, Olek, Sven, Sachsenmaier, Christoph, Roncarolo, Maria-Grazia, and Bacchetta, Rosa

Published
2023
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12. Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency.

Author

Kohn, Donald B, Hershfield, Michael S, Puck, Jennifer M, Aiuti, Alessandro, Blincoe, Annaliesse, Gaspar, H Bobby, Notarangelo, Luigi D, and Grunebaum, Eyal

Subjects
Animals, Humans, Agammaglobulinemia, Severe Combined Immunodeficiency, Adenosine Deaminase, Hematopoietic Stem Cell Transplantation, Consensus, Enzyme Replacement Therapy, Genetic Therapy, Adenosine deaminase deficiency, enzyme replacement therapy, gene therapy, hematopoietic stem cell transplantation, lentivirus, severe combined immune deficiency, Pediatric, Stem Cell Research, Transplantation, Clinical Research, Stem Cell Research - Nonembryonic - Human, Regenerative Medicine, Hematology, Stem Cell Research - Nonembryonic - Non-Human, 5.2 Cellular and gene therapies, Development of treatments and therapeutic interventions, Immunology, Allergy
Abstract

Inherited defects in adenosine deaminase (ADA) cause a subtype of severe combined immunodeficiency (SCID) known as severe combined immune deficiency caused by adenosine deaminase defects (ADA-SCID). Most affected infants can receive a diagnosis while still asymptomatic by using an SCID newborn screening test, allowing early initiation of therapy. We review the evidence currently available and propose a consensus management strategy. In addition to treatment of the immune deficiency seen in patients with ADA-SCID, patients should be followed for specific noninfectious respiratory, neurological, and biochemical complications associated with ADA deficiency. All patients should initially receive enzyme replacement therapy (ERT), followed by definitive treatment with either of 2 equal first-line options. If an HLA-matched sibling donor or HLA-matched family donor is available, allogeneic hematopoietic stem cell transplantation (HSCT) should be pursued. The excellent safety and efficacy observed in more than 100 patients with ADA-SCID who received gammaretrovirus- or lentivirus-mediated autologous hematopoietic stem cell gene therapy (HSC-GT) since 2000 now positions HSC-GT as an equal alternative. If HLA-matched sibling donor/HLA-matched family donor HSCT or HSC-GT are not available or have failed, ERT can be continued or reinstituted, and HSCT with alternative donors should be considered. The outcomes of novel HSCT, ERT, and HSC-GT strategies should be evaluated prospectively in "real-life" conditions to further inform these management guidelines.

Published
2019

14. Characterizing CD38 expression in terminally differentiated B cells using variable lymphocyte receptor B tetramers.

Author

Nair, Arundhati G., Leon-Ponte, Matilde, Kim, Vy HD, Sussman, Gordon, Ehrhardt, Götz R.A., and Grunebaum, Eyal

Subjects
MONONUCLEAR leukocytes, B cells, ANTIBODY formation, SEA lamprey, CD38 antigen
Abstract

Introduction: CD38 is an ectoenzyme receptor found on hematopoietic cells and its expression is used in the flow cytometric analysis of sub-populations of circulating B cells among peripheral blood mononuclear cells (PBMC) to aid in diagnosing patients with different antibody production defects (AbD). Monoclonal antibodies derived from the sea lamprey Variable Lymphocyte Receptor B (VLRB) are emerging as an alternative to conventional mammalian antibodies. We hypothesized that VLRB MM3 (V-CD38) which specifically recognizes CD38 in a manner correlating with its enzymatic activity could identify terminally differentiated B cells in human PBMC. Here we investigate the ability of V-CD38 as a tool to diagnose patients with diverse immune abnormalities including AbD. Methods: The expression of CD38 on CD3-CD19+CD27+ plasmablasts and CD3-CD19+IgMhiCD27- transitional B cells in PBMC was analyzed by flow cytometry using V-CD38 and compared with a commercial conventional antibody to CD38 (C-CD38). Results: A highly significant correlation (p<0.001, r=0.99) between the percentages of plasmablasts recognized by V-CD38 and C-CD38 was observed among 36 healthy controls (HC), 7 patients with AbD and 24 allergic individuals (AI). The use of V-CD38 enabled improved gating of the CD38 expressing cells (CD38+), aiding in the observation that patients with AbD had significantly lower (p=0.002) CD38+ plasmablasts (0.13%±0.13%) than HC (0.52%±0.57%). Only 61.3% of the transitional B cells detected by C-CD38 were also recognized by V-CD38 (r=0.95, p<0.001) among the 67 participants. AI had significantly reduced V-CD38 and C-CD38 transitional cells compared to HC (p=0.026 and p=0.012, respectively). Conclusions: V-CD38 is a novel reagent that can assess B cells in human PBMC. [ABSTRACT FROM AUTHOR]

Published
2024
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18. 3 Development of the Canadian Inborn Errors of Immunity National Registry (CIEINR)

Author

Kalashnikova, Tatiana, primary, Mattison, Taylor, additional, Alger, Alyssa, additional, Uppal, Mandi, additional, Grunebaum, Eyal, additional, Suresh, Sneha, additional, Ritchie, Bruce, additional, Cowan, Juthaporn, additional, Rubin, Tamar, additional, Murguia-Favela, Luis, additional, Grossman, Jennifer, additional, Wu, Caren, additional, Chapdelaine, Hugo, additional, Lee, Kevin, additional, Biggs, Catherine, additional, Brager, Rae, additional, Geerlinks, Ashley V., additional, Goulstone, Whitney, additional, Derfalvi, Beata, additional, and Wright, Nicola, additional

Published
2024
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19. 106 Outcomes Following Hematopoietic Cell Transplant for CD3δ Severe Combined Immune Deficiency: a PIDTC Natural History Study

Author

Kalashnikova, Tatiana, primary, Cuvelier, Geoff, additional, Logan, Brent, additional, Grunebaum, Eyal, additional, Guilcher, Gregory, additional, Lewis, Victor, additional, McAuley, Grace, additional, Marwaha, Ashish, additional, Murguia-Favela, Luis, additional, Prince, Bradley, additional, Romero, Zulema, additional, Rubin, Tamar, additional, Suresh, Sneha, additional, Buckley, Rebecca, additional, Dvorak, Christopher, additional, Satter, Lisa, additional, Aquino, Victor, additional, Bunin, Nancy, additional, Joshi, Avni, additional, Prokop, Susan, additional, Heimall, Jennifer, additional, Haddad, Elie, additional, Leiding, Jennifer, additional, Puck, Jennifer, additional, Burroughs, Lauri, additional, Griffith, Linda, additional, Notarangelo, Luigi, additional, Pulsipher, Michael, additional, Cowan, Morton, additional, Marsh, Rebecca, additional, Pai, Sung-Yun, additional, Torgerson, Troy, additional, Kohn, Donald B., additional, and Wright, Nicola, additional

Published
2024
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20. Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders

Author

Slack, James, Albert, Michael H, Balashov, Dmitry, Belohradsky, Bernd H, Bertaina, Alice, Bleesing, Jack, Booth, Claire, Buechner, Jochen, Buckley, Rebecca H, Ouachée-Chardin, Marie, Deripapa, Elena, Drabko, Katarzyna, Eapen, Mary, Feuchtinger, Tobias, Finocchi, Andrea, Gaspar, H Bobby, Ghosh, Sujal, Gillio, Alfred, Gonzalez-Granado, Luis I, Grunebaum, Eyal, Güngör, Tayfun, Heilmann, Carsten, Helminen, Merja, Higuchi, Kohei, Imai, Kohsuke, Kalwak, Krzysztof, Kanazawa, Nubuo, Karasu, Gülsün, Kucuk, Zeynep Y, Laberko, Alexandra, Lange, Andrzej, Mahlaoui, Nizar, Meisel, Roland, Moshous, D, Muramatsu, Hideki, Parikh, Suhag, Pasic, Srdjan, Schmid, Irene, Schuetz, Catharina, Schulz, Ansgar, Schultz, Kirk R, Shaw, Peter J, Slatter, Mary A, Sykora, Karl-Walter, Tamura, Shinobu, Taskinen, Mervi, Wawer, Angela, Wolska-Kuśnierz, Beata, Cowan, Morton J, Fischer, Alain, and Gennery, Andrew R

Subjects
Rare Diseases, Transplantation, Hematology, Genetics, Cancer, Pediatric, Adolescent, Alleles, Child, Child, Preschool, DNA Breaks, Double-Stranded, DNA Repair, DNA Repair-Deficiency Disorders, Female, Follow-Up Studies, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Humans, Infant, Kaplan-Meier Estimate, Male, Mutation, Prognosis, Treatment Outcome, Virus Diseases, Young Adult, Ataxia-telangiectasia, Cernunnos-XLF deficiency, DNA repair disorders, DNA ligase IV deficiency, hematopoietic stem cell transplantation, Nijmegen breakage syndrome, Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation and the European Society for Immunodeficiencies, Stem Cell Transplant for Immunodeficiencies in Europe, Center for International Blood and Marrow Transplant Research, Primary Immunodeficiency Treatment Consortium, Immunology, Allergy
Abstract

BackgroundRare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos-XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT).MethodsData from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced-intensity conditioning (RIC) if no alkylators and/or 150 mg/m2 fludarabine or less and 40 mg/kg cyclophosphamide or less were used.ResultsFifty-five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48 months (range, 1.5-552 months). Twenty-nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre-emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty-two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy-three of 77 patients with DNA ligase IV deficiency, Cernunnos-XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC (P = .006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty-one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 [46%] vs 12/21 [57%], P = .45). Median follow-up was 35 months (range, 2-168 months). No secondary malignancies were reported during 15 years of follow-up. Growth and developmental delay remained after HCT; immune-mediated complications resolved.ConclusionRIC HCT resolves DNA repair disorder-associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.

Published
2018

21. 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

23. Aberrant early hematopoietic progenitor formation marks the onset of hematopoietic defects in Shwachman–Diamond syndrome.

Author

Lagos‐Monzon, Alejandra, Ng, Stephanie, Luca, Alice M., Li, Hongbing, Sabanayagam, Mathura, Benicio, Mariana, Moshiri, Houtan, Armstrong, Richard, Tailor, Chetan, Kennedy, Marion, Grunebaum, Eyal, Keller, Gordon, and Dror, Yigal

Subjects
PLURIPOTENT stem cells, HEMATOPOIETIC stem cells, HUMAN stem cells, BONE marrow, CELL analysis
Abstract

Shwachman–Diamond syndrome (SDS) is an inherited bone marrow failure disorder that often presents at infancy. Progress has been made in revealing causal mutated genes (SBDS and others), ribosome defects, and hematopoietic aberrations in SDS. However, the mechanism underlying the hematopoietic failure remained unknown, and treatment options are limited. Herein, we investigated the onset of SDS embryonic hematopoietic impairments. We generated SDS and control human‐derived induced pluripotent stem cells (iPSCs). SDS iPSCs recapitulated the SDS hematological phenotype. Detailed stepwise evaluation of definitive hematopoiesis revealed defects that started at the early emerging hematopoietic progenitor (EHP) stage after mesoderm and hemogenic endothelium were normally induced. Hematopoietic potential of EHPs was markedly reduced, and the introduction of SBDS in SDS iPSCs improved colony formation. Transcriptome analysis revealed reduced expression of ribosome and oxidative phosphorylation‐related genes in undifferentiated and differentiated iPSCs. However, certain pathways (e.g., DNA replication) and genes (e.g., CHCHD2) were exclusively or more severely dysregulated in EHPs compared with earlier and later stages. To our knowledge, this study offers for the first time an insight into the embryonic onset of human hematopoietic defects in an inherited bone marrow failure syndrome and reveals cellular and molecular aberrations at critical stages of hematopoietic development toward EHPs. [ABSTRACT FROM AUTHOR]

Published
2024
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24. A comprehensive approach integrating epinephrine use into symptom-based scoring systems to improve severity grading of reactions at milk oral challenge

Author

Ke, Danbing, primary, Mule, Pasquale, additional, Cohen, Casey, additional, Lejtenyi, Duncan, additional, Beaudette, Liane, additional, McCusker, Christine, additional, Upton, Julia, additional, Chan, Edmond, additional, Clarke, Ann, additional, Begin, Philippe, additional, Grunebaum, Eyal, additional, Mazer, Bruce, additional, and Ben-Shoshan, Moshe, additional

Published
2024
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26. 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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28. High symptom burden in female X-linked chronic granulomatous disease carriers

Author

Miranda, Mary Ann, Tsalatsanis, Athanasios, Trotter, Jessica R., Arnold, Danielle E., Squire, Jacqueline D., Kidd, Sharon, Parikh, Suhag, Marsh, Rebecca A., Griffith, Linda M., Mallhi, Kanwaldeep, Chellapandian, Deepak, Lim, Stephanie Si, Grunebaum, Eyal, Sullivan, Kathleen E., Newburger, Peter E., Dinauer, Mary C., Cowan, Morton J., Dvorak, Christopher C., Haddad, Elie, Kohn, Donald B., Notarangelo, Luigi D., Pai, Sung-Yun, Puck, Jennifer M., Pulsipher, Michael A., Torgerson, Troy R., Malech, Harry L., Kang, Elizabeth M., Morton, Felicia B., and Leiding, Jennifer W.

Published
2024
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33. Gut Immunomodulation with Vedolizumab prior to Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients with Inflammatory Bowel Disease

Author

Chopra, Yogi, Acevedo, Karol, Muise, Aleixo, Frost, Karen, Schechter, Tal, Krueger, Joerg, Ali, Muhammad, Chiang, Kuang-Yueh, Kim, Vy Hong-Diep, Grunebaum, Eyal, and Wall, Donna

Abstract

•Vedolizumab prophylaxis in patients with inborn errors of immunity and inflammatory bowel disease undergoing allogeneic HSCT is well tolerated and safe.•All patients engrafted.•No patients developed acute gut graft-versus-host disease.•Early discontinuation within the first 6 months post-HSCT was feasible in all cases.

Published
2024
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35. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency

Author

Cicalese, Maria Pia, Ferrua, Francesca, Castagnaro, Laura, Pajno, Roberta, Barzaghi, Federica, Giannelli, Stefania, Dionisio, Francesca, Brigida, Immacolata, Bonopane, Marco, Casiraghi, Miriam, Tabucchi, Antonella, Carlucci, Filippo, Grunebaum, Eyal, Adeli, Mehdi, Bredius, Robbert G., Puck, Jennifer M., Stepensky, Polina, Tezcan, Ilhan, Rolfe, Katie, De Boever, Erika, Reinhardt, Rickey R., Appleby, Jonathan, Ciceri, Fabio, Roncarolo, Maria Grazia, and Aiuti, Alessandro

Published
2016
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36. List of Contributors

Author

Afek, Arnon, primary, Afeltra, Antonella, additional, Afflitto, Gabriele Gallo, additional, Alessandri, Cristiano, additional, Alivernini, Stefano, additional, Alunno, Alessia, additional, Amital, Howard, additional, Andreoli, Laura, additional, Antonelli, Alessandro, additional, Arisi, Mariachiara, additional, Artusi, Carolina, additional, Atzeni, Fabiola, additional, Ballanti, Eleonora, additional, Barbati, Cristiana, additional, Barilaro, Giuseppe, additional, Bartoloni, Elena, additional, Ben-Ami, Dana, additional, Bettencourt, Andreia, additional, Bizzaro, Nicola, additional, Blank, Miri, additional, Bogdanos, Dimitrios P., additional, Boleixa, Daniela, additional, Borba, Vânia Vieira, additional, Borgiani, Paola, additional, Bragazzi, Nicola Luigi, additional, Brzosko, Iwona, additional, Brzosko, Marek, additional, Calzavara-Pinton, Piergiacomo, additional, Campi, Irene, additional, Cantarini, Luca, additional, Carranza-Muleiro, Rosa A., additional, Carvalho, Cláudia, additional, Caso, Francesco, additional, Ceccarelli, Fulvia, additional, Cervera, Ricard, additional, Chapman, Joab, additional, Chen, Xian, additional, Chimenti, Maria Sole, additional, Ciccacci, Cinzia, additional, Cipriano, Enrica, additional, Cohen Tervaert, Jan Willem, additional, Colasanti, Tania, additional, Conigliaro, Paola, additional, Conti, Fabrizio, additional, Coplan, Louis, additional, Costa, Luisa, additional, Croci, Stefania, additional, Cruz-Domínguez, María del Pilar, additional, Cutolo, Maurizio, additional, Dahan, Shani, additional, Damoiseaux, Jan, additional, De Carolis, Caterina, additional, Del Puente, Antonio, additional, Domingues, Vinicius, additional, Dreyfus, David H., additional, Drori, Tali, additional, Ehrenfeld, Michael, additional, Espinosa, Gerard, additional, Farina, Antonella, additional, Farina, Giuseppina Alessandra, additional, Ferraccioli, Gianfranco, additional, Finucci, Annacarla, additional, Fioravanti, Antonella, additional, Fischer, Katarzyna, additional, Fonti, Giulia Lavinia, additional, Francesca, Barone, additional, Franceschini, Franco, additional, Freire de Carvalho, Jozélio, additional, Fujio, Keishi, additional, García-Collinot, Grettel, additional, Generali, Elena, additional, Gerardi, Maria Chiara, additional, Gerli, Roberto, additional, Gertel, Smadar, additional, Giat, Eitan, additional, Greco, Elisabetta, additional, Gremese, Elisa, additional, Grunebaum, Eyal, additional, Gualtierotti, Roberta, additional, Guarino, Maria Domenica, additional, Guzner-Gur, Hanan, additional, He, Shu-Gui, additional, Iannuccelli, Cristina, additional, Jara, Luis J., additional, Jeandel, Pierre-Yves, additional, Kivity, Dr Shaye, additional, Kotyla, Przemyslaw J., additional, Krosser, Alec, additional, Latini, Andrea, additional, Leon-Ponte, Matilde, additional, Lerner, Aaron, additional, Levy, Roger Abramino, additional, Lichtbroun, Benjamin, additional, Lucchetti, Ramona, additional, Lu, Qianjin, additional, Margiotta, Domenico P.E., additional, Marinho, António, additional, Martínez-Bencomo, Michel A., additional, Matthias, Torsten, additional, Medina, Gabriela, additional, Meroni, Pier Luigi, additional, Lichtbroun, Michael, additional, Moreira Balbi, Gustavo Guimarães, additional, Muratore, Francesco, additional, Navarini, Luca, additional, Novelli, Giuseppe, additional, Pacucci, Viviana Antonella, additional, Peluso, Rosario, additional, Pendolino, Monica, additional, Pérez, Dolores, additional, Perricone, Carlo, additional, Perricone, Roberto, additional, Persani, Luca, additional, Petricca, Luca, additional, Pipitone, Nicolò, additional, Ramires de Jesús, Guilherme, additional, Resende, Gustavo, additional, Rizenbah, Chen, additional, Rodríguez-Pintó, Ignasi, additional, Rose, Noel R., additional, Rosenthal, Eric, additional, Rossi, Mariateresa, additional, Sakkas, Lazaros I., additional, Salvarani, Carlo, additional, Sarzi-Puttini, Piercarlo, additional, Scarpa, Raffaele, additional, Segal, Yahel, additional, Segel, Michael J., additional, Selmi, Carlo, additional, Seluk, Dr Lior, additional, Serena, Colafrancesco, additional, Sharabi, Amir, additional, Sharif, Kassem, additional, Shoenfeld, Netta, additional, Shoenfeld, Yehuda, additional, Signorelli, Flavio, additional, Silva, Ana Martins, additional, Silva, Berta Martins, additional, Slomovich, Sharon, additional, Somech, Raz, additional, Soriano, Alessandra, additional, Szekanecz, Zoltán, additional, Tanaka, Yoshiya, additional, Tenti, Sara, additional, Tincani, Angela, additional, Tolusso, Barbara, additional, Torres-Ruiz, Jiram, additional, Toubi, Elias, additional, Tozzoli, Renato, additional, Triggianese, Paola, additional, Trombetta, Amelia Chiara, additional, Tsokos, George C., additional, Tsuchida, Yumi, additional, Vadasz, Zahava, additional, Valesini, Guido, additional, van Beers, Joyce, additional, van Paassen, Pieter, additional, Vannucchi, Guia Maria, additional, Vasconcelos, Carlos, additional, Venturini, Marina, additional, Vera-Lastra, Olga, additional, Versini, Mathilde, additional, Vomero, Marta, additional, Watad, Abdulla, additional, Wu, Haijing, additional, and Zeng, Yong, additional

Published
2019
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39. Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome

Author

Leiding, Jennifer W., Vogel, Tiphanie P., Santarlas, Valentine G. J., Mhaskar, Rahul, Smith, Madison R., Carisey, Alexandre, Vargas-Hernández, Alexander, Silva-Carmona, Manuel, Heeg, Maximilian, Rensing-Ehl, Anne, Neven, Bénédicte, Hadjadj, Jérôme, Hambleton, Sophie, Ronan Leahy, Timothy, Meesilpavikai, Kornvalee, Cunningham-Rundles, Charlotte, Dutmer, Cullen M., Sharapova, Svetlana O., Taskinen, Mervi, Chua, Ignatius, Hague, Rosie, Klemann, Christian, Kostyuchenko, Larysa, Morio, Tomohiro, Thatayatikom, Akaluck, Ozen, Ahmet, Scherbina, Anna, Bauer, Cindy S., Flanagan, Sarah E., Gambineri, Eleonora, Giovannini-Chami, Lisa, Heimall, Jennifer, Sullivan, Kathleen E., Allenspach, Eric, Romberg, Neil, Deane, Sean G., Prince, Benjamin T., Rose, Melissa J., Bohnsack, John, Mousallem, Talal, Jesudas, Rohith, Dos Santos Vilela, Maria Marluce, O'Sullivan, Michael, Pachlopnik Schmid, Jana, Průhová, Štěpánka, Klocperk, Adam, Rees, Matthew, Su, Helen, Bahna, Sami, Baris, Safa, Bartnikas, Lisa M., Chang Berger, Amy, Briggs, Tracy A., Brothers, Shannon, Bundy, Vanessa, Chan, Alice Y., Chandrakasan, Shanmuganathan, Christiansen, Mette, Cole, Theresa, Cook, Matthew C., Desai, Mukesh M., Fischer, Ute, Fulcher, David A., Gallo, Silvanna, Gauthier, Amelie, Gennery, Andrew R., Gonçalo Marques, José, Gottrand, Frédéric, Grimbacher, Bodo, Grunebaum, Eyal, Haapaniemi, Emma, Hämäläinen, Sari, Heiskanen, Kaarina, Heiskanen-Kosma, Tarja, Hoffman, Hal M., Gonzalez-Granado, Luis Ignacio, Guerrerio, Anthony L., Kainulainen, Leena, Kumar, Ashish, Lawrence, Monica G., Levin, Carina, Martelius, Timi, Neth, Olaf, Olbrich, Peter, Palma, Alejandro, Patel, Niraj C., Pozos, Tamara, Preece, Kahn, Lugo Reyes, Saúl Oswaldo, Russell, Mark A., Schejter, Yael, Seroogy, Christine, Sinclair, Jan, Skevofilax, Effie, Suan, Daniel, Suez, Daniel, Szabolcs, Paul, Velasco, Helena, Warnatz, Klaus, Walkovich, Kelly, Worth, Austen, STAT3 GOF Working Group members, Seppänen, Mikko R. J., Torgerson, Troy R., Sogkas, Georgios, Ehl, Stephan, Tangye, Stuart G., Cooper, Megan A., Milner, Joshua D., Forbes Satter, Lisa R., Leiding, Jennifer W., Vogel, Tiphanie P., Santarlas, Valentine G. J., Mhaskar, Rahul, Smith, Madison R., Carisey, Alexandre, Vargas-Hernández, Alexander, Silva-Carmona, Manuel, Heeg, Maximilian, Rensing-Ehl, Anne, Neven, Bénédicte, Hadjadj, Jérôme, Hambleton, Sophie, Ronan Leahy, Timothy, Meesilpavikai, Kornvalee, Cunningham-Rundles, Charlotte, Dutmer, Cullen M., Sharapova, Svetlana O., Taskinen, Mervi, Chua, Ignatius, Hague, Rosie, Klemann, Christian, Kostyuchenko, Larysa, Morio, Tomohiro, Thatayatikom, Akaluck, Ozen, Ahmet, Scherbina, Anna, Bauer, Cindy S., Flanagan, Sarah E., Gambineri, Eleonora, Giovannini-Chami, Lisa, Heimall, Jennifer, Sullivan, Kathleen E., Allenspach, Eric, Romberg, Neil, Deane, Sean G., Prince, Benjamin T., Rose, Melissa J., Bohnsack, John, Mousallem, Talal, Jesudas, Rohith, Dos Santos Vilela, Maria Marluce, O'Sullivan, Michael, Pachlopnik Schmid, Jana, Průhová, Štěpánka, Klocperk, Adam, Rees, Matthew, Su, Helen, Bahna, Sami, Baris, Safa, Bartnikas, Lisa M., Chang Berger, Amy, Briggs, Tracy A., Brothers, Shannon, Bundy, Vanessa, Chan, Alice Y., Chandrakasan, Shanmuganathan, Christiansen, Mette, Cole, Theresa, Cook, Matthew C., Desai, Mukesh M., Fischer, Ute, Fulcher, David A., Gallo, Silvanna, Gauthier, Amelie, Gennery, Andrew R., Gonçalo Marques, José, Gottrand, Frédéric, Grimbacher, Bodo, Grunebaum, Eyal, Haapaniemi, Emma, Hämäläinen, Sari, Heiskanen, Kaarina, Heiskanen-Kosma, Tarja, Hoffman, Hal M., Gonzalez-Granado, Luis Ignacio, Guerrerio, Anthony L., Kainulainen, Leena, Kumar, Ashish, Lawrence, Monica G., Levin, Carina, Martelius, Timi, Neth, Olaf, Olbrich, Peter, Palma, Alejandro, Patel, Niraj C., Pozos, Tamara, Preece, Kahn, Lugo Reyes, Saúl Oswaldo, Russell, Mark A., Schejter, Yael, Seroogy, Christine, Sinclair, Jan, Skevofilax, Effie, Suan, Daniel, Suez, Daniel, Szabolcs, Paul, Velasco, Helena, Warnatz, Klaus, Walkovich, Kelly, Worth, Austen, STAT3 GOF Working Group members, Seppänen, Mikko R. J., Torgerson, Troy R., Sogkas, Georgios, Ehl, Stephan, Tangye, Stuart G., Cooper, Megan A., Milner, Joshua D., and Forbes Satter, Lisa R.

Abstract

[Background] In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity., [Objective] This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants., [Methods] We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3., [Results] Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4−CD8−) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate., [Conclusion] : STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

Published
2023

40. Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome

Author

Leiding, Jennifer W., primary, Vogel, Tiphanie P., additional, Santarlas, Valentine G.J., additional, Mhaskar, Rahul, additional, Smith, Madison R., additional, Carisey, Alexandre, additional, Vargas-Hernández, Alexander, additional, Silva-Carmona, Manuel, additional, Heeg, Maximilian, additional, Rensing-Ehl, Anne, additional, Neven, Bénédicte, additional, Hadjadj, Jérôme, additional, Hambleton, Sophie, additional, Ronan Leahy, Timothy, additional, Meesilpavikai, Kornvalee, additional, Cunningham-Rundles, Charlotte, additional, Dutmer, Cullen M., additional, Sharapova, Svetlana O., additional, Taskinen, Mervi, additional, Chua, Ignatius, additional, Hague, Rosie, additional, Klemann, Christian, additional, Kostyuchenko, Larysa, additional, Morio, Tomohiro, additional, Thatayatikom, Akaluck, additional, Ozen, Ahmet, additional, Scherbina, Anna, additional, Bauer, Cindy S., additional, Flanagan, Sarah E., additional, Gambineri, Eleonora, additional, Giovannini-Chami, Lisa, additional, Heimall, Jennifer, additional, Sullivan, Kathleen E., additional, Allenspach, Eric, additional, Romberg, Neil, additional, Deane, Sean G., additional, Prince, Benjamin T., additional, Rose, Melissa J., additional, Bohnsack, John, additional, Mousallem, Talal, additional, Jesudas, Rohith, additional, Santos Vilela, Maria Marluce Dos, additional, O’Sullivan, Michael, additional, Pachlopnik Schmid, Jana, additional, Průhová, Štěpánka, additional, Klocperk, Adam, additional, Rees, Matthew, additional, Su, Helen, additional, Bahna, Sami, additional, Baris, Safa, additional, Bartnikas, Lisa M., additional, Chang Berger, Amy, additional, Briggs, Tracy A., additional, Brothers, Shannon, additional, Bundy, Vanessa, additional, Chan, Alice Y., additional, Chandrakasan, Shanmuganathan, additional, Christiansen, Mette, additional, Cole, Theresa, additional, Cook, Matthew C., additional, Desai, Mukesh M., additional, Fischer, Ute, additional, Fulcher, David A., additional, Gallo, Silvanna, additional, Gauthier, Amelie, additional, Gennery, Andrew R., additional, Gonçalo Marques, José, additional, Gottrand, Frédéric, additional, Grimbacher, Bodo, additional, Grunebaum, Eyal, additional, Haapaniemi, Emma, additional, Hämäläinen, Sari, additional, Heiskanen, Kaarina, additional, Heiskanen-Kosma, Tarja, additional, Hoffman, Hal M., additional, Gonzalez-Granado, Luis Ignacio, additional, Guerrerio, Anthony L., additional, Kainulainen, Leena, additional, Kumar, Ashish, additional, Lawrence, Monica G., additional, Levin, Carina, additional, Martelius, Timi, additional, Neth, Olaf, additional, Olbrich, Peter, additional, Palma, Alejandro, additional, Patel, Niraj C., additional, Pozos, Tamara, additional, Preece, Kahn, additional, Lugo Reyes, Saúl Oswaldo, additional, Russell, Mark A., additional, Schejter, Yael, additional, Seroogy, Christine, additional, Sinclair, Jan, additional, Skevofilax, Effie, additional, Suan, Daniel, additional, Suez, Daniel, additional, Szabolcs, Paul, additional, Velasco, Helena, additional, Warnatz, Klaus, additional, Walkovich, Kelly, additional, Worth, Austen, additional, Seppänen, Mikko R.J., additional, Torgerson, Troy R., additional, Sogkas, Georgios, additional, Ehl, Stephan, additional, Tangye, Stuart G., additional, Cooper, Megan A., additional, Milner, Joshua D., additional, Forbes Satter, Lisa R., additional, Aleshkevich, Svetlana, additional, Allende, Luis M., additional, Atkinson, T. Prescott, additional, Atschekzei, Faranaz, additional, Aydemir, Sezin, additional, Aygunes, Utku, additional, Barlogis, Vincent, additional, Baumann, Ulrich, additional, Belko, John, additional, Bezrodnik, Liliana, additional, Biebl, Ariane, additional, Broderick, Lori, additional, Bunin, Nancy J., additional, Caldirola, Maria Soledad, additional, Castelle, Martin, additional, Celmeli, Fatih, additional, Charbonnier, Louis-Marie, additional, Chatila, Talal A., additional, Chellapandian, Deepak, additional, Cokugras, Haluk, additional, Conlon, Niall, additional, Cox, Fionnuala, additional, Crickx, Etienne, additional, Dalgic, Buket, additional, ASH Dalm, Virgil, additional, Danielian, Silvia, additional, Dominguez-Pinilla, Nerea, additional, Dujovny, Tal, additional, Ebbo, Mikael, additional, Eken, Ahmet, additional, Esty, Brittany, additional, Fabre, Alexandre, additional, Fischer, Alain, additional, Hannibal, Mark, additional, Huppert, Laura, additional, Ikeda, Marc D., additional, Jolles, Stephen, additional, Jolly, Kent W., additional, Jones, Neil, additional, Kanariou, Maria, additional, Karakoc-Aydiner, Elif, additional, Karamantziani, Theoni, additional, Kelaidi, Charikleia, additional, Keogan, Mary, additional, Pac Kisaarslan, Ayşenur, additional, Kiykim, Ayca, additional, Kotsonis, Kosmas, additional, Kuzmenko, Natalia, additional, Leroy, Sylvie, additional, Lianou, Dimitra, additional, Longhurst, Hilary, additional, Lorenz, Myriam Ricarda, additional, Maffucci, Patrick, additional, Manson, Ania, additional, Marchal, Sarah, additional, Malphettes, Marion, additional, Marega, Lia Furlaneto, additional, Mauracher, Andrea A., additional, Miller, Holly, additional, Mombourquette, Joy, additional, Morgan, Noel G., additional, Mukhina, Anna, additional, Nathalie, Aladjidi, additional, Nelken, Brigitte, additional, Nolan, David, additional, Norlin, Anna-Carin, additional, Oleastro, Matias, additional, Ozcan, Alper, additional, Pasquet, Marlene, additional, Pegler, José Roberto, additional, Picard, Capucine, additional, Polychronopoulou, Sophia, additional, Quartier, Pierre, additional, Quesada, Juan Francisco, additional, Ramakers, Jan, additional, Randall, Katrina L., additional, Rao, V. Koneti, additional, Remiker, Allison, additional, Resin, Geraldine, additional, Richmond, Peter, additional, Rieux-Laucat, Frederic, additional, Rodina, Yulia, additional, Rohrlich, Pierre, additional, Sachs, Johnathan, additional, Sakovich, Inga, additional, Santarlas, Christopher, additional, Sari, Sinan, additional, Sawicki, Gregory, additional, Schauer, Uwe, additional, Scheffler Mendoza, Selma C., additional, Schvetz, Oksana, additional, Schmidt, Reinhold Ernst, additional, Schwarz, Klaus, additional, Sediva, Anna, additional, Sinclair, Kyle, additional, Slatter, Mary, additional, Sleasman, John, additional, Stergiou, Katerina, additional, Suratannon, Narissara, additional, Tanita, Kay, additional, Thompson, Grace, additional, Travis, Stephen, additional, Trojan, Timothy, additional, Tsinti, Maria, additional, Unal, Ekrem, additional, Urdinez, Luciano, additional, Vazquez-Gomez, Felisa, additional, Villa, Mariana, additional, Weinrich, Michael, additional, Weiss, Mitchell J., additional, Wright, Benjamin, additional, Yilmaz, Ebru, additional, Zachova, Radana, additional, and Zhang, Yu, additional

Published
2023
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41. Risk of Allergic Reactions in Children Who Attained Peanut Oral Immunotherapy (OIT) Maintenance

Author

Colli, Luca Delli, primary, Lawson, Benjamin, additional, Gabrielli, Sofianne, additional, Mazer, Bruce, additional, Ke, Danbing, additional, Zhang, Lydia, additional, Lejtenyi, Duncan, additional, Lucchesi, Chiara, additional, Beaudette, Liane, additional, Upton, Julia, additional, Grunebaum, Eyal, additional, Piccirillo, Ciro, additional, Chan, Edmond, additional, Clarke, Ann, additional, Zhang, Xun, additional, McCusker, Christine, additional, and Ben-Shoshan, Moshe, additional

Published
2023
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42. How low can we go: preliminary efficacy of very low dose peanut oral immunotherapy

Author

Upton, Julia, primary, Lejteyni, Duncan, additional, Ke, Danbing, additional, Berenjy, Alireza, additional, Beaudette, Liane, additional, McCusker, Christine, additional, Yin, Xiaojun, additional, Li, Carmen, additional, Duan, Lucy, additional, Marzouk, Shireen, additional, Grunebaum, Eyal, additional, Eiwegger, Thomas, additional, and Ben-Shoshan, Moshe, additional

Published
2023
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44. Allogenic Hematopoietic Cell Transplantations Are Effective in Patients with p47phox Chronic Granulomatous Disease: A Primary Immune Deficiency Treatment Consortium Study

Author

Grunebaum, Eyal, primary, Arnold, Danielle E., additional, Logan, Brent, additional, Parikh, Suhag, additional, Marsh, Rebecca A., additional, Griffith, Linda M., additional, Mallhi, Kanwaldeep, additional, Chellapandian, Deepak, additional, Lim, Stephanie Si, additional, Deal, Christin L., additional, Murguía-Favela, Luis, additional, Mousallem, Talal I., additional, Prasad, Prof. Vinod K., additional, Teira, Pierre, additional, Touzot, Fabien, additional, Bunin, Nancy J., additional, Heimall, Jennifer R., additional, Burroughs, Lauri M., additional, Kapadia, Malika, additional, Prockop, Susan, additional, Chandra, Sharat, additional, Chandrakasan, Shanmuganathan, additional, Chaudhury, Sonali, additional, Broglie, Larisa, additional, O’Reilly, Richard J., additional, Dávila Saldaña, Blachy J., additional, Schaefer, Edo, additional, Chong, Hey, additional, Bednarski, Jeffrey J., additional, Rayes, Ahmad, additional, DeSantes, Kenneth, additional, Kohn, Donald B., additional, Notarangelo, Luigi D., additional, Pai, Sung-Yun, additional, Puck, Jennifer, additional, Torgerson, Troy, additional, Cowan, Morton J., additional, Dvorak, Christopher C., additional, Satter, Lisa Forbes, additional, Haddad, Elie, additional, Pulsipher, Michael, additional, Malech, Harry L., additional, Kang, Elizabeth M., additional, and Leiding, Jennifer W., additional

Published
2023
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47. 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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