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1. COVID-19 Vaccination in Patients with Inborn Errors of Immunity Reduces Hospitalization and Critical Care Needs Related to COVID-19: a USIDNET Report.

Author

McDonnell, John, McDonnell, John, Cousins, Kimberley, Younger, M, Lane, Adam, Abolhassani, Hassan, Abraham, Roshini, Al-Tamemi, Salem, Aldave-Becerra, Juan, Al-Faris, Eman, Alfaro-Murillo, Alberto, AlKhater, Suzan, Alsaati, Nouf, Doss, Alexa, Anderson, Melissa, Angarola, Ernestina, Ariue, Barbara, Arnold, Danielle, Assaad, Amal, Aytekin, Caner, Bank, Meaghan, Bergerson, Jenna, Bleesing, Jack, Boesing, John, Bouso, Carolina, Brodszki, Nicholas, Cabanillas, Diana, Cady, Carol, Callahan, Meghan, Caorsi, Roberta, Carbone, Javier, Carrabba, Maria, Castagnoli, Riccardo, Catanzaro, Jason, Chan, Samantha, Chandra, Sharat, Chapdelaine, Hugo, Chavoshzadeh, Zahra, Chong, Hey, Connors, Lori, Consonni, Filippo, Correa-Jimenez, Oscar, Cunningham-Rundles, Charlotte, DAstous-Gauthier, Katherine, Delmonte, Ottavia, Demirdag, Yesim, Deshpande, Deepti, Diaz-Cabrera, Natalie, Dimitriades, Victoria, El-Owaidy, Rasha, ElGhazali, Gehad, Al-Hammadi, Suleiman, Fabio, Giovanna, Faure, Astrid, Feng, Jin, Fernandez, James, Fill, Lauren, Franco, Guacira, Frenck, Robert, Fuleihan, Ramsay, Giardino, Giuliana, Galant-Swafford, Jessica, Gambineri, Eleonora, Garabedian, Elizabeth, Geerlinks, Ashley, Goudouris, Ekaterini, Grecco, Octavio, Pan-Hammarström, Qiang, Khani, Hedieh, Hammarström, Lennart, Hartog, Nicholas, Heimall, Jennifer, Hernandez-Molina, Gabriela, Horner, Caroline, Hostoffer, Robert, Hristova, Nataliya, Hsiao, Kuang-Chih, Ivankovich-Escoto, Gabriela, Jaber, Faris, Jalil, Maaz, Jamee, Mahnaz, Jean, Tiffany, Jeong, Stephanie, Jhaveri, Devi, Jordan, Michael, Joshi, Avni, Kalkat, Amanpreet, Kanarek, Henry, Kellner, Erinn, Khojah, Amer, Khoury, Ruby, Kokron, Cristina, Kumar, Ashish, Lecerf, Kelsey, Lehman, Heather, Leiding, Jennifer, Lesmana, Harry, Lim, Xin, Lopes, Joao, López, Ana, Tarquini, Lucia, McDonnell, John, McDonnell, John, Cousins, Kimberley, Younger, M, Lane, Adam, Abolhassani, Hassan, Abraham, Roshini, Al-Tamemi, Salem, Aldave-Becerra, Juan, Al-Faris, Eman, Alfaro-Murillo, Alberto, AlKhater, Suzan, Alsaati, Nouf, Doss, Alexa, Anderson, Melissa, Angarola, Ernestina, Ariue, Barbara, Arnold, Danielle, Assaad, Amal, Aytekin, Caner, Bank, Meaghan, Bergerson, Jenna, Bleesing, Jack, Boesing, John, Bouso, Carolina, Brodszki, Nicholas, Cabanillas, Diana, Cady, Carol, Callahan, Meghan, Caorsi, Roberta, Carbone, Javier, Carrabba, Maria, Castagnoli, Riccardo, Catanzaro, Jason, Chan, Samantha, Chandra, Sharat, Chapdelaine, Hugo, Chavoshzadeh, Zahra, Chong, Hey, Connors, Lori, Consonni, Filippo, Correa-Jimenez, Oscar, Cunningham-Rundles, Charlotte, DAstous-Gauthier, Katherine, Delmonte, Ottavia, Demirdag, Yesim, Deshpande, Deepti, Diaz-Cabrera, Natalie, Dimitriades, Victoria, El-Owaidy, Rasha, ElGhazali, Gehad, Al-Hammadi, Suleiman, Fabio, Giovanna, Faure, Astrid, Feng, Jin, Fernandez, James, Fill, Lauren, Franco, Guacira, Frenck, Robert, Fuleihan, Ramsay, Giardino, Giuliana, Galant-Swafford, Jessica, Gambineri, Eleonora, Garabedian, Elizabeth, Geerlinks, Ashley, Goudouris, Ekaterini, Grecco, Octavio, Pan-Hammarström, Qiang, Khani, Hedieh, Hammarström, Lennart, Hartog, Nicholas, Heimall, Jennifer, Hernandez-Molina, Gabriela, Horner, Caroline, Hostoffer, Robert, Hristova, Nataliya, Hsiao, Kuang-Chih, Ivankovich-Escoto, Gabriela, Jaber, Faris, Jalil, Maaz, Jamee, Mahnaz, Jean, Tiffany, Jeong, Stephanie, Jhaveri, Devi, Jordan, Michael, Joshi, Avni, Kalkat, Amanpreet, Kanarek, Henry, Kellner, Erinn, Khojah, Amer, Khoury, Ruby, Kokron, Cristina, Kumar, Ashish, Lecerf, Kelsey, Lehman, Heather, Leiding, Jennifer, Lesmana, Harry, Lim, Xin, Lopes, Joao, López, Ana, and Tarquini, Lucia

Abstract

BACKGROUND: The CDC and ACIP recommend COVID-19 vaccination for patients with inborn errors of immunity (IEI). Not much is known about vaccine safety in IEI, and whether vaccination attenuates infection severity in IEI. OBJECTIVE: To estimate COVID-19 vaccination safety and examine effect on outcomes in patients with IEI. METHODS: We built a secure registry database in conjunction with the US Immunodeficiency Network to examine vaccination frequency and indicators of safety and effectiveness in IEI patients. The registry opened on January 1, 2022, and closed on August 19, 2022. RESULTS: Physicians entered data on 1245 patients from 24 countries. The most common diagnoses were antibody deficiencies (63.7%). At least one COVID-19 vaccine was administered to 806 patients (64.7%), and 216 patients received vaccination prior to the development of COVID-19. The most common vaccines administered were mRNA-based (84.0%). Seventeen patients were reported to seek outpatient clinic or emergency room care for a vaccine-related complication, and one patient was hospitalized for symptomatic anemia. Eight hundred twenty-three patients (66.1%) experienced COVID-19 infection. Of these, 156 patients required hospitalization (19.0%), 47 required ICU care (5.7%), and 28 died (3.4%). Rates of hospitalization (9.3% versus 24.4%, p < 0.001), ICU admission (2.8% versus 7.6%, p = 0.013), and death (2.3% versus 4.3%, p = 0.202) in patients who had COVID-19 were lower in patients who received vaccination prior to infection. In adjusted logistic regression analysis, not having at least one COVID-19 vaccine significantly increased the odds of hospitalization and ICU admission. CONCLUSION: Vaccination for COVID-19 in the IEI population appears safe and attenuates COVID-19 severity.

Published
2024

2. Updated guidance regarding the risk of allergic reactions to COVID-19 vaccines and recommended evaluation and management:A GRADE assessment and international consensus approach

Author

Greenhawt, Matthew, Dribin, Timothy E., Abrams, Elissa M., Shaker, Marcus, Chu, Derek K., Golden, David B.K., Akin, Cem, Anagnostou, Akterini, ALMuhizi, Faisal, Alqurashi, Waleed, Arkwright, Peter, Baldwin, James L., Banerji, Aleena, Bégin, Philippe, Ben-Shoshan, Moshe, Bernstein, Jonathan, Bingemann, Theresa A., Bindslev-Jensen, Carsten, Blumenthal, Kim, Byrne, Aideen, Cahill, Julia, Cameron, Scott, Campbell, Dianne, Campbell, Ronna, Cavender, Michael, Chan, Edmond S., Chinthrajah, Sharon, Comberiati, Pasquale, Eastman, Jacqueline J., Ellis, Anne K., Fleischer, David M., Fox, Adam, Frischmeyer-Guerrerio, Pamela A., Gagnon, Remi, Garvey, Lene H., Grayson, Mitchell H., Isabwe, Ghislaine Annie Clarisse, Hartog, Nicholas, Hendron, David, Horner, Caroline C., Hourihane, Johnathan O.B., Iglesia, Edward, Kan, Manstein, Kaplan, Blanka, Katelaris, Constance H., Kim, Harold, Kelso, John M., Khan, David A., Lang, David, Ledford, Dennis, Levin, Michael, Lieberman, Jay A., Loh, Richard, Mack, Douglas P., Mazer, Bruce, Mody, Ketan, Mosnaim, Gisele, Munblit, Daniel, Mustafa, S. Shahzad, Nanda, Anil, Nathan, Richard, Oppenheimer, John, Otani, Iris M., Park, Miguel, Pawankar, Ruby, Perrett, Kirsten P., Peter, Jonny, Phillips, Elizabeth J., Picard, Matthieu, Pitlick, Mitchell, Ramsey, Allison, Rasmussen, Trine Holm, Rathkopf, Melinda M., Reddy, Hari, Robertson, Kara, Rodriguez del Rio, Pablo, Sample, Stephen, Sheshadri, Ajay, Sheik, Javed, Sindher, Sayantani B., Spergel, Jonathan M., Stone, Cosby A., Stukus, David, Tang, Mimi L.K., Tracy, James M., Turner, Paul J., Vander Leek, Timothy K., Wallace, Dana V., Wang, Julie, Wasserman, Susan, Weldon, David, Wolfson, Anna R., Worm, Margitta, Yacoub, Mona Rita, Greenhawt, Matthew, Dribin, Timothy E., Abrams, Elissa M., Shaker, Marcus, Chu, Derek K., Golden, David B.K., Akin, Cem, Anagnostou, Akterini, ALMuhizi, Faisal, Alqurashi, Waleed, Arkwright, Peter, Baldwin, James L., Banerji, Aleena, Bégin, Philippe, Ben-Shoshan, Moshe, Bernstein, Jonathan, Bingemann, Theresa A., Bindslev-Jensen, Carsten, Blumenthal, Kim, Byrne, Aideen, Cahill, Julia, Cameron, Scott, Campbell, Dianne, Campbell, Ronna, Cavender, Michael, Chan, Edmond S., Chinthrajah, Sharon, Comberiati, Pasquale, Eastman, Jacqueline J., Ellis, Anne K., Fleischer, David M., Fox, Adam, Frischmeyer-Guerrerio, Pamela A., Gagnon, Remi, Garvey, Lene H., Grayson, Mitchell H., Isabwe, Ghislaine Annie Clarisse, Hartog, Nicholas, Hendron, David, Horner, Caroline C., Hourihane, Johnathan O.B., Iglesia, Edward, Kan, Manstein, Kaplan, Blanka, Katelaris, Constance H., Kim, Harold, Kelso, John M., Khan, David A., Lang, David, Ledford, Dennis, Levin, Michael, Lieberman, Jay A., Loh, Richard, Mack, Douglas P., Mazer, Bruce, Mody, Ketan, Mosnaim, Gisele, Munblit, Daniel, Mustafa, S. Shahzad, Nanda, Anil, Nathan, Richard, Oppenheimer, John, Otani, Iris M., Park, Miguel, Pawankar, Ruby, Perrett, Kirsten P., Peter, Jonny, Phillips, Elizabeth J., Picard, Matthieu, Pitlick, Mitchell, Ramsey, Allison, Rasmussen, Trine Holm, Rathkopf, Melinda M., Reddy, Hari, Robertson, Kara, Rodriguez del Rio, Pablo, Sample, Stephen, Sheshadri, Ajay, Sheik, Javed, Sindher, Sayantani B., Spergel, Jonathan M., Stone, Cosby A., Stukus, David, Tang, Mimi L.K., Tracy, James M., Turner, Paul J., Vander Leek, Timothy K., Wallace, Dana V., Wang, Julie, Wasserman, Susan, Weldon, David, Wolfson, Anna R., Worm, Margitta, and Yacoub, Mona Rita

Abstract

This guidance updates 2021 GRADE (Grading of Recommendations Assessment, Development and Evaluation) recommendations regarding immediate allergic reactions following coronavirus disease 2019 (COVID-19) vaccines and addresses revaccinating individuals with first-dose allergic reactions and allergy testing to determine revaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 revaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommendations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the United Kingdom, and the United States formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy and revaccination after a prior immediate allergic reaction. We suggest against >15-minute postvaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest revaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise in a properly equipped setting. We suggest against premedication, split-dosing, or special precautions because of a comorbid allergic history.

Published
2023

3. Review of Treatment for Adenosine Deaminase Deficiency (ADA) Severe Combined Immunodeficiency (SCID)

Author

Secord,Elizabeth, Hartog,Nicholas L, Secord,Elizabeth, and Hartog,Nicholas L

Abstract

Elizabeth Secord,1 Nicholas L Hartog2 1Pediatrics, Division of Allergy and Immunology, Wayne State University School of Medicine, Detroit, MI, USA; 2Pediatrics, Division of Allergy and Immunology, Michigan State University College of Human Medicine, Helen DeVos Children’s Hospital, Grand Rapids, MI, USACorrespondence: Elizabeth Secord, Wayne State University School of Medicine, Wayne Pediatrics, 400 Mack Avenue, Detroit, MI, 48201, USA, Tel +1-313-448-9600, Fax +1-313-448-9978, Email esecord@med.wayne.eduAbstract: Adenosine deaminase deficiency (ADA) is a purine salvage pathway deficiency that results in buildup of toxic metabolites causing death in rapidly dividing cells, especially lymphocytes. The most complete form of ADA leads to severe combined immune deficiency (SCID). Treatment with enzyme replacement therapy (ERT) was developed in the 1970s and became the treatment for ADA SCID by the 1980s. It remains an option for some infants with SCID, and a stopgap measure for others awaiting curative therapy. For some infants with ADA SCID who have matching family donors hematopoietic stem cell transplant (HSCT) is an option for cure. Gene therapy for ADA SCID, approved in some countries and in trials in others, is becoming possible for more infants with this disorder. This review covers the history of ADA SCID, the treatment options to date and particularly the history of the development of gene therapy for ADA SCID and the current state of the risks and benefits of the gene therapy option.Keywords: adenosine deaminase deficiency, ADA, severe combined immunodeficiency, SCID, enzyme replacement therapy, ERT, gene therapy

Published
2022

4. Genetic and phenotypic spectrum associated with IFIH1 gain‐of‐function

Author

Pediatría, Pediatria, Rice, Gillian I., Park, Sehoon, Gavazzi, Francesco, Adang, Laura A., Ayuk, Loveline A., Van Eyck, Lien, Seabra, Luis, Barrea, Christophe, Battini, Roberta, Belot, Alexandre, Berg, Stefan, Billette de Villemeur, Thierry, Bley, Annette E., Blumkin, Lubov, Boespflug‐Tanguy, Odile, Briggs, Tracy A., Brimble, Elise, Dale, Russell C., Darin, Niklas, Debray, François Guillaume, De Giorgis, Valentina, Denecke, Jonas, Doummar, Diane, Drake af Hagelsrum, Gunilla, Eleftheriou, Despina, Estienne, Margherita, Fazzi, Elisa, Feillet, François, Galli, Jessica, Hartog, Nicholas, Harvengt, Julie, Heron, Bénédicte, Heron, Delphine, Kelly, Diedre A., Lev, Dorit, Levrat, Virginie, Livingston, John H., Martí Carrera, María Itxaso, Mignot, Cyril, Mochel, Fanny, Nougues, Marie Christine, Oppermann, Ilena, Pérez Dueñas, Belén, Popp, Bernt, Rodero, Mathieu P., Rodríguez, Diana, Saletti, Veronica, Sharpe, Cia, Tonduti, Davide, Vadlamani, Gayatri, Van Haren, Keith, Tomás Vila, Miguel, Vogt, Julie, Wassmer, Evangeline, Wiedemann, Arnaud, Wilson, Callum J., Zerem, Ayelet, Zweier, Christiane, Zuberi, Sameer M., Orcesi, Simona, Vanderver, Adeline L., Hur, Sun, Crow, Yanick J., Pediatría, Pediatria, Rice, Gillian I., Park, Sehoon, Gavazzi, Francesco, Adang, Laura A., Ayuk, Loveline A., Van Eyck, Lien, Seabra, Luis, Barrea, Christophe, Battini, Roberta, Belot, Alexandre, Berg, Stefan, Billette de Villemeur, Thierry, Bley, Annette E., Blumkin, Lubov, Boespflug‐Tanguy, Odile, Briggs, Tracy A., Brimble, Elise, Dale, Russell C., Darin, Niklas, Debray, François Guillaume, De Giorgis, Valentina, Denecke, Jonas, Doummar, Diane, Drake af Hagelsrum, Gunilla, Eleftheriou, Despina, Estienne, Margherita, Fazzi, Elisa, Feillet, François, Galli, Jessica, Hartog, Nicholas, Harvengt, Julie, Heron, Bénédicte, Heron, Delphine, Kelly, Diedre A., Lev, Dorit, Levrat, Virginie, Livingston, John H., Martí Carrera, María Itxaso, Mignot, Cyril, Mochel, Fanny, Nougues, Marie Christine, Oppermann, Ilena, Pérez Dueñas, Belén, Popp, Bernt, Rodero, Mathieu P., Rodríguez, Diana, Saletti, Veronica, Sharpe, Cia, Tonduti, Davide, Vadlamani, Gayatri, Van Haren, Keith, Tomás Vila, Miguel, Vogt, Julie, Wassmer, Evangeline, Wiedemann, Arnaud, Wilson, Callum J., Zerem, Ayelet, Zweier, Christiane, Zuberi, Sameer M., Orcesi, Simona, Vanderver, Adeline L., Hur, Sun, and Crow, Yanick J.

Abstract

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutieres syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.

Published
2020

5. Genetic and phenotypic spectrum associated with IFIH1 gain‐of‐function

Author

Pediatría, Pediatria, Rice, Gillian I., Park, Sehoon, Gavazzi, Francesco, Adang, Laura A., Ayuk, Loveline A., Van Eyck, Lien, Seabra, Luis, Barrea, Christophe, Battini, Roberta, Belot, Alexandre, Berg, Stefan, Billette de Villemeur, Thierry, Bley, Annette E., Blumkin, Lubov, Boespflug‐Tanguy, Odile, Briggs, Tracy A., Brimble, Elise, Dale, Russell C., Darin, Niklas, Debray, François Guillaume, De Giorgis, Valentina, Denecke, Jonas, Doummar, Diane, Drake af Hagelsrum, Gunilla, Eleftheriou, Despina, Estienne, Margherita, Fazzi, Elisa, Feillet, François, Galli, Jessica, Hartog, Nicholas, Harvengt, Julie, Heron, Bénédicte, Heron, Delphine, Kelly, Diedre A., Lev, Dorit, Levrat, Virginie, Livingston, John H., Martí Carrera, María Itxaso, Mignot, Cyril, Mochel, Fanny, Nougues, Marie Christine, Oppermann, Ilena, Pérez Dueñas, Belén, Popp, Bernt, Rodero, Mathieu P., Rodríguez, Diana, Saletti, Veronica, Sharpe, Cia, Tonduti, Davide, Vadlamani, Gayatri, Van Haren, Keith, Tomás Vila, Miguel, Vogt, Julie, Wassmer, Evangeline, Wiedemann, Arnaud, Wilson, Callum J., Zerem, Ayelet, Zweier, Christiane, Zuberi, Sameer M., Orcesi, Simona, Vanderver, Adeline L., Hur, Sun, Crow, Yanick J., Pediatría, Pediatria, Rice, Gillian I., Park, Sehoon, Gavazzi, Francesco, Adang, Laura A., Ayuk, Loveline A., Van Eyck, Lien, Seabra, Luis, Barrea, Christophe, Battini, Roberta, Belot, Alexandre, Berg, Stefan, Billette de Villemeur, Thierry, Bley, Annette E., Blumkin, Lubov, Boespflug‐Tanguy, Odile, Briggs, Tracy A., Brimble, Elise, Dale, Russell C., Darin, Niklas, Debray, François Guillaume, De Giorgis, Valentina, Denecke, Jonas, Doummar, Diane, Drake af Hagelsrum, Gunilla, Eleftheriou, Despina, Estienne, Margherita, Fazzi, Elisa, Feillet, François, Galli, Jessica, Hartog, Nicholas, Harvengt, Julie, Heron, Bénédicte, Heron, Delphine, Kelly, Diedre A., Lev, Dorit, Levrat, Virginie, Livingston, John H., Martí Carrera, María Itxaso, Mignot, Cyril, Mochel, Fanny, Nougues, Marie Christine, Oppermann, Ilena, Pérez Dueñas, Belén, Popp, Bernt, Rodero, Mathieu P., Rodríguez, Diana, Saletti, Veronica, Sharpe, Cia, Tonduti, Davide, Vadlamani, Gayatri, Van Haren, Keith, Tomás Vila, Miguel, Vogt, Julie, Wassmer, Evangeline, Wiedemann, Arnaud, Wilson, Callum J., Zerem, Ayelet, Zweier, Christiane, Zuberi, Sameer M., Orcesi, Simona, Vanderver, Adeline L., Hur, Sun, and Crow, Yanick J.

Abstract

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutieres syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.

Published
2020

6. Diagnostic assay to assist clinical decisions for unclassified severe combined immune deficiency.

Author

Bifsha, Panojot, Bifsha, Panojot, Leiding, Jennifer W, Pai, Sung-Yun, Colamartino, Aurelien BL, Hartog, Nicholas, Church, Joseph A, Oshrine, Benjamin R, Puck, Jennifer M, Markert, M Louise, Haddad, Elie, Bifsha, Panojot, Bifsha, Panojot, Leiding, Jennifer W, Pai, Sung-Yun, Colamartino, Aurelien BL, Hartog, Nicholas, Church, Joseph A, Oshrine, Benjamin R, Puck, Jennifer M, Markert, M Louise, and Haddad, Elie

Abstract

3D organoid T-cell differentiation from a few hundred peripheral blood CD34+ cells was successfully achieved. 3D organoid T-cell differentiation could help physicians distinguish intrinsic from extrinsic defects underlying a clinical SCID phenotype.

Published
2020

7. Genetic and phenotypic spectrum associated with IFIH1 gain‐of‐function

Author

Pediatría, Pediatria, Rice, Gillian I., Park, Sehoon, Gavazzi, Francesco, Adang, Laura A., Ayuk, Loveline A., Van Eyck, Lien, Seabra, Luis, Barrea, Christophe, Battini, Roberta, Belot, Alexandre, Berg, Stefan, Billette de Villemeur, Thierry, Bley, Annette E., Blumkin, Lubov, Boespflug‐Tanguy, Odile, Briggs, Tracy A., Brimble, Elise, Dale, Russell C., Darin, Niklas, Debray, François Guillaume, De Giorgis, Valentina, Denecke, Jonas, Doummar, Diane, Drake af Hagelsrum, Gunilla, Eleftheriou, Despina, Estienne, Margherita, Fazzi, Elisa, Feillet, François, Galli, Jessica, Hartog, Nicholas, Harvengt, Julie, Heron, Bénédicte, Heron, Delphine, Kelly, Diedre A., Lev, Dorit, Levrat, Virginie, Livingston, John H., Martí Carrera, María Itxaso, Mignot, Cyril, Mochel, Fanny, Nougues, Marie Christine, Oppermann, Ilena, Pérez Dueñas, Belén, Popp, Bernt, Rodero, Mathieu P., Rodríguez, Diana, Saletti, Veronica, Sharpe, Cia, Tonduti, Davide, Vadlamani, Gayatri, Van Haren, Keith, Tomás Vila, Miguel, Vogt, Julie, Wassmer, Evangeline, Wiedemann, Arnaud, Wilson, Callum J., Zerem, Ayelet, Zweier, Christiane, Zuberi, Sameer M., Orcesi, Simona, Vanderver, Adeline L., Hur, Sun, Crow, Yanick J., Pediatría, Pediatria, Rice, Gillian I., Park, Sehoon, Gavazzi, Francesco, Adang, Laura A., Ayuk, Loveline A., Van Eyck, Lien, Seabra, Luis, Barrea, Christophe, Battini, Roberta, Belot, Alexandre, Berg, Stefan, Billette de Villemeur, Thierry, Bley, Annette E., Blumkin, Lubov, Boespflug‐Tanguy, Odile, Briggs, Tracy A., Brimble, Elise, Dale, Russell C., Darin, Niklas, Debray, François Guillaume, De Giorgis, Valentina, Denecke, Jonas, Doummar, Diane, Drake af Hagelsrum, Gunilla, Eleftheriou, Despina, Estienne, Margherita, Fazzi, Elisa, Feillet, François, Galli, Jessica, Hartog, Nicholas, Harvengt, Julie, Heron, Bénédicte, Heron, Delphine, Kelly, Diedre A., Lev, Dorit, Levrat, Virginie, Livingston, John H., Martí Carrera, María Itxaso, Mignot, Cyril, Mochel, Fanny, Nougues, Marie Christine, Oppermann, Ilena, Pérez Dueñas, Belén, Popp, Bernt, Rodero, Mathieu P., Rodríguez, Diana, Saletti, Veronica, Sharpe, Cia, Tonduti, Davide, Vadlamani, Gayatri, Van Haren, Keith, Tomás Vila, Miguel, Vogt, Julie, Wassmer, Evangeline, Wiedemann, Arnaud, Wilson, Callum J., Zerem, Ayelet, Zweier, Christiane, Zuberi, Sameer M., Orcesi, Simona, Vanderver, Adeline L., Hur, Sun, and Crow, Yanick J.

Abstract

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutieres syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.

Published
2020

8. Geographic Variability and Pathogen-Specific Considerations in the Diagnosis and Management of Chronic Granulomatous Disease

Author

Prince,Benjamin T, Thielen,Beth K, Williams,Kelli W, Kellner,Erinn S, Arnold,Danielle E, Cosme-Blanco,Wilfredo, Redmond,Margaret T, Hartog,Nicholas L, Chong,Hey J, Holland,Steven M, Prince,Benjamin T, Thielen,Beth K, Williams,Kelli W, Kellner,Erinn S, Arnold,Danielle E, Cosme-Blanco,Wilfredo, Redmond,Margaret T, Hartog,Nicholas L, Chong,Hey J, and Holland,Steven M

Abstract

Benjamin T Prince,1 Beth K Thielen,2 Kelli W Williams,3 Erinn S Kellner,4 Danielle E Arnold,5 Wilfredo Cosme-Blanco,6 Margaret T Redmond,1 Nicholas L Hartog,7 Hey J Chong,8 Steven M Holland9 1Division of Allergy and Immunology, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, USA; 2Division of Pediatric Infectious Diseases and Immunology, University of Minnesota, Minneapolis, MN, USA; 3Department of Pediatrics, Division of Pediatric Pulmonology, Allergy & Immunology, Medical University of South Carolina, Charleston, SC, USA; 4Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 5Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; 6Department of Allergy and Immunology, Veteran Affairs Caribbean Healthcare System, San Juan, Puerto Rico; 7Department of Allergy and Immunology, Spectrum Health Helen DeVos Children’s Hospital, Michigan State University College of Human Medicine, Grand Rapids, MI, USA; 8Division of Allergy and Immunology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA; 9National Institute of Allergy and Infectious Diseases, Bethesda, Maryland National Institutes of Health, Bethesda, MD, USACorrespondence: Benjamin T PrinceNationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USATel +1 (614) 722-4404Fax +1 (614) 722-4423Email Benjamin.Prince@Nationwidechildrens.orgAbstract: Chronic granulomatous disease (CGD) is a rare but serious primary immunodeficiency with varying prevalence and rates of X-linked and autosomal recessive disease worldwide. Functional defects in the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex predispose patients to a relatively narrow spectrum of bacterial and fungal infections that are sometimes fastidious and often difficult to identify. W

Published
2020

9. Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis.

Author

Bosticardo, Marita, Bosticardo, Marita, Yamazaki, Yasuhiro, Cowan, Jennifer, Giardino, Giuliana, Corsino, Cristina, Scalia, Giulia, Prencipe, Rosaria, Ruffner, Melanie, Hill, David A, Sakovich, Inga, Yemialyanava, Irma, Tam, Jonathan S, Padem, Nurcicek, Elder, Melissa E, Sleasman, John W, Perez, Elena, Niebur, Hana, Seroogy, Christine M, Sharapova, Svetlana, Gebbia, Jennifer, Kleiner, Gary Ira, Peake, Jane, Abbott, Jordan K, Gelfand, Erwin W, Crestani, Elena, Biggs, Catherine, Butte, Manish J, Hartog, Nicholas, Hayward, Anthony, Chen, Karin, Heimall, Jennifer, Seeborg, Filiz, Bartnikas, Lisa M, Cooper, Megan A, Pignata, Claudio, Bhandoola, Avinash, Notarangelo, Luigi D, Bosticardo, Marita, Bosticardo, Marita, Yamazaki, Yasuhiro, Cowan, Jennifer, Giardino, Giuliana, Corsino, Cristina, Scalia, Giulia, Prencipe, Rosaria, Ruffner, Melanie, Hill, David A, Sakovich, Inga, Yemialyanava, Irma, Tam, Jonathan S, Padem, Nurcicek, Elder, Melissa E, Sleasman, John W, Perez, Elena, Niebur, Hana, Seroogy, Christine M, Sharapova, Svetlana, Gebbia, Jennifer, Kleiner, Gary Ira, Peake, Jane, Abbott, Jordan K, Gelfand, Erwin W, Crestani, Elena, Biggs, Catherine, Butte, Manish J, Hartog, Nicholas, Hayward, Anthony, Chen, Karin, Heimall, Jennifer, Seeborg, Filiz, Bartnikas, Lisa M, Cooper, Megan A, Pignata, Claudio, Bhandoola, Avinash, and Notarangelo, Luigi D

Abstract

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.

Published
2019

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