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1. Human inherited complete STAT2 deficiency underlies inflammatory viral diseases

Author

Bucciol, Giorgia, Moens, Leen, Ogishi, Masato, Rinchai, Darawan, Matuozzo, Daniela, Momenilandi, Mana, Kerrouche, Nacim, Cale, Catherine M, Treffeisen, Elsa R, Al Salamah, Mohammad, Al-Saud, Bandar K, Lachaux, Alain, Duclaux-Loras, Remi, Meignien, Marie, Bousfiha, Aziz, Benhsaien, Ibtihal, Shcherbina, Anna, Roppelt, Anna, COVID Human Genetic Effort, Gothe, Florian, Houhou-Fidouh, Nadhira, Hackett, Scott J, Bartnikas, Lisa M, Maciag, Michelle C, Alosaimi, Mohammed F, Chou, Janet, Mohammed, Reem W, Freij, Bishara J, Jouanguy, Emmanuelle, Zhang, Shen-Ying, Boisson-Dupuis, Stephanie, Béziat, Vivien, Zhang, Qian, Duncan, Christopher Ja, Hambleton, Sophie, Casanova, Jean-Laurent, and Meyts, Isabelle

Subjects
Innate immunity, Immunology, General Medicine, Influenza, Genetic diseases
Abstract

STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients' cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood onward included severe adverse reaction to live attenuated viral vaccines (LAV) and severe viral infections, particularly critical influenza pneumonia, critical COVID-19 pneumonia, and herpes simplex virus type 1 (HSV-1) encephalitis. The patients displayed various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attested to unresolved viral infection in the absence of STAT2-dependent types I and III IFN immunity. Transcriptomic analysis revealed that circulating monocytes, neutrophils, and CD8+ memory T cells contributed to this inflammation. Several patients died from viral infection or heart failure during a febrile illness with no identified etiology. Notably, the highest mortality occurred during early childhood. These findings show that AR complete STAT2 deficiency underlay severe viral diseases and substantially impacts survival. ispartof: J Clin Invest vol:133 issue:12 pages:e168321- ispartof: location:United States status: Published online

Published
2023

2. Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency

Author

Lévy, Romain, Gothe, Florian, Momenilandi, Mana, Magg, Thomas, Materna, Marie, Peters, Philipp, Raedler, Johannes, Philippot, Quentin, Rack-Hoch, Anita, Langlais, David, Bourgey, Mathieu, Lanz, Anna-Lisa, Ogishi, Masato, Rosain, Jérémie, Martin, Emmanuel, Latour, Sylvain, Vladikine, Natasha, Distefano, Marco, Khan, Taushif, Rapaport, Franck, Schulz, Marian, Holzer, Ursula, Fasth, Anders, Sogkas, Georgios, Speckmann, Carsten, Troilo, Arianna, Bigley, Venetia, Roppelt, Anna, Dinur-Schejter, Yael, Toker, Ori, Bronken Martinsen, Karen, Sherkat, Roya, Somekh, Ido, Somech, Raz, Shouval, Dror, Kühl, Jörn-Sven, Ip, Winnie, Mcdermott, Elizabeth, Cliffe, Lucy, Ozen, Ahmet, Baris, Safa, Rangarajan, Hemalatha, Jouanguy, Emmanuelle, Puel, Anne, Bustamante, Jacinta, Alyanakian, Marie-Alexandra, Fusaro, Mathieu, Wang, Yi, Kong, Xiao-Fei, Cobat, Aurélie, Boutboul, David, Castelle, Martin, Aguilar, Claire, Hermine, Olivier, Cheminant, Morgane, Suarez, Felipe, Yildiran, Alisan, Bousfiha, Aziz, Al-Mousa, Hamoud, Alsohime, Fahad, Cagdas, Deniz, Abraham, Roshini, Knutsen, Alan, Fevang, Borre, Bhattad, Sagar, Kiykim, Ayca, Erman, Baran, Arikoglu, Tugba, Unal, Ekrem, Kumar, Ashish, Geier, Christoph, Baumann, Ulrich, Neven, Bénédicte, Calas, Julie, Feuille, Elizabeth, Chan, Angela, Yesil, Gozde, Nammour, Justine, Bandet, Élise, Picard, Capucine, Benhsaien, Ibtihal, Lang, Peter, Atschekzei, Faranaz, Warnatz, Klaus, Hambleton, Sophie, Desai, Mukesh, Karakoc-Aydiner, Elif, Kolukisa, Burcu, Al-Muhsen, Saleh, Alosaimi, Mohammed, Cipe, Funda, Alazami, Anas, Hancioglu, Gonca, Can Meydan, Bilge, Sorte, Hanne, Stray-Pedersen, Asbjørg, Mammayil, Geetha, Tökmeci, Nazan, Shcherbina, Anna, Stepensky, Polina, Nasereddin, Adeeb, Rouzaud, Claire, Hoshino, Akihiro, Shamriz, Oded, Ledder, Oren, Maccari, Maria, Castro, Carla, Grimbacher, Bodo, Schmidt, Reinhold, Collin, Matthew, Zakharova, Victorya, Rohlfs, Meino, Walz, Christoph, Abel, Laurent, Malissen, Bernard, Marr, Nico, Klein, Christoph, Casanova, Jean-Laurent, Hauck, Fabian, Béziat, Vivien, Lévy R., Gothe F., Momenilandi M., Magg T., Materna M., Peters P., Raedler J., Philippot Q., Rack-Hoch A. L., Langlais D., et al., Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunophénomique (CIPHE), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-IAHU-0003,Méditerranée Infection,I.H.U. Méditerranée Infection(2010), and ANR-21-CE15-0034,CARMIL2,Bases moléculaires, cellulaires et immunologiques de la déficience combinée résultant de mutations dans CARMIL2(2021)

Subjects
CD4-Positive T-Lymphocytes, Phenotype, CD28 Antigens, [SDV]Life Sciences [q-bio], Microfilament Proteins, Mutation, Immunology, Humans, Immunology and Allergy
Abstract

International audience; Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4 + and CD8 + memory T cells and CD4 + T REG s. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV + smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4 + T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.

Published
2022

3. Studying severe long COVID to understand post-infectious disorders beyond COVID-19

Author

Brodin, Petter, Casari, Giorgio, Townsend, Liam, O’Farrelly, Cliona, Tancevski, Ivan, Löffler-Ragg, Judith, Mogensen, Trine H., Casanova, Jean Laurent, Abel, Laurent, Aiuti, Alessandro, Al-Muhsen, Saleh, Al-Mulla, Fahd, Anderson, Mark S., Andreakos, Evangelos, Arias, Andrés A., Feldman, Hagit Baris, Belot, Alexandre, Biggs, Catherine M., Bogunovic, Dusan, Bolze, Alexandre, Bondarenko, Anastasiia, Bousfiha, Ahmed A., Bryceson, Yenan, Bustamante, Carlos D., Butte, Manish J., Christodoulou, John, Condino-Neto, Antonio, Constantinescu, Stefan N., Cooper, Megan A., Dalgard, Clifton L., Desai, Murkesh, Drolet, Beth A., Baghdadi, Jamila El, Espinosa-Padilla, Sara, Fellay, Jacques, Flores, Carlos, Franco, José Luis, Froidure, Antoine, Gregersen, Peter K., Grimbacher, Bodo, Haerynck, Filomeen, Hagin, David, Halwani, Rabih, Hammarström, Lennart, Heath, James R., Henrickson, Sarah E., Hsieh, Elena W. Y., Husebye, Eystein, Imai, Kohsuke, Itan, Yuval, Jarvis, Erich D., Karamitros, Timokratis, Kisand, Kai, Ku, Cheng-Lung, Lau, Yu-Lung, Ling, Yun, Lucas, Carrie L., Maniatis, Tom, Mansouri, Davood, Maródi, L. szló, Meyts, Isabelle, Milner, Joshua D., Mironska, Kristina, Morio, Tomohiro, Ng, Lisa F. P., Novelli, Antonio, Novelli, Giuseppe, Okada, Satoshi, Okamoto, Keisuke, Ozcelik, Tayfun, Pan-Hammarström, Qiang, Pape, Jean W., de Diego, Rebeca Perez, Perlin, David S., Pesole, Graziano, Planas, Anna M., Prando, Carolina, Pujol, Aurora, Quintana-Murci, Lluis, Ramaswamy, Sathishkumar, Renia, Laurent, Resnick, Igor, Rodríguez-Gallego, Carlos, Sancho-Shimizu, Vanessa, Sediva, Anna, Seppänen, Mikko R. J., Shahrooei, Mohammed, Shcherbina, Anna, Slaby, Ondrej, Snow, Andrew L., Soler-Palacín, Pere, Spaan, András N., Tangye, Stuart G., Tayoun, Ahmad Abou, Turvey, Stuart E., Uddin, K. M. Furkan, Uddin, Mohammed J., van de Beek, Diederik, Vinh, Donald C., von Bernuth, Horst, Wauters, Joost, Zatz, Mayana, Zawadzki, Pawel, Casanova, Jean-Laurent, Ozcelik, Tayfun, UCL - SSS/IREC/PNEU - Pôle de Pneumologie, ORL et Dermatologie, UCL - (SLuc) Service de pneumologie, Neurology, AII - Infectious diseases, and ANS - Neuroinfection & -inflammation

Subjects
Post-Acute COVID-19 Syndrome, SARS-CoV-2, Research, COVID-19, Humans, General Medicine, IMUNOLOGIA, General Biochemistry, Genetics and Molecular Biology
Published
2022

4. Additional file 1 of Ex vivo observation of granulocyte activity during thrombus formation

Author

Morozova, Daria S., Martyanov, Alexey A., Obydennyi, Sergei I., Korobkin, Julia-Jessica D., Sokolov, Alexey V., Shamova, Ekaterina V., Gorudko, Irina V., Khoreva, Anna L., Shcherbina, Anna, Panteleev, Mikhail A., and Sveshnikova, Anastasia N.

Abstract

Additional file 1: Figure S1. Comparison of the anti-coagulant impact on NC incorporation to the growing thrombi. Figure S2. Instant NC velocities and averaged velocities. Figure S3. Comparison between heparin and hirudin impact on NCs. Figure S4. Classification of the NC cells among the thrombi. Figure S5. Analysis of the CD11b/CD18 distribution in granulocytes and MNCs. Figure S6. The number of NCs per FOV increased gradually up to the 20th minute of the experiment. Figure S7. Blood cell composition changes after perfusion through flow chamber with fibrillar collagen or BSA. Figure S8. Impact of platelet depletion on granulocyte crawling velocity. Figure S9. Fucoidan impact on platelet P-selectin exposure in growing thrombi. Figure S10. Granulocyte movement around thrombi. Figure S11. Thrombus area and percentage of highly activated granulocytes in the presence of leukocyte activators and in patients with WAS. Figure S12. Crawling granulocytes bear Annexin-V positive platelets. Figure S13. Annexin-V and CD66b staining. Figure S14. Assay of the granulocyte crawling in the blood of WAS patients in the presence of healthy donor platelets. Table S1. LAL-test results for endotoxin characterization in the protein samples. Table S2. Calibration of the LAL-test system.

Published
2022
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5. Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients

Author

Le Coz, Carole, Nguyen, David N, Su, Chun, Nolan, Brian E, Albrecht, Amanda V, Xhani, Suela, Sun, Di, Demaree, Benjamin, Pillarisetti, Piyush, Khanna, Caroline, Wright, Francis, Chen, Peixin Amy, Yoon, Samuel, Stiegler, Amy L, Maurer, Kelly, Garifallou, James P, Rymaszewski, Amy, Kroft, Steven H, Olson, Timothy S, Seif, Alix E, Wertheim, Gerald, Grant, Struan FA, Vo, Linda T, Puck, Jennifer M, Sullivan, Kathleen E, Routes, John M, Zakharova, Viktoria, Shcherbina, Anna, Mukhina, Anna, Rudy, Natasha L, Hurst, Anna CE, Atkinson, T Prescott, Boggon, Titus J, Hakonarson, Hakon, Abate, Adam R, Hajjar, Joud, Nicholas, Sarah K, Lupski, James R, Verbsky, James, Chinn, Ivan K, Gonzalez, Michael V, Wells, Andrew D, Marson, Alex, Poon, Gregory MK, and Romberg, Neil

Subjects
Adult, Male, Adolescent, Precursor Cells, Immunology, Regenerative Medicine, Medical and Health Sciences, Cell Line, Young Adult, Agammaglobulinemia, Clinical Research, Stem Cell Research - Nonembryonic - Human, Proto-Oncogene Proteins, Genetics, Humans, Developmental, Child, Preschool, B-Lymphoid, B-Lymphocytes, Stem Cells, Lymphopoiesis, Human Genome, Infant, Cell Differentiation, Dendritic Cells, Hematology, Hematopoietic Stem Cells, Stem Cell Research, Chromatin, Hematopoiesis, HEK293 Cells, Gene Expression Regulation, Mutation, Trans-Activators, Female, Stem Cell Research - Nonembryonic - Non-Human, Biotechnology
Abstract

The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.

Published
2021

6. Autoantibodies neutralizing type I IFNs are present in similar to 4% of uninfected individuals over 70 years old and account for similar to 20% of COVID-19 deaths

Author

Bastard, Paul, Gervais, Adrian, Le Voyer, Tom, Rosain, Jeremie, Philippot, Quentin, Manry, Jeremy, Michailidis, Eleftherios, Hoffmann, Hans-Heinrich, Eto, Shohei, Garcia-Prat, Marina, Bizien, Lucy, Parra-Martinez, Alba, Yang, Rui, Haljasmagi, Liis, Migaud, Melanie, Sarekannu, Karita, Maslovskaja, Julia, de Prost, Nicolas, Tandjaoui-Lambiotte, Yacine, Luyt, Charles-Edouard, Amador-Borrero, Blanca, Gaudet, Alexandre, Poissy, Julien, Morel, Pascal, Richard, Pascale, Cognasse, Fabrice, Troya, Jesus, Trouillet-Assant, Sophie, Belot, Alexandre, Saker, Kahina, Garcon, Pierre, Riviere, Jacques G., Lagier, Jean-Christophe, Gentile, Stephanie, Rosen, Lindsey B., Shaw, Elana, Morio, Tomohiro, Tanaka, Junko, Dalmau, David, Tharaux, Pierre-Louis, Sene, Damien, Stepanian, Alain, Megarbane, Bruno, Triantafyllia, Vasiliki, Fekkar, Arnaud, Heath, James R., Franco, Jose Luis, Anaya, Juan-Manuel, Sole-Violan, Jordi, Imberti, Luisa, Biondi, Andrea, Bonfanti, Paolo, Castagnoli, Riccardo, Delmonte, Ottavia M., Zhang, Yu, Snow, Andrew L., Holland, Steven M., Biggs, Catherine M., Moncada-Velez, Marcela, Arias, Andres Augusto, Lorenzo, Lazaro, Boucherit, Soraya, Coulibaly, Boubacar, Anglicheau, Dany, Planas, Anna M., Haerynck, Filomeen, Duvlis, Sotirija, Nussbaum, Robert L., Ozcelik, Tayfun, Keles, Sevgi, Bousfiha, Ahmed A., El Bakkouri, Jalila, Ramirez-Santana, Carolina, Paul, Stephane, Pan-Hammarstrom, Qiang, Hammarstrom, Lennart, Dupont, Annabelle, Kurolap, Alina, Metz, Christine N., Aiuti, Alessandro, Casari, Giorgio, Lampasona, Vito, Ciceri, Fabio, Barreiros, Lucila A., Dominguez-Garrido, Elena, Vidigal, Mateus, Zatz, Mayana, van de Beek, Diederik, Sahanic, Sabina, Tancevski, Ivan, Stepanovskyy, Yurii, Boyarchuk, Oksana, Nukui, Yoko, Tsumura, Miyuki, Vidaur, Loreto, Tangye, Stuart G., Burrel, Sonia, Duffy, Darragh, Quintana-Murci, Lluis, Klocperk, Adam, Kann, Nelli Y., Shcherbina, Anna, Lau, Yu-Lung, Leung, Daniel, Coulongeat, Matthieu, Marlet, Julien, Koning, Rutger, Reyes, Luis Felipe, Chauvineau-Grenier, Angelique, Venet, Fabienne, Monneret, Guillaume, Nussenzweig, Michel C., Arrestier, Romain, Boudhabhay, Idris, Baris-Feldman, Hagit, Hagin, David, Wauters, Joost, Meyts, Isabelle, Dyer, Adam H., Kennelly, Sean P., Bourke, Nollaig M., Halwani, Rabih, Sharif-Askari, Narjes Saheb, Dorgham, Karim, Sallette, Jerome, Sedkaoui, Souad Mehlal, AlKhater, Suzan, Rigo-Bonnin, Raul, Morandeira, Francisco, Roussel, Lucie, Vinh, Donald C., Ostrowski, Sisse Rye, Condino-Neto, Antonio, Prando, Carolina, Bondarenko, Anastasiia, Spaan, Andras N., Gilardin, Laurent, Fellay, Jacques, Lyonnet, Stanislas, Bilguvar, Kaya, Lifton, Richard P., Mane, Shrikant, Anderson, Mark S., Boisson, Bertrand, Beziat, Vivien, Zhang, Shen-Ying, Andreakos, Evangelos, Hermine, Olivier, Pujol, Aurora, Peterson, Part, Mogensen, Trine H., Rowen, Lee, Mond, James, Debette, Stephanie, de Lamballerie, Xavier, Duval, Xavier, Mentre, France, Zins, Marie, Soler-Palacin, Pere, Colobran, Roger, Gorochov, Guy, Solanich, Xavier, Susen, Sophie, Martinez-Picado, Javier, Raoult, Didier, Vasse, Marc, Gregersen, Peter K., Piemonti, Lorenzo, Rodriguez-Gallego, Carlos, Notarangelo, Luigi D., Su, Helen C., Kisand, Kai, Okada, Satoshi, Puel, Anne, Jouanguy, Emmanuelle, Rice, Charles M., Tiberghien, Pierre, Zhang, Qian, Cobat, Aurelie, Abel, Laurent, Casanova, Jean-Laurent, and Gunst, Jan

Subjects
INTERFERON, alpha, Science & Technology, ANTINUCLEAR, myasthenia-gravis patients, AUTOIMMUNITY, autoimmunity, Immunology, interferon, IMMUNITY, immunity, DISTINCT FUNCTIONS, PATIENT, ALPHA, ANTIBODIES, antibodies, patient, distinct functions, Life Sciences & Biomedicine, MYASTHENIA-GRAVIS PATIENTS, antinuclear
Abstract

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases. ispartof: SCIENCE IMMUNOLOGY vol:6 issue:62 ispartof: location:United States status: published

Published
2021

7. Single-cell epigenomic analyses implicate candidate causal variants at inherited risk loci for Alzheimer's and Parkinson's diseases

Author

Corces, M Ryan, Shcherbina, Anna, Kundu, Soumya, Gloudemans, Michael J, Frésard, Laure, Granja, Jeffrey M, Louie, Bryan H, Eulalio, Tiffany, Shams, Shadi, Bagdatli, S Tansu, Mumbach, Maxwell R, Liu, Boxiang, Montine, Kathleen S, Greenleaf, William J, Kundaje, Anshul, Montgomery, Stephen B, Chang, Howard Y, and Montine, Thomas J

Subjects
Adult, Epigenomics, Enhancer Elements, Population, tau Proteins, Medical and Health Sciences, Cohort Studies, Promoter Regions, Machine Learning, Genetic Heterogeneity, Atlases as Topic, Genetic, Alzheimer Disease, Humans, Genetic Predisposition to Disease, Polymorphism, Neurons, Brain, Biological Variation, Parkinson Disease, Single Nucleotide, Biological Sciences, Chromatin Assembly and Disassembly, Haplotypes, Genome-Wide Association Study, Developmental Biology
Abstract

Genome-wide association studies of neurological diseases have identified thousands of variants associated with disease phenotypes. However, most of these variants do not alter coding sequences, making it difficult to assign their function. Here, we present a multi-omic epigenetic atlas of the adult human brain through profiling of single-cell chromatin accessibility landscapes and three-dimensional chromatin interactions of diverse adult brain regions across a cohort of cognitively healthy individuals. We developed a machine-learning classifier to integrate this multi-omic framework and predict dozens of functional SNPs for Alzheimer's and Parkinson's diseases, nominating target genes and cell types for previously orphaned loci from genome-wide association studies. Moreover, we dissected the complex inverted haplotype of the MAPT (encoding tau) Parkinson's disease risk locus, identifying putative ectopic regulatory interactions in neurons that may mediate this disease association. This work expands understanding of inherited variation and provides a roadmap for the epigenomic dissection of causal regulatory variation in disease.

Published
2020

8. Long-Term Outcome Of Lrba Deficiency In 76 Patients After Various Treatment Modalities As Evaluated By The Immune Deficiency And Dysregulation Activity (Idda) Score

Author

Tesch, Victoria Katharina, Abolhassani, Hassan, Shadur, Bella, Zobel, Joachim, Mareika, Yuliya, Sharapova, Svetlana, Karakoc-Aydiner, Elif, Riviere, Jacques G., Garcia-Prat, Marina, Moes, Nicolette, Haerynck, Filomeen, Gonzales-Granado, Luis I., Santos Perez, Juan Luis, Mukhina, Anna, Shcherbina, Anna, Aghamohammadi, Asghar, Hammarstrom, Lennart, Dogu, Figen, Haskologlu, Sule, and Ikinciogullari, Aydan I.

Subjects
surgical procedures, operative
Abstract

Background: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant.

Published
2020

9. Technical Note on Transcription Factor Motif Discovery from Importance Scores (TF-MoDISco) version 0.5.6.5

Author

Shrikumar, Avanti, Tian, Katherine, Avsec, Žiga, Shcherbina, Anna, Banerjee, Abhimanyu, Sharmin, Mahfuza, Nair, Surag, and Kundaje, Anshul

Subjects
Genomics (q-bio.GN), FOS: Computer and information sciences, Computer Science - Machine Learning, Statistics - Machine Learning, FOS: Biological sciences, Quantitative Biology - Genomics, Machine Learning (stat.ML), Machine Learning (cs.LG)
Abstract

TF-MoDISco (Transcription Factor Motif Discovery from Importance Scores) is an algorithm for identifying motifs from basepair-level importance scores computed on genomic sequence data. This technical note focuses on version v0.5.6.5. The implementation is available at https://github.com/kundajelab/tfmodisco/tree/v0.5.6.5

Published
2018
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10. Europe immunoglobulin map

Author

Šedivá, A, Chapel, H., Gardulf, A., Wolf, Hermann, Förster Waldl, Elisabeth, Belevtsev, Michail, Meyts, Isabelle, Mulaosmanović, Velma, Naumova, Elisaveta, Kelecic, Jadranka, Litzman, Jiří, Heilmann, Carsten, Velbri, Sirje, Seppänen, Mikko, Oksenhendler, Eric, Warnatz, Klaus, Kanariou, Maria, Maródi, László, Lúdvíksson, Björn R., Keogan, Mary, Quinti, Isabella, Prokofjeva, Tatjana, Duobiene, Rasa, Hentges, François, Mironska, Kristina, Vries, Esther de, Fevang, Borre, Pac, Malgorzata, Kowalczyk, Danuta, Silva, Susana Lopes da, Bataneant, Mihaela, Alexis, Cochino, Shcherbina, Anna, Tuzankina, Irina, Koruga, Dragana, Ciznar, Peter, Avcin, Tadej, Español, Teresa, Gardulf, Ann, Hoernes, Miriam, Chapel, Helen, and Reisli, Ismail

Subjects
Infusions, Subcutaneous, Immunology, Immunization, Passive, Immunologic Deficiency Syndromes, Immunoglobulins, Immunoglobulins, Intravenous, Passive, Infusions, Subcutaneous, Europe, Poster Presentations, Humans, Immunology and Allergy, Immunization, Intravenous
Published
2014

12. 4WHIM: Evaluating the Oral CXCR4 Antagonist Mavorixafor in Patients With WHIM Syndrome via a Global Phase 3, Randomized, Placebo-Controlled Trial With Open-label Extension

Author

Dale, David, Alsina, Laia, Azar, Antoine, Badolato, Raffaele, Bertrand, Yves, Ezra, Navid, Hasle, Henrik, Kang, Hyoung Jin, Kiani-Alikhan, Sorena, Kuijpers, Taco, Alexander Kulagin, Langguth, Daman, Levin, Carina, Neth, Olaf, Peake, Jane, Shcherbina, Anna, Tarrant, Teresa, Vossen, Matthias, Wysocki, Christian, Belschner, Andrea, Cadavid, Diego, Jiang, Honghua, Macleod, Richard, Tang, Weihua, and Donadieu, Jean

Subjects
CXCR4, randomized, neutropenia, clinical trial, primary immunodeficiency, myelokathexis, WHIM syndrome

13. Efficacy and Safety of Canakinumab in Patients with Colchicine-Resistant Familial Mediterranean Fever, Hyper-Immunoglobulin D Syndrome/Mevalonate Kinase Deficiency and TNF Receptor-Associated Periodic Syndrome: 40 Week Results from the Pivotal Phase 3 Umbrella Cluster Trial

Author

fabrizio De Benedetti, Frenkel, Joost, Calvo, Inmaculada, Gattorno, Marco, Moutschen, Michel, Quartier, Pierre, Kasapcopur, Ozgur, Ozen, Seza, Anton, Jordi, Kone-Paut, Isabelle, Lachmann, Helen, Hoffman, Hal M., Ben-Chetrit, Eldad, Shcherbina, Anna, Hofer, Michael, Hashkes, Philip J., Zeft, Andrew, Lheritier, Karine, Gong, Yankun, Speziale, Antonio, and Junge, Guido

14. Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study

Author

Barzaghi, F., Hernandez, L.C.A., Neven, B., Ricci, S., Kucuk, Z.Y., Bleesing, J.J., Nademi, Z., Slatter, M.A., Ulloa, E.R., Shcherbina, A., Roppelt, A., Worth, A., Silva, J., Aiuti, A., Murguia-Favela, L., Speckmann, C., Carneiro-Sampaio, M., Fernandes, J.F., Baris, S., Ozen, A., Karakoc-Aydiner, E., Kiykim, A., Schulz, A., Steinmann, S., Notarangelo, L.D., Gambineri, E., Lionetti, P., Shearer, W.T., Forbes, L.R., Martinez, C., Moshous, D., Blanche, S., Fisher, A., Ruemmele, F.M., Tissandier, C., Ouachee-Chardin, M., Rieux-Laucat, F., Cavazzana, M., Qasim, W., Lucarelli, B., Albert, M.H., Kobayashi, I., Alonso, L., Heredia, C.D. de, Kanegane, H., Lawitschka, A., Seo, J.J., Gonzalez-Vicent, M., Diaz, M.A., Goyal, R.K., Sauer, M.G., Yesilipek, A., Kim, M., Yilmaz-Demirdag, Y., Bhatia, M., Khlevner, J., Padilla, E.J.R., Martino, S., Montin, D., Neth, O., Molinos-Quintana, A., Valverde-Fernandez, J., Broides, A., Pinsk, V., Ballauf, A., Haerynck, F., Bordon, V., Dhooge, C., Garcia-Lloret, M.L., Bredius, R.G., Kawak, K., Haddad, E., Seidel, M.G., Duckers, G., Pai, S.Y., Dvorak, C.C., Ehl, S., Locatelli, F., Goldman, F., Gennery, A.R., Cowan, M.J., Roncarolo, M.G., Bacchetta, R., PIDTC, IEWP, European Soc Blood Marrow, Barzaghi, Federica, Hernandez, Laura Cristina Amaya, Neven, Benedicte, Ricci, Silvia, Kucuk, Zeynep Yesim, Bleesing, Jack J., Nademi, Zohreh, Slatter, Mary Anne, Ulloa, Erlinda Rose, Shcherbina, Anna, Roppelt, Anna, Worth, Austen, Silva, Juliana, Aiuti, Alessandro, Murguia-Favela, Luis, Speckmann, Carsten, Carneiro-Sampaio, Magda, Fernandes, Juliana Folloni, Baris, Safa, Ozen, Ahmet, Karakoc-Aydiner, Elif, Kiykim, Ayca, Schulz, Ansgar, Steinmann, Sandra, Notarangelo, Lucia Dora, Gambineri, Eleonora, Lionetti, Paolo, Shearer, William Thomas, Forbes, Lisa R., Martinez, Caridad, Moshous, Despina, Blanche, Stephane, Fisher, Alain, Ruemmele, Frank M., Tissandier, Come, Ouachee-Chardin, Marie, Rieux-Laucat, Frederic, Cavazzana, Marina, Qasim, Waseem, Lucarelli, Barbarella, Albert, Michael H., Kobayashi, Ichiro, Alonso, Laura, De Heredia, Cristina Diaz, Kanegane, Hirokazu, Lawitschka, Anita, Seo, Jong Jin, Gonzalez-Vicent, Marta, Diaz, Miguel Angel, Goyal, Rakesh Kumar, Sauer, Martin G., Yesilipek, Akif, Kim, Minsoo, Yilmaz-Demirdag, Yesim, Bhatia, Monica, Khlevner, Julie, Padilla, Erick J. Richmond, Martino, Silvana, Montin, Davide, Neth, Olaf, Molinos-Quintana, Agueda, Valverde-Fernandez, Justo, Broides, Arnon, Pinsk, Vered, Ballauf, Antje, Haerynck, Filomeen, Bordon, Victoria, Dhooge, Catharina, Garcia-Lloret, Maria Laura, Bredius, Robbert G., Kalwak, Krzysztof, Haddad, Elie, Seidel, Markus Gerhard, Duckers, Gregor, Pai, Sung-Yun, Dvorak, Christopher C., Ehl, Stephan, Locatelli, Franco, Goldman, Frederick, Gennery, Andrew Richard, Cowan, Mort J., Roncarolo, Maria-Grazia, Bacchetta, Rosa, Amaya Hernandez, Laura Cristina, Murguia-Favela, Lui, Shearer, William Thoma, Rieux-Laucat, Frédéric, Diaz De Heredia, Cristina, Richmond Padilla, Erick J., and Kałwak, Krzysztof

Subjects
0301 basic medicine, Male, Allergy, medicine.medical_treatment, Medizin, Disease, Hematopoietic stem cell transplantation, SIROLIMUS, Regenerative Medicine, primary immune deficiency, Medicine and Health Sciences, IPEX, Immunology and Allergy, 2.1 Biological and endogenous factors, Enteropathy, Aetiology, POLYENDOCRINOPATHY, Child, Pediatric, CÉLULAS-TRONCO, immunosuppression, Hematopoietic Stem Cell Transplantation, Genetic Diseases, X-Linked, Immunosuppression, Forkhead Transcription Factors, X-LINKED SYNDROME, Allografts, Survival Rate, surgical procedures, operative, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Immune System Diseases, Genetic Diseases, Child, Preschool, hematopoietic stem cell transplantation, Female, hematopoietic stem, neonatal diabetes, FOXP3, Primary Immune Deficiency, Treg cells, enteropathy, genetic autoimmunity, rapamycin, Type 1, Diarrhea, Adult, medicine.medical_specialty, Adolescent, Immunology, Neonatal onset, Article, Disease-Free Survival, 03 medical and health sciences, Neonatal diabete, Clinical Research, Internal medicine, IMMUNODYSREGULATION, medicine, Primary Immune Deficiency Treatment Consortium (PIDTC) and the Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation, Diabetes Mellitus, Genetics, Humans, REGULATORY T-CELLS, cell transplantation, Preschool, Retrospective Studies, Immunosuppression Therapy, Transplantation, IMMUNE DYSREGULATION, business.industry, MUTATIONS, Infant, Retrospective cohort study, STEM-CELL TRANSPLANTATION, IPEX syndrome, X-Linked, medicine.disease, Stem Cell Research, BONE-MARROW-TRANSPLANTATION, Treg cell, FOXP3 MUTATIONS, Diabetes Mellitus, Type 1, 030104 developmental biology, ENGRAFTMENT, Mutation, business, Follow-Up Studies
Abstract

Background Immunodysregulation polyendocrinopathy enteropathy x-linked(IPEX) syndromeis a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. Methods Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. Conclusions Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen., GRAPHICAL ABSTRACT

Published
2018

15. In vivo Monitoring of Transcriptional Dynamics After Lower-Limb Muscle Injury Enables Quantitative Classification of Healing

Author

Casey A. Gifford, Christopher T. Carrigan, Anna Shcherbina, Maria L. Urso, Melissa A. Kottke, Ramona Pop, Carlos A. Aguilar, Alexander Meissner, Darrell O. Ricke, Lincoln Laboratory, Aguilar, Carlos A., Shcherbina, Anna, and Ricke, Darrell O.

Subjects
Male, Cell type, Support Vector Machine, Gene regulatory network, Biology, Bioinformatics, Article, Transcriptome, Mice, medicine, Animals, Gene Regulatory Networks, Muscle, Skeletal, Wound Healing, Multidisciplinary, Receptors, Notch, Gene Expression Profiling, Chronic pain, Computational Biology, Reproducibility of Results, Molecular Sequence Annotation, Complement System Proteins, Fibroblasts, medicine.disease, Wnt Proteins, Gene expression profiling, Phenotype, Traumatic injury, Gene Expression Regulation, Lower Extremity, Musculoskeletal injury, Wound healing, Signal Transduction
Abstract

Traumatic lower-limb musculoskeletal injuries are pervasive amongst athletes and the military and typically an individual returns to activity prior to fully healing, increasing a predisposition for additional injuries and chronic pain. Monitoring healing progression after a musculoskeletal injury typically involves different types of imaging but these approaches suffer from several disadvantages. Isolating and profiling transcripts from the injured site would abrogate these shortcomings and provide enumerative insights into the regenerative potential of an individual’s muscle after injury. In this study, a traumatic injury was administered to a mouse model and healing progression was examined from 3 hours to 1 month using high-throughput RNA-Sequencing (RNA-Seq). Comprehensive dissection of the genome-wide datasets revealed the injured site to be a dynamic, heterogeneous environment composed of multiple cell types and thousands of genes undergoing significant expression changes in highly regulated networks. Four independent approaches were used to determine the set of genes, isoforms, and genetic pathways most characteristic of different time points post-injury and two novel approaches were developed to classify injured tissues at different time points. These results highlight the possibility to quantitatively track healing progression in situ via transcript profiling using high- throughput sequencing., United States. Air Force (Contract FA8721-05-C-0002)

Published
2015

16. FASTQSim: platform-independent data characterization and in silico read generation for NGS datasets

Author

Anna Shcherbina, Lincoln Laboratory, and Shcherbina, Anna

Subjects
FASTQ format, Test data generation, Computer science, In silico, computer.software_genre, General Biochemistry, Genetics and Molecular Biology, Bottleneck, Software, Next generation sequencing, Humans, Computer Simulation, Indel, Medicine(all), Biochemistry, Genetics and Molecular Biology(all), business.industry, High-Throughput Nucleotide Sequencing, General Medicine, Benchmarking, FASTQ, Algorithm, Metagenomics, Simulator, Data mining, business, computer, Algorithms, Research Article
Abstract

Background High-throughput next generation sequencing technologies have enabled rapid characterization of clinical and environmental samples. Consequently, the largest bottleneck to actionable data has become sample processing and bioinformatics analysis, creating a need for accurate and rapid algorithms to process genetic data. Perfectly characterized in silico datasets are a useful tool for evaluating the performance of such algorithms. Background contaminating organisms are observed in sequenced mixtures of organisms. In silico samples provide exact truth. To create the best value for evaluating algorithms, in silico data should mimic actual sequencer data as closely as possible. Results FASTQSim is a tool that provides the dual functionality of NGS dataset characterization and metagenomic data generation. FASTQSim is sequencing platform-independent, and computes distributions of read length, quality scores, indel rates, single point mutation rates, indel size, and similar statistics for any sequencing platform. To create training or testing datasets, FASTQSim has the ability to convert target sequences into in silico reads with specific error profiles obtained in the characterization step. Conclusions FASTQSim enables users to assess the quality of NGS datasets. The tool provides information about read length, read quality, repetitive and non-repetitive indel profiles, and single base pair substitutions. FASTQSim allows the user to simulate individual read datasets that can be used as standardized test scenarios for planning sequencing projects or for benchmarking metagenomic software. In this regard, in silico datasets generated with the FASTQsim tool hold several advantages over natural datasets: they are sequencing platform independent, extremely well characterized, and less expensive to generate. Such datasets are valuable in a number of applications, including the training of assemblers for multiple platforms, benchmarking bioinformatics algorithm performance, and creating challenge datasets for detecting genetic engineering toolmarks, etc., United States. Defense Threat Reduction Agency (Air Force Contract FA8721-05-C-0002)

Published
2014

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