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3. CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease.

Author

Magg, Thomas, Shcherbina, Anna, Arslan, Duran, Desai, Mukesh M, Wall, Sarah, Mitsialis, Vanessa, Conca, Raffaele, Unal, Ekrem, Karacabey, Neslihan, Mukhina, Anna, Rodina, Yulia, Taur, Prasad D, Illig, David, Marquardt, Benjamin, Hollizeck, Sebastian, Jeske, Tim, Gothe, Florian, Schober, Tilmann, Rohlfs, Meino, Koletzko, Sibylle, Lurz, Eberhard, Muise, Aleixo M, Snapper, Scott B, Hauck, Fabian, Klein, Christoph, and Kotlarz, Daniel

Subjects
Autoimmune Disease, Clinical Research, Genetics, Human Genome, Inflammatory Bowel Disease, Pediatric, Crohn's Disease, Digestive Diseases, 2.1 Biological and endogenous factors, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, Inflammatory and immune system, Oral and gastrointestinal, Age of Onset, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Humans, Inflammatory Bowel Diseases, Lymphocytes, Male, Microfilament Proteins, Mutation, Phenotype, Exome Sequencing, immunodeficiency, very early onset inflammatory bowel diseases, CARMIL2, Clinical Sciences, Gastroenterology & Hepatology
Abstract

BackgroundChildren with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes.MethodsTo identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID.ResultsWhole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency.ConclusionOur study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.

Published
2019

4. 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., Salamah, Mohammad Al, Saud, Bandar K. Al-, Lachaux, Alain, Duclaux-Loras, Remi, Meignien, Marie, Bousfiha, Aziz, Benhsaien, Ibtihal, Shcherbina, Anna, Roppelt, Anna, 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, Beziat, Vivien, Zhang, Qian, Duncan, Christopher J.A., Hambleton, Sophie, Casanova, Jean- Laurent, and Meyts, Isabelle

Subjects
Genetic disorders -- Causes of -- Complications and side effects, Inflammation -- Genetic aspects -- Risk factors, STAT proteins -- Health aspects -- Genetic aspects, Virus diseases -- Risk factors -- Genetic aspects, Health care industry
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.sup.+] 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., Introduction Human type I and III IFNs operate in almost all cell types (1, 2). Type I IFNs (IFN-[alpha]/[beta]) are thought to be secreted by most, if not all, of [...]

Published
2023
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5. Successful atorvastatin treatment of pulmonary alveolar proteinosis in a child with GM‐CSF receptor deficiency

Author

Nayır Büyükşahin, Halime, primary, Yalçın, Ebru, additional, Özdemir, Ali, additional, Haliloglu, Mithat, additional, Orhan, Diclehan, additional, Griese, Matthias, additional, Gothe, Florian, additional, Rapp, Christina, additional, Hardenberg, Sandra Gräfin v., additional, Debbağ, Sehend, additional, Güzelkaş, İsmail, additional, Emiralioğlu, Nagehan, additional, Doğru, Deniz, additional, Özçelik, Uğur, additional, and Kiper, Nural, additional

Published
2024
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6. Single-center prospective evaluation of the first five years of cystic fibrosis newborn screening in Germany

Author

Gesenhues, Florian, primary, Michel, Katarzyna, additional, Greve, Tobias, additional, Röschinger, Wulf, additional, Gothe, Florian, additional, Nübling, Jenna, additional, Feilcke, Maria, additional, Kröner, Carolin, additional, Pawlita, Ingo, additional, Sattler, Franziska, additional, Seidl, Elias, additional, Griese, Matthias, additional, and Kappler, Matthias, additional

Published
2024
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7. Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

Author

Lévy, Romain, Okada, Satoshi, Béziat, Vivien, Moriya, Kunihiko, Liu, Caini, Chai, Louis Yi Ann, Migaud, Mélanie, Hauck, Fabian, Al Ali, Amein, Cyrus, Cyril, Vatte, Chittibabu, Patiroglu, Turkan, Unal, Ekrem, Ferneiny, Marie, Hyakuna, Nobuyuki, Nepesov, Serdar, Oleastro, Matias, Ikinciogullari, Aydan, Dogu, Figen, Asano, Takaki, Ohara, Osamu, Yun, Ling, Della Mina, Erika, Bronnimann, Didier, Itan, Yuval, Gothe, Florian, Bustamante, Jacinta, Boisson-Dupuis, Stéphanie, Tahuil, Natalia, Aytekin, Caner, Salhi, Aicha, Al Muhsen, Saleh, Kobayashi, Masao, Toubiana, Julie, Abel, Laurent, Li, Xiaoxia, Camcioglu, Yildiz, Celmeli, Fatih, Klein, Christoph, AlKhater, Suzan A, Casanova, Jean-Laurent, and Puel, Anne

Subjects
Pediatric, Genetics, Clinical Research, Infectious Diseases, Rare Diseases, Emerging Infectious Diseases, Aetiology, 2.1 Biological and endogenous factors, Infection, Good Health and Well Being, Alleles, Bacterial Infections, Candida, Candidiasis, Cell Membrane, Child, Child, Preschool, Family Health, Female, Fibroblasts, Genes, Recessive, Genome-Wide Association Study, HEK293 Cells, Homozygote, Humans, Immunophenotyping, Infant, Infant, Newborn, Interleukin-17, Male, Mutation, Mycoses, Open Reading Frames, Pedigree, Receptors, Interleukin-17, Skin, T-Lymphocytes, genetics, immunodeficiency, candidiasis
Abstract

Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensal Candida species. The first genetic etiology of isolated CMC-autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency-was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity to Candida and Staphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.

Published
2016

9. Delayed induction of type I and III interferons mediates nasal epithelial cell permissiveness to SARS-CoV-2

Author

Hatton, Catherine F., Botting, Rachel A., Dueñas, Maria Emilia, Haq, Iram J., Verdon, Bernard, Thompson, Benjamin J., Spegarova, Jarmila Stremenova, Gothe, Florian, Stephenson, Emily, Gardner, Aaron I., Murphy, Sandra, Scott, Jonathan, Garnett, James P., Carrie, Sean, Powell, Jason, Khan, C. M. Anjam, Huang, Lei, Hussain, Rafiqul, Coxhead, Jonathan, Davey, Tracey, Simpson, A. John, Haniffa, Muzlifah, Hambleton, Sophie, Brodlie, Malcolm, Ward, Chris, Trost, Matthias, Reynolds, Gary, and Duncan, Christopher J. A.

Published
2021
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18. CF, PAP und EAA – oder doch ganz anders?

Author

Tröltzsch, Louise, additional, Lejeune, Alice C., additional, Yoosefi, Mehrak, additional, Lau, Susanne, additional, Mall, Marcus A., additional, Michel, Katarzyna, additional, Gothe, Florian, additional, Griese, Matthias, additional, and Stahl, Mirjam, additional

Published
2023
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19. ABCA3-related interstitial lung disease beyond infancy

Author

Li, Yang, primary, Seidl, Elias, additional, Knoflach, Katrin, additional, Gothe, Florian, additional, Forstner, Maria Elisabeth, additional, Michel, Katarzyna, additional, Pawlita, Ingo, additional, Gesenhues, Florian, additional, Sattler, Franziska, additional, Yang, Xiaohua, additional, Kroener, Carolin, additional, Reu-Hofer, Simone, additional, Ley-Zaporozhan, Julia, additional, Kammer, Birgit, additional, Krüger-Stollfuß, Ingrid, additional, Dinkel, Julien, additional, Carlens, Julia, additional, Wetzke, Martin, additional, Moreno-Galdó, Antonio, additional, Torrent-Vernetta, Alba, additional, Lange, Joanna, additional, Krenke, Katarzyna, additional, Rumman, Nisreen, additional, Mayell, Sarah, additional, Sismanlar, Tugba, additional, Aslan, Ayse, additional, Regamey, Nicolas, additional, Proesmans, Marijke, additional, Stehling, Florian, additional, Naehrlich, Lutz, additional, Ayse, Kilinc, additional, Becker, Sebastian, additional, Koerner-Rettberg, Cordula, additional, Plattner, Erika, additional, Manali, Effrosyni D, additional, Papiris, Spyridon A, additional, Campo, Ilaria, additional, Kappler, Matthias, additional, Schwerk, Nicolaus, additional, and Griese, Matthias, additional

Published
2023
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20. Diffuse alveolar hemorrhage in children with interstitial lung disease:Determine etiologies!

Author

Knoflach, Katrin, Rapp, Christina Katharina, Schwerk, Nicolaus, Carlens, Julia, Wetzke, Martin, Emiralioğlu, Nagehan, Kiper, Nural, Ring, Astrid Madsen, Buchvald, Frederik, Manali, Effrosyni, Papiris, Spyros, Reu-Hofer, Simone, Kappler, Matthias, Schieber, Alexandra, Seidl, Elias, Gothe, Florian, Robinson, Peter N., Griese, Matthias, Knoflach, Katrin, Rapp, Christina Katharina, Schwerk, Nicolaus, Carlens, Julia, Wetzke, Martin, Emiralioğlu, Nagehan, Kiper, Nural, Ring, Astrid Madsen, Buchvald, Frederik, Manali, Effrosyni, Papiris, Spyros, Reu-Hofer, Simone, Kappler, Matthias, Schieber, Alexandra, Seidl, Elias, Gothe, Florian, Robinson, Peter N., and Griese, Matthias

Abstract

Objective: Diffuse alveolar hemorrhage (DAH) in children is a rare condition resulting from different underlying diseases. This study aimed at describing characteristics and diagnostic measures in children with ILD (children's interstitial lung disease, chILD) and DAH to improve the diagnostic approach by increasing clinician's awareness of diagnostic shortcomings. Patients and Methods: A retrospective data analysis of patients with ILD and DAH treated in our own or collaborating centers between 01/07/1997 and 31/12/2020 was performed. Data on clinical courses and diagnostic measures were systematically retrieved as case-vignettes and investigated. To assess suitability of diagnostic software-algorithms, the Human Phenotype Ontology (HPO) was revised and expanded to optimize conditions of its associated tool the “Phenomizer.”. Results: For 97 (74%) of 131 patients, etiology of pulmonary hemorrhage was clarified. For 34 patients (26%), no underlying condition was found (termed as idiopathic pulmonary hemorrhage, IPH). Based on laboratory findings or clinical phenotype/comorbidities, 20 of these patients were assigned to descriptive clusters: IPH associated with autoimmune features (9), eosinophilia (5), renal disease (3) or multiorgan involvement (3). For 14 patients, no further differentiation was possible. Conclusion: Complete and sometimes repeated diagnostics are essential for establishing the correct diagnosis in children with DAH. We suggest assignment of patients with IPH to descriptive clusters, which may also guide further research. Digital tools such as the Phenomizer/HPO are promising, but need to be extended to increase diagnostic accuracy.

Published
2023

21. Type I interferon receptor (IFNAR2) deficiency reveals Zika virus cytopathicity in human macrophages and microglia

Author

Hanrath, Aidan T., primary, Hatton, Catherine F., additional, Gothe, Florian, additional, Browne, Cathy, additional, Vowles, Jane, additional, Leary, Peter, additional, Cockell, Simon J., additional, Cowley, Sally A., additional, James, William S., additional, Hambleton, Sophie, additional, and Duncan, Christopher J. A., additional

Published
2022
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22. 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

23. STAT5B restrains human B-cell differentiation to maintain humoral immune homeostasis

Author

Pelham, Simon J., primary, Caldirola, Maria Soledad, additional, Avery, Danielle T., additional, Mackie, Joseph, additional, Rao, Geetha, additional, Gothe, Florian, additional, Peters, Timothy J., additional, Guerin, Antoine, additional, Neumann, David, additional, Vokurkova, Doris, additional, Hwa, Vivian, additional, Zhang, Wenming, additional, Lyu, Shu-Chen, additional, Chang, Iris, additional, Manohar, Monali, additional, Nadeau, Kari C., additional, Gaillard, Maria Isabel, additional, Bezrodnik, Liliana, additional, Iotova, Violeta, additional, Zwirner, Norberto Walter, additional, Gutierrez, Mavel, additional, Al-Herz, Waleed, additional, Goodnow, Christopher C., additional, Vargas-Hernández, Alexander, additional, Forbes Satter, Lisa R., additional, Hambleton, Sophie, additional, Deenick, Elissa K., additional, Ma, Cindy S., additional, and Tangye, Stuart G., additional

Published
2022
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24. Aberrant inflammatory responses to type I interferon in STAT2 or IRF9 deficiency

Author

Gothe, Florian, primary, Stremenova Spegarova, Jarmila, additional, Hatton, Catherine F., additional, Griffin, Helen, additional, Sargent, Thomas, additional, Cowley, Sally A., additional, James, William, additional, Roppelt, Anna, additional, Shcherbina, Anna, additional, Hauck, Fabian, additional, Reyburn, Hugh T., additional, Duncan, Christopher J.A., additional, and Hambleton, Sophie, additional

Published
2022
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25. ABCA3-related interstitial lung disease beyond infancy.

Author

Yang Li, Seidl, Elias, Knoflach, Katrin, Gothe, Florian, Forstner, Maria Elisabeth, Michel, Katarzyna, Pawlita, Ingo, Gesenhues, Florian, Sattler, Franziska, Xiaohua Yang, Kroener, Carolin, Reu-Hofer, Simone, Ley-Zaporozhan, Julia, Kammer, Birgit, Krüger-Stollfuß, Ingrid, Dinkel, Julien, Carlens, Julia, Wetzke, Martin, Moreno-Galdó, Antonio, and Torrent-Vernetta, Alba

Subjects
INTERSTITIAL lung diseases, INFANTS, IDIOPATHIC pulmonary fibrosis, FORCED expiratory volume
Published
2023
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26. Single-cell multi-omics analysis of the immune response in COVID-19

Author

Stephenson, Emily, Reynolds, Gary, Botting, Rachel A., Calero-Nieto, Fernando J., Morgan, Michael D., Tuong, Zewen Kelvin, Bach, Karsten, Sungnak, Waradon, Worlock, Kaylee B., Yoshida, Masahiro, Kumasaka, Natsuhiko, Kania, Katarzyna, Engelbert, Justin, Olabi, Bayanne, Spegarova, Jarmila Stremenova, Wilson, Nicola K., Mende, Nicole, Jardine, Laura, Gardner, Louis C. S., Goh, Issac, Horsfall, Dave, McGrath, Jim, Webb, Simone, Mather, Michael W., Lindeboom, Rik G. H., Dann, Emma, Huang, Ni, Polanski, Krzysztof, Prigmore, Elena, Gothe, Florian, Scott, Jonathan, Payne, Rebecca P., Baker, Kenneth F., Hanrath, Aidan T., Schim van der Loeff, Ina C. D., Barr, Andrew S., Sanchez-Gonzalez, Amada, Bergamaschi, Laura, Mescia, Federica, Barnes, Josephine L., Kilich, Eliz, de Wilton, Angus, Saigal, Anita, Saleh, Aarash, Janes, Sam M., Smith, Claire M., Gopee, Nusayhah, Wilson, Caroline, Coupland, Paul, Coxhead, Jonathan M., Kiselev, Vladimir Yu, van Dongen, Stijn, Bacardit, Jaume, King, Hamish W., Rostron, Anthony J., Simpson, A. John, Hambleton, Sophie, Laurenti, Elisa, Lyons, Paul A., Meyer, Kerstin B., Nikolić, Marko Z., Duncan, Christopher J. A., Smith, Kenneth G. C., Teichmann, Sarah A., Clatworthy, Menna R., Marioni, John C., Göttgens, Berthold, and Haniffa, Muzlifah

Subjects
Proteome, COVID-19, Cross-Sectional Studies, Humans, Monocytes, Receptors, Antigen, B-Cell, Receptors, Antigen, T-Cell, SARS-CoV-2, Single-Cell Analysis, T-Lymphocytes, Transcriptome, CD34, Biology, Peripheral blood mononuclear cell, Article, General Biochemistry, Genetics and Molecular Biology, Immune system, Antigen, Receptors, Platelet activation, Progenitor cell, B-Cell, RNA sequencing, General Medicine, T-Cell, Haematopoiesis, Viral infection, Immunology, Infection, CD8
Abstract

Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16+C1QA/B/C+) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy., Transcriptomic and proteomic profiling of blood samples from individuals with COVID-19 reveals immune cell and hematopoietic progenitor cell alterations that are differentially associated with disease severity.

Published
2021

28. Autoimmune PAP (aPAP) in children

Author

Griese, Matthias, primary, Panagiotou, Panagiota, additional, Manali, Effrosyni D., additional, Stahl, Mirjam, additional, Schwerk, Nicolaus, additional, Costa, Vanessa, additional, Douros, Konstantinos, additional, Kallieri, Maria, additional, Urbantat, Ruth Maria, additional, von Bernuth, Horst, additional, Kolilekas, Lykourgos, additional, Morais, Lurdes, additional, Ramos, Ana, additional, Landwehr, Kerstin, additional, Knoflach, Katrin, additional, Gothe, Florian, additional, Reiter, Karl, additional, Papaevangelou, Vassiliki, additional, Kaditis, Athanasios G., additional, Kanaka-Gantenbein, Christina, additional, and Papiris, Spyros A., additional

Published
2022
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30. Immune dysregulation as a consequence of genetic variants within the JAK-STAT signalling pathway

Author

Gothe, Florian

Subjects
FOS: Medical and Health Sciences
Abstract

Research in immunology has been a rapidly evolving field in recent years, largely facilitated by the advent of next-generation sequencing techniques. The opportunity to study the entire coding sequence of the genome has resulted in the discovery of more than 400 well-characterized, mon-ogenic inborn errors of immunity. Research on these rare patients, who mostly present early in life to pediatric hospitals, has informed our understanding of human immunity since it allows to study the function of a mutated gene product in the context of human disease. Whilst the power of the immune system has evolved to fight infection, fine-tuned regulatory mech-anisms gained importance. Keeping the balance between tolerance and protection involves close communication between immune cells and their environment. Such interactions are often medi-ated by soluble factors, i.e. cytokines. The work presented in this thesis is centered around two important signalling pathways: Interleu-kin-2 signalling has long been recognized pivotal for T cell immunity. The discovery of homozy-gous loss-of-function variants in IL2RB underscores its non-redundant role in preventing autoim-munity by promoting regulatory T cell survival and function. Additionally, a terminal differentiation defect of cytotoxic lymphocytes renders affected patients specifically susceptible to Cytomegalo-virus disease. Additional work on patients with loss- and gain-of-functions in the downstream sig-nalling molecule STAT5B expands the phenotypic spectrum and explores potential treatment op-tions using Janus tyrosine kinase inhibitors. The second pathway under study is type I interferon signalling. Functional validation of a new biallelic IFNAR1 variant abrogating responses to type I interferon was undertaken in an individual presenting with haemophagocytic lymphohistiocytosis following receipt of live-viral vaccine. Le-thal autoinflammation was also seen in patients where homozygous STAT2 variants were found to hamper negative feedback regulation and thus causing unrestrained type I interferon activity. Mechanistic studies on the inflammatory consequences of dysregulated type I interferon re-sponses in STAT2- and IRF9-deficient primary cells and induced pluripotent stem cell derived macrophages offer a molecular explanation for the clinically observed inflammation in these indi-viduals. By dissecting the molecular mechanisms underlying immune dysregulation in these rare patients with monogenic errors of immunity I am hoping to contribute to improved diagnostic rates and to help pave the way for personalized treatment options in these ‘orphan’ diseases.

Published
2022
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32. The expansion of human T-bet high CD21 low B cells is T cell dependent

Author

Keller, Baerbel, primary, Strohmeier, Valentina, additional, Harder, Ina, additional, Unger, Susanne, additional, Payne, Kathryn J., additional, Andrieux, Geoffroy, additional, Boerries, Melanie, additional, Felixberger, Peter Tobias, additional, Landry, Jonathan J. M., additional, Nieters, Alexandra, additional, Rensing-Ehl, Anne, additional, Salzer, Ulrich, additional, Frede, Natalie, additional, Usadel, Susanne, additional, Elling, Roland, additional, Speckmann, Carsten, additional, Hainmann, Ina, additional, Ralph, Elizabeth, additional, Gilmour, Kimberly, additional, Wentink, Marjolein W. J., additional, van der Burg, Mirjam, additional, Kuehn, Hye Sun, additional, Rosenzweig, Sergio D., additional, Kölsch, Uwe, additional, von Bernuth, Horst, additional, Kaiser-Labusch, Petra, additional, Gothe, Florian, additional, Hambleton, Sophie, additional, Vlagea, Alexandru Daniel, additional, Garcia Garcia, Ana, additional, Alsina, Laia, additional, Markelj, Gašper, additional, Avcin, Tadej, additional, Vasconcelos, Julia, additional, Guedes, Margarida, additional, Ding, Jing-Ya, additional, Ku, Cheng-Lung, additional, Shadur, Bella, additional, Avery, Danielle T., additional, Venhoff, Nils, additional, Thiel, Jens, additional, Becker, Heiko, additional, Erazo-Borrás, Lucía, additional, Trujillo-Vargas, Claudia Milena, additional, Franco, José Luis, additional, Fieschi, Claire, additional, Okada, Satoshi, additional, Gray, Paul E., additional, Uzel, Gulbu, additional, Casanova, Jean-Laurent, additional, Fliegauf, Manfred, additional, Grimbacher, Bodo, additional, Eibel, Hermann, additional, Ehl, Stephan, additional, Voll, Reinhard E., additional, Rizzi, Marta, additional, Stepensky, Polina, additional, Benes, Vladimir, additional, Ma, Cindy S., additional, Bossen, Claudia, additional, Tangye, Stuart G., additional, and Warnatz, Klaus, additional

Published
2021
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34. Early‐onset, fatal interstitial lung disease in STAT3 gain‐of‐function patients

Author

Gothe, Florian, primary, Gehrig, Jonathan, additional, Rapp, Christina K., additional, Knoflach, Katrin, additional, Reu‐Hofer, Simone, additional, Länger, Florian, additional, Schramm, Dirk, additional, Ley‐Zaporozhan, Julia, additional, Ehl, Stephan, additional, Schwerk, Nicolaus, additional, Faletti, Laura, additional, and Griese, Matthias, additional

Published
2021
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36. Delayed induction of type I and III interferons mediates nasal epithelial cell permissiveness to SARS-CoV-2

Author

Hatton, Catherine F, primary, Botting, Rachel A, additional, Dueñas, Maria Emilia, additional, Haq, Iram J, additional, Verdon, Bernard, additional, Thompson, Benjamin J, additional, Spegarova, Jarmila Stremenova, additional, Gothe, Florian, additional, Stephenson, Emily, additional, Gardner, Aaron I, additional, Murphy, Sandra, additional, Scott, Jonathan, additional, Garnett, James P, additional, Carrie, Sean, additional, Powell, Jason, additional, Khan, C M Anjam, additional, Huang, Lei, additional, Hussain, Rafiqul, additional, Coxhead, Jonathan, additional, Davey, Tracey, additional, Simpson, A John, additional, Haniffa, Muzlifah, additional, Hambleton, Sophie, additional, Brodlie, Malcolm, additional, Ward, Chris, additional, Trost, Matthias, additional, Reynolds, Gary, additional, and Duncan, Christopher J A, additional

Published
2021
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37. A Novel Case of Homozygous Interferon Alpha/Beta Receptor Alpha Chain (IFNAR1) Deficiency With Hemophagocytic Lymphohistiocytosis

Author

Gothe, Florian, primary, Hatton, Catherine F, additional, Truong, Linh, additional, Klimova, Zofia, additional, Kanderova, Veronika, additional, Fejtkova, Martina, additional, Grainger, Angela, additional, Bigley, Venetia, additional, Perthen, Joanna, additional, Mitra, Dipayan, additional, Janda, Ales, additional, Fronkova, Eva, additional, Moravcikova, Dusana, additional, Hambleton, Sophie, additional, and Duncan, Christopher J A, additional

Published
2020
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39. Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2

Author

Duncan, Christopher J. A., primary, Thompson, Benjamin J., additional, Chen, Rui, additional, Rice, Gillian I., additional, Gothe, Florian, additional, Young, Dan F., additional, Lovell, Simon C., additional, Shuttleworth, Victoria G., additional, Brocklebank, Vicky, additional, Corner, Bronte, additional, Skelton, Andrew J., additional, Bondet, Vincent, additional, Coxhead, Jonathan, additional, Duffy, Darragh, additional, Fourrage, Cecile, additional, Livingston, John H., additional, Pavaine, Julija, additional, Cheesman, Edmund, additional, Bitetti, Stephania, additional, Grainger, Angela, additional, Acres, Meghan, additional, Innes, Barbara A., additional, Mikulasova, Aneta, additional, Sun, Ruyue, additional, Hussain, Rafiqul, additional, Wright, Ronnie, additional, Wynn, Robert, additional, Zarhrate, Mohammed, additional, Zeef, Leo A. H., additional, Wood, Katrina, additional, Hughes, Stephen M., additional, Harris, Claire L., additional, Engelhardt, Karin R., additional, Crow, Yanick J., additional, Randall, Richard E., additional, Kavanagh, David, additional, Hambleton, Sophie, additional, and Briggs, Tracy A., additional

Published
2019
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41. Novel Case of Homozygous Interferon Alpha/Beta Receptor Alpha Chain (IFNAR1) Deficiency With Hemophagocytic Lymphohistiocytosis.

Author

Gothe, Florian, Hatton, Catherine F, Truong, Linh, Klimova, Zofia, Kanderova, Veronika, Fejtkova, Martina, Grainger, Angela, Bigley, Venetia, Perthen, Joanna, Mitra, Dipayan, Janda, Ales, Fronkova, Eva, Moravcikova, Dusana, Hambleton, Sophie, and Duncan, Christopher J A

Subjects
*HEMOPHAGOCYTIC lymphohistiocytosis, *IMMUNIZATION, *INFLAMMATION, *CELL receptors, *INTERFERONS, *IMMUNOLOGICAL deficiency syndromes, *INBORN errors of metabolism
Abstract

We present a case of complete deficiency of the interferon alpha/beta receptor alpha chain (IFNAR1) in a child with fatal systemic hyperinflammation, apparently provoked by live-attenuated viral vaccination. Such pathologic hyperinflammation, fulfilling criteria for hemophagocytic lymphohistiocytosis, is an emerging phenotype accompanying inborn errors of type I interferon immunity. [ABSTRACT FROM AUTHOR]

Published
2022
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42. Human interleukin-2 receptor beta mutations associated with defects in immunity and peripheral tolerance

Author

Zhang, Zinan, primary, Gothe, Florian, additional, Pennamen, Perrine, additional, James, John, additional, McDonald, David, additional, Mata, Carlos, additional, Modis, Yorgo, additional, Alazami, Anas, additional, Acres, Megan, additional, Haller, Wolfram, additional, Bowen, Claire, additional, Doffinger, Rainer, additional, Sinclair, Jan, additional, Brothers, Shannon, additional, Zhang, Yu, additional, Matthews, Helen, additional, Naudion, Sophie, additional, Pelluard, Fanny, additional, Alajlan, Huda, additional, Yamazaki, Yasuhiro, additional, Notarangelo, Luigi, additional, Thaventhiran, James, additional, Engelhardt, Karin, additional, Al-Mousa, Hamoud, additional, Hambleton, Sophie, additional, Rooryck, Caroline, additional, Smith, Kenneth G.C., additional, and Lenardo, Michael J, additional

Published
2019
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43. Human interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance

Author

Zhang, Zinan, primary, Gothe, Florian, additional, Pennamen, Perrine, additional, James, John R., additional, McDonald, David, additional, Mata, Carlos P., additional, Modis, Yorgo, additional, Alazami, Anas M., additional, Acres, Meghan, additional, Haller, Wolfram, additional, Bowen, Claire, additional, Döffinger, Rainer, additional, Sinclair, Jan, additional, Brothers, Shannon, additional, Zhang, Yu, additional, Matthews, Helen F., additional, Naudion, Sophie, additional, Pelluard, Fanny, additional, Alajlan, Huda, additional, Yamazaki, Yasuhiro, additional, Notarangelo, Luigi D., additional, Thaventhiran, James E., additional, Engelhardt, Karin R., additional, Al-Mousa, Hamoud, additional, Hambleton, Sophie, additional, Rooryck, Caroline, additional, Smith, Kenneth G.C., additional, and Lenardo, Michael J., additional

Published
2019
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44. Human IL-2 receptor β mutations associated with defects in immunity and peripheral tolerance

Author

Zhang, Zinan, primary, Gothe, Florian, additional, Pennamen, Perrine, additional, James, John, additional, MacDonald, David, additional, Mata, Carlos P., additional, Modis, Yorgo, additional, Acres, Meghan, additional, Haller, Wolfram, additional, Bowen, Claire, additional, Doffinger, Rainer, additional, Sinclair, Jan, additional, Brothers, Shannon, additional, Alazami, Anas, additional, Zhang, Yu, additional, Matthews, Helen, additional, Naudion, Sophie, additional, Pelluard, Fanny, additional, Yamazaki, Yasuhiro, additional, Notarangelo, Luigi, additional, Almousa, Hamoud, additional, Thaventhiran, James, additional, Engelhardt, Karin R., additional, Hambleton, Sophie, additional, Rooryck, Caroline, additional, Smith, Ken, additional, and Lenardo, Michael J., additional

Published
2018
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46. Additional file 5: Table S4. of Categorizing diffuse parenchymal lung disease in children

Author

Griese, Matthias, Irnstetter, Armin, Hengst, Meike, Burmester, Helen, Nagel, Felicitas, Ripper, Jan, Feilcke, Maria, Pawlita, Ingo, Gothe, Florian, Kappler, Matthias, Schams, Andrea, Wesselak, Traudl, Rauch, Daniela, Wittmann, Thomas, Lohse, Peter, Brasch, Frank, and KrĂśner, Carolin

Abstract

Overall frequencies of diagnostics available for the establishment of the final working diagnosis, categorization and sub-categorization. Note that not all tests were performed in all patients. (DOCX 15Â kb)

Published
2015
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48. Additional file 2: Figure S1. of Categorizing diffuse parenchymal lung disease in children

Author

Griese, Matthias, Irnstetter, Armin, Hengst, Meike, Burmester, Helen, Nagel, Felicitas, Ripper, Jan, Feilcke, Maria, Pawlita, Ingo, Gothe, Florian, Kappler, Matthias, Schams, Andrea, Wesselak, Traudl, Rauch, Daniela, Wittmann, Thomas, Lohse, Peter, Brasch, Frank, and KrĂśner, Carolin

Abstract

Routine work-flow used in the Kids lung register (KLR) to obtain a final working diagnosis and to categorize and subcategorize cases with suspected DPLD (black and red). The work-flow used for re-rating is depicted in red. *reference pathologist was Frank Brasch, **genetical diagnosis was made by Peter Lohse and ***lavage report on surfactant protein analysis, as well as the establishment of the final working diagnosis during routine KLR workflow were done by Matthias Griese. (PDF 176Â kb)

Published
2015
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50. Categorizing diffuse parenchymal lung disease in children

Author

Griese, Matthias, primary, Irnstetter, Armin, additional, Hengst, Meike, additional, Burmester, Helen, additional, Nagel, Felicitas, additional, Ripper, Jan, additional, Feilcke, Maria, additional, Pawlita, Ingo, additional, Gothe, Florian, additional, Kappler, Matthias, additional, Schams, Andrea, additional, Wesselak, Traudl, additional, Rauch, Daniela, additional, Wittmann, Thomas, additional, Lohse, Peter, additional, Brasch, Frank, additional, and Kröner, Carolin, additional

Published
2015
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