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2. Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents Infection of Omicron lineages

Author

Marcotte, Harold, Cao, Yunlong, Zuo, Fanglei, Simonelli, Luca, Sammartino, Jose Camilla, Pedotti, Mattia, Sun, Rui, Cassaniti, Irene, Hagbom, Marie, Piralla, Antonio, Yang, Jinxuan, Du, Likun, Percivalle, Elena, Bertoglio, Federico, Schubert, Maren, Abolhassani, Hassan, Sherina, Natalia, Guerra, Concetta, Borte, Stephan, Rezaei, Nima, Kumagai-Braesch, Makiko, Xue, Yintong, Su, Chen, Yan, Qihong, He, Ping, Groenwall, Caroline, Klareskog, Lars, Calzolai, Luigi, Cavalli, Andrea, Wang, Qiao, Robbiani, Davide F., Hust, Michael, Shi, Zhengli, Feng, Liqiang, Svensson, Lennart, Chen, Ling, Bao, Linlin, Baldanti, Fausto, Xiao, Junyu, Qin, Chuan, Hammarstrom, Lennart, Yang, Xinglou, Varani, Luca, Xie, Xiaoliang Sunney, Pan-Hammarstrom, Qiang, Marcotte, Harold, Cao, Yunlong, Zuo, Fanglei, Simonelli, Luca, Sammartino, Jose Camilla, Pedotti, Mattia, Sun, Rui, Cassaniti, Irene, Hagbom, Marie, Piralla, Antonio, Yang, Jinxuan, Du, Likun, Percivalle, Elena, Bertoglio, Federico, Schubert, Maren, Abolhassani, Hassan, Sherina, Natalia, Guerra, Concetta, Borte, Stephan, Rezaei, Nima, Kumagai-Braesch, Makiko, Xue, Yintong, Su, Chen, Yan, Qihong, He, Ping, Groenwall, Caroline, Klareskog, Lars, Calzolai, Luigi, Cavalli, Andrea, Wang, Qiao, Robbiani, Davide F., Hust, Michael, Shi, Zhengli, Feng, Liqiang, Svensson, Lennart, Chen, Ling, Bao, Linlin, Baldanti, Fausto, Xiao, Junyu, Qin, Chuan, Hammarstrom, Lennart, Yang, Xinglou, Varani, Luca, Xie, Xiaoliang Sunney, and Pan-Hammarstrom, Qiang

Abstract

The emergence of Omicron lineages and descendent subvariants continues to present a severe threat to the effectiveness of vaccines and therapeutic antibodies. We have previ- ously suggested that an insufficient mucosal immunoglobulin A (IgA) response induced by the mRNA vaccines is associated with a surge in breakthrough infections. Here, we further show that the intramuscular mRNA and/or inactivated vaccines cannot suffi- ciently boost the mucosal secretory IgA response in uninfected individuals, particu- larly against the Omicron variant. We thus engineered and characterized recombinant monomeric, dimeric, and secretory IgAl antibodies derived from four neutralizing IgG monoclonal antibodies (mAbs 01A05, rmAb23, DXP-604, and XG014) targeting the receptor-binding domain of the spike protein. Compared to their parental IgG antibod- ies, dimeric and secretory IgAl antibodies showed a higher neutralizing activity against different variants of concern (VOCs), in part due to an increased avidity. Importantly, the dimeric or secretory IgAl form of the DXP-604 antibody significantly outperformed its parental IgG antibody, and neutralized the Omicron lineages BA.1, BA.2, and BA.4/5 with a 25- to 75-fold increase in potency. In human angiotensin converting enzyme 2 (ACE2) transgenic mice, a single intranasal dose of the dimeric IgA DXP-604 conferred prophylactic and therapeutic protection against Omicron BA.5. Thus, dimeric or secre- tory IgA delivered by nasal administration may potentially be exploited for the treatment Iand prevention of Omicron infection, thereby providing an alternative tool for combating immune evasion by the current circulating subvariants and, potentially, future VOCs.

Published
2024
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3. Ribosomal Protein SA Haploinsufficiency in Humans with Isolated Congenital Asplenia

Author

Bolze, Alexandre, Mahlaoui, Nizar, Byun, Minji, Turner, Bridget, Trede, Nikolaus, Ellis, Steven R, Abhyankar, Avinash, Itan, Yuval, Patin, Etienne, Brebner, Samuel, Sackstein, Paul, Puel, Anne, Picard, Capucine, Abel, Laurent, Quintana-Murci, Lluis, Faust, Saul N, Williams, Anthony P, Baretto, Richard, Duddridge, Michael, Kini, Usha, Pollard, Andrew J, Gaud, Catherine, Frange, Pierre, Orbach, Daniel, Emile, Jean-Francois, Stephan, Jean-Louis, Sorensen, Ricardo, Plebani, Alessandro, Hammarstrom, Lennart, Conley, Mary Ellen, Selleri, Licia, and Casanova, Jean-Laurent

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Research, Congenital Structural Anomalies, Pediatric, DNA Mutational Analysis, Genetic Loci, Haploinsufficiency, Heterotaxy Syndrome, Humans, Mutation, Pedigree, Penetrance, Receptors, Laminin, Ribosomal Proteins, Spleen, General Science & Technology
Abstract

Isolated congenital asplenia (ICA) is characterized by the absence of a spleen at birth in individuals with no other developmental defects. The patients are prone to life-threatening bacterial infections. The unbiased analysis of exomes revealed heterozygous mutations in RPSA in 18 patients from eight kindreds, corresponding to more than half the patients and over one-third of the kindreds studied. The clinical penetrance in these kindreds is complete. Expression studies indicated that the mutations carried by the patients-a nonsense mutation, a frameshift duplication, and five different missense mutations-cause autosomal dominant ICA by haploinsufficiency. RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome. This discovery establishes an essential role for RPSA in human spleen development.

Published
2013

4. Vaccination with Helicobacter pylori attachment proteins protects against gastric cancer

Author

Boren, Thomas, primary, Bugaytsova, Jeanna A., additional, Piddubnyi, Artem, additional, Tkachenko, Iryna, additional, Rakhimova, Lena, additional, Olofsson Edlund, Johan, additional, Thorell, Kaisa, additional, Marcotte, Harold, additional, Lundquist, Anders, additional, Schon, Karin, additional, Suerbaum, Sebastian, additional, Schulz, Christian, additional, Malfertheiner, Peter, additional, Hansen, Lori M., additional, Solnick, Jay V., additional, Moskalenko, Roman, additional, and Hammarstrom, Lennart, additional

Published
2023
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5. Helicobacter pylori attachment-blocking antibodies protect against duodenal ulcer disease

Author

Boren, Thomas, primary, Bugaytsova, Jeanna A., additional, Moonens, Kristof, additional, Piddubnyi, Artem, additional, Schmidt, Alexej, additional, Edlund, Johan Olofsson, additional, Lisiutin, Gennadii, additional, Brannstrom, Kristoffer, additional, Chernov, Yevgen A., additional, Thorell, Kaisa, additional, Tkachenko, Iryna, additional, Sharova, Oleksandra, additional, Vikhrova, Iryna, additional, Butsyk, Anna, additional, Shubin, Pavlo, additional, Chyzhma, Ruslana, additional, Johansson, Daniel X., additional, Marcotte, Harold, additional, Sjostrom, Rolf, additional, Shevtsova, Anna, additional, Bylund, Goran, additional, Rakhimova, Lena, additional, Lundquist, Anders, additional, Berhilevych, Oleksandra, additional, Kasianchuk, Victoria, additional, Loboda, Andrii, additional, Ivanytsia, Volodymyr, additional, Hultenby, Kjell, additional, Persson, Mats A. A., additional, Gomes, Joana, additional, Matos, Rita, additional, Gartner, Fatima, additional, Reis, Celso A., additional, Whitmire, Jeannette M., additional, Merrell, Douglas Scott, additional, Pan-Hammarstrom, Qiang, additional, Landstrom, Marene, additional, Oscarson, Stefan, additional, DElios, Mario M., additional, Agreus, Lars, additional, Ronkainen, Jukka, additional, Aro, Pertti, additional, Engstrand, Lars, additional, Graham, David Y., additional, Kachkovska, Vladyslava, additional, Mukhopadhyay, Asish, additional, Chaudhuri, Sujit, additional, Karmakar, Bipul Chandra, additional, Paul, Sangita, additional, Kravets, Oleksandr, additional, Camorlinga-Ponce, Margarita, additional, Torres, Javier, additional, Berg, Douglas E., additional, Moskalenko, Roman, additional, Haas, Rainer, additional, Remaut, Han, additional, and Hammarstrom, Lennart, additional

Published
2023
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6. Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents infection of Omicron lineages

Author

Marcotte, Harold, primary, Cao, Yunlong, additional, Zuo, Fanglei, additional, Simonelli, Luca, additional, Sammartino, Jose Camilla, additional, Pedotti, Mattia, additional, Sun, Rui, additional, Cassaniti, Irene, additional, Hagbom, Marie, additional, Piralla, Antonio, additional, Yang, Jinxuan, additional, Du, Likun, additional, Percivalle, Elena, additional, Bertoglio, Federico, additional, Schubert, Maren, additional, Abolhassani, Hassan, additional, Sherina, Natalia, additional, Guerra, Concetta, additional, Borte, Stephan, additional, Razaei, Nima, additional, Kumagai-Braesch, Makiko, additional, Xue, Yintong, additional, Gronwall, Caroline, additional, Klareskog, Lars, additional, Calzolai, Luigi, additional, Cavalli, Andrea, additional, Wang, Qiao, additional, Robbiani, Davide F., additional, Hust, Michael, additional, Shi, Zhengli, additional, Feng, Liqiang, additional, Svensson, Lennart, additional, Chen, Ling, additional, Bao, Linlin, additional, Baldanti, Fausto, additional, Qin, Chuan, additional, Xiao, Junyu, additional, Hammarstrom, Lennart, additional, Yang, Xing Lou, additional, Varani, Luca, additional, Sunney Xie, Xiaoliang, additional, and Pan-Hammarstrom, Qiang, additional

Published
2023
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7. Heterologous inactivated virus/mRNA vaccination response to BF.7, BQ.1.1, and XBB.1

Author

Zuo, Fanglei, primary, Sun, Rui, additional, Abolhassani, Hassan, additional, Du, Likun, additional, Wang, Yating, additional, Vlachiotis, Stelios, additional, Bertoglio, Federico, additional, Schubert, Maren, additional, Rezaei, Nima, additional, Chavoshzadeh, Zahra, additional, Guerra, Concetta, additional, Cavalli, Andrea, additional, Andrell, Juni, additional, Kumagai-Braesch, Makiko, additional, Xue, Yintong, additional, Cao, Yunlong, additional, Hust, Michael, additional, F. Robbiani, Davide, additional, Xie, Xiaoliang, additional, Hammarstrom, Lennart, additional, Marcotte, Harold, additional, and Pan-Hammarstrom, Qiang, additional

Published
2023
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8. Somatic reversion of pathogenic DOCK8 variants alters lymphocyte differentiation and function to effectively cure DOCK8 deficiency

Author

Pillay, Bethany A., Fusaro, Mathieu, Gray, Paul E., Statham, Aaron L., Burne, Leslie, Bezrodnik, Liliana, Kane, Alisa, Tong, Winnie, Abdo, Chrystelle, Winter, Sarah, Chevalier, Samuel, Levy, Romain, Masson, Cecile, Schmi, Yohann, Bole, Christine, Malphettes, Marion, Macintyre, Elizabeth, De Villartay, Jean-Pierre, Ziegler, John B., Peake, Joanne M. Smar Jane, Aghamohammadi, Asghar, Hammarstrom, Lennart, Abolhassani, Hassan, Picard, Capucine, Fischer, Alain, Latour, Sylvain, Neven, Benedicte, Tangye, Stuart G., and Ma, Cindy S.

Subjects
Immunological deficiency syndromes -- Development and progression -- Genetic aspects, Lymphocytes -- Physiological aspects -- Genetic aspects -- Health aspects, Genetic variation -- Health aspects, Health care industry
Abstract

Inborn errors of immunity cause monogenic immune dysregulatory conditions such as severe and recurrent pathogen infection, inflammation, allergy, and malignancy. Somatic reversion refers to the spontaneous repair of a pathogenic germline genetic variant and has been reported to occur in a number of inborn errors of immunity, with a range of impacts on clinical outcomes of these conditions. DOCK8 deficiency due to biallelic inactivating mutations in DOCK8 causes a combined immunodeficiency characterized by severe bacterial, viral, and fungal infections, as well as allergic disease and some cancers. Here, we describe the clinical, genetic, and cellular features of 3 patients with biallelic DOCK8 variants who, following somatic reversion in multiple lymphocyte subsets, exhibited improved clinical features, including complete resolution of infection and allergic disease, and cure over time. Acquisition of DOCK8 expression restored defective lymphocyte signalling, survival and proliferation, as well as CD[8.sup.+] T cell cytotoxicity, CD[4.sup.+] T cell cytokine production, and memory B cell generation compared with typical DOCK8-deficient patients. Our temporal analysis of DOCK8-revertant and DOCK8-deficient cells within the same individual established mechanisms of clinical improvement in these patients following somatic reversion and revealed further nonredundant functions of DOCK8 in human lymphocyte biology. Last, our findings have significant implications for future therapeutic options for the treatment of DOCK8 deficiency., Introduction Primary immunodeficiencies (PIDs) or inborn errors of immunity (IEI) are caused by mutations in single genes that compromise the function of the immune system (1). Somatic reversion is the [...]

Published
2021
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9. CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses

Author

Block, Violeta, primary, Sevdali, Eirini, additional, Recher, Mike, additional, Abolhassani, Hassan, additional, Hammarstrom, Lennart, additional, Smulski, Cristian R., additional, Baronio, Manuela, additional, Plebani, Alessandro, additional, Proietti, Michele, additional, Speletas, Matthaios, additional, Warnatz, Klaus, additional, Voll, Reinhard E., additional, Lougaris, Vassilios, additional, Schneider, Pascal, additional, and Eibel, Hermann, additional

Published
2022
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10. Design, structure and plasma binding of ancestral β-CoV scaffold antigens

Author

Syren, Per-Olof, primary, Hueting, David, additional, Schriever, Karen, additional, Zuo, Fanglei, additional, Du, Likun, additional, Persson, Helena, additional, Hofström, Camilla, additional, Ohlin, Mats, additional, Wallden, Karin, additional, Hammarstrom, Lennart, additional, Marcotte, Harold, additional, Pan-Hammarstrom, Qiang, additional, and Andrell, Juni, additional

Published
2022
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11. Impaired IL-23–dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency

Author

Ogishi, Masato, primary, Arias, Andrés Augusto, additional, Yang, Rui, additional, Han, Ji Eun, additional, Zhang, Peng, additional, Rinchai, Darawan, additional, Halpern, Joshua, additional, Mulwa, Jeanette, additional, Keating, Narelle, additional, Chrabieh, Maya, additional, Lainé, Candice, additional, Seeleuthner, Yoann, additional, Ramírez-Alejo, Noé, additional, Nekooie-Marnany, Nioosha, additional, Guennoun, Andrea, additional, Muller-Fleckenstein, Ingrid, additional, Fleckenstein, Bernhard, additional, Kilic, Sara S., additional, Minegishi, Yoshiyuki, additional, Ehl, Stephan, additional, Kaiser-Labusch, Petra, additional, Kendir-Demirkol, Yasemin, additional, Rozenberg, Flore, additional, Errami, Abderrahmane, additional, Zhang, Shen-Ying, additional, Zhang, Qian, additional, Bohlen, Jonathan, additional, Philippot, Quentin, additional, Puel, Anne, additional, Jouanguy, Emmanuelle, additional, Pourmoghaddas, Zahra, additional, Bakhtiar, Shahrzad, additional, Willasch, Andre M., additional, Horneff, Gerd, additional, Llanora, Genevieve, additional, Shek, Lynette P., additional, Chai, Louis Y.A., additional, Tay, Sen Hee, additional, Rahimi, Hamid H., additional, Mahdaviani, Seyed Alireza, additional, Nepesov, Serdar, additional, Bousfiha, Aziz A., additional, Erdeniz, Emine Hafize, additional, Karbuz, Adem, additional, Marr, Nico, additional, Navarrete, Carmen, additional, Adeli, Mehdi, additional, Hammarstrom, Lennart, additional, Abolhassani, Hassan, additional, Parvaneh, Nima, additional, Al Muhsen, Saleh, additional, Alosaimi, Mohammed F., additional, Alsohime, Fahad, additional, Nourizadeh, Maryam, additional, Moin, Mostafa, additional, Arnaout, Rand, additional, Alshareef, Saad, additional, El-Baghdadi, Jamila, additional, Genel, Ferah, additional, Sherkat, Roya, additional, Kiykim, Ayça, additional, Yücel, Esra, additional, Keles, Sevgi, additional, Bustamante, Jacinta, additional, Abel, Laurent, additional, Casanova, Jean-Laurent, additional, and Boisson-Dupuis, Stéphanie, additional

Published
2022
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12. X-Linked TLR7 Deficiency Underlies Critical COVID-19 Pneumonia in a Male Patient with Ataxia-Telangiectasia

Author

Abolhassani, Hassan, Vosughimotlagh, Ahmad, Asano, Takaki, Landegren, Nils, Boisson, Bertrand, Delavari, Samaneh, Bastard, Paul, Aranda-Guillen, Maribel, Wang, Yating, Zuo, Fanglei, Sardh, Fabian, Marcotte, Harold, Du, Likun, Zhang, Shen-Ying, Zhang, Qian, Rezaei, Nima, Kampe, Olle, Casanova, Jean-Laurent, Hammarstrom, Lennart, Pan-Hammarstrom, Qiang, Abolhassani, Hassan, Vosughimotlagh, Ahmad, Asano, Takaki, Landegren, Nils, Boisson, Bertrand, Delavari, Samaneh, Bastard, Paul, Aranda-Guillen, Maribel, Wang, Yating, Zuo, Fanglei, Sardh, Fabian, Marcotte, Harold, Du, Likun, Zhang, Shen-Ying, Zhang, Qian, Rezaei, Nima, Kampe, Olle, Casanova, Jean-Laurent, Hammarstrom, Lennart, and Pan-Hammarstrom, Qiang

Abstract

Background Coronavirus disease 2019 (COVID-19) exhibits a wide spectrum of clinical manifestations, ranging from asymptomatic to critical conditions. Understanding the mechanism underlying life-threatening COVID-19 is instrumental for disease prevention and treatment in individuals with a high risk. Objectives We aimed to identify the genetic cause for critical COVID-19 pneumonia in a patient with a preexisting inborn error of immunity (IEI). Methods Serum levels of specific antibodies against the virus and autoantibodies against type I interferons (IFNs) were measured. Whole exome sequencing was performed, and the impacts of candidate gene variants were investigated. We also evaluated 247 ataxia-telangiectasia (A-T) patients in the Iranian IEI registry. Results We report a 7-year-old Iranian boy with a preexisting hyper IgM syndrome who developed critical COVID-19 pneumonia. IgM only specific COVID-19 immune response was detected but no autoantibodies against type I IFN were observed. A homozygous deleterious mutation in the ATM gene was identified, which together with his antibody deficiency, radiosensitivity, and neurological signs, established a diagnosis of A-T. Among the 247 A-T patients evaluated, 36 had SARS-CoV-2 infection, but all had mild symptoms or were asymptomatic except the index patient. A hemizygous deleterious mutation in the TLR7 gene was subsequently identified in the patient. Conclusions We report a unique IEI patient with combined ATM and TLR7 deficiencies. The two genetic defects underlie A-T and critical COVID-19 in this patient, respectively.

Published
2022
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13. Impaired IL-23-dependent induction of IFN-gamma underlies mycobacterial disease in patients with inherited TYK2 deficiency

Author

Ogishi, Masato, Augusto Arias, Andres, Yang, Rui, Han, Ji Eun, Zhang, Peng, Rinchai, Darawan, Halpern, Joshua, Mulwa, Jeanette, Keating, Narelle, Chrabieh, Maya, Laine, Candice, Seeleuthner, Yoann, Ramirez-Alejo, Noe, Nekooie-Marnany, Nioosha, Guennoun, Andrea, Muller-Fleckenstein, Ingrid, Fleckenstein, Bernhard, Kilic, Sara S., Minegishi, Yoshiyuki, Ehl, Stephan, Kaiser-Labusch, Petra, Kendir-Demirkol, Yasemin, Rozenberg, Flore, Errami, Abderrahmane, Zhang, Shen-Ying, Zhang, Qian, Bohlen, Jonathan, Puel, Anne, Jouanguy, Emmanuelle, Pourmoghaddas, Zahra, Bakhtiar, Shahrzad, Willasch, Andre M., Horneff, Gerd, Llanora, Genevieve, Shek, Lynette P., Chai, Louis Y. A., Tay, Sen Hee, Rahimi, Hamid H., Mahdaviani, Seyed Alireza, Nepesov, Serdar, Bousfiha, Aziz A., Erdeniz, Emine Hafize, Karbuz, Adem, Marr, Nico, Navarrete, Carmen, Adeli, Mehdi, Hammarstrom, Lennart, Abolhassani, Hassan, Parvaneh, Nima, Al Muhsen, Saleh, Alosaimi, Mohammed F., Alsohime, Fahad, Nourizadeh, Maryam, Moin, Mostafa, Arnaout, Rand, Alshareef, Saad, El-Baghdadi, Jamila, Genel, Ferah, Sherkat, Roya, Kiykim, Ayca, Yucel, Esra, Keles, Sevgi, Bustamante, Jacinta, Abel, Laurent, Casanova, Jean-Laurent, Boisson-Dupuis, Stephanie, Ogishi, Masato, Augusto Arias, Andres, Yang, Rui, Han, Ji Eun, Zhang, Peng, Rinchai, Darawan, Halpern, Joshua, Mulwa, Jeanette, Keating, Narelle, Chrabieh, Maya, Laine, Candice, Seeleuthner, Yoann, Ramirez-Alejo, Noe, Nekooie-Marnany, Nioosha, Guennoun, Andrea, Muller-Fleckenstein, Ingrid, Fleckenstein, Bernhard, Kilic, Sara S., Minegishi, Yoshiyuki, Ehl, Stephan, Kaiser-Labusch, Petra, Kendir-Demirkol, Yasemin, Rozenberg, Flore, Errami, Abderrahmane, Zhang, Shen-Ying, Zhang, Qian, Bohlen, Jonathan, Puel, Anne, Jouanguy, Emmanuelle, Pourmoghaddas, Zahra, Bakhtiar, Shahrzad, Willasch, Andre M., Horneff, Gerd, Llanora, Genevieve, Shek, Lynette P., Chai, Louis Y. A., Tay, Sen Hee, Rahimi, Hamid H., Mahdaviani, Seyed Alireza, Nepesov, Serdar, Bousfiha, Aziz A., Erdeniz, Emine Hafize, Karbuz, Adem, Marr, Nico, Navarrete, Carmen, Adeli, Mehdi, Hammarstrom, Lennart, Abolhassani, Hassan, Parvaneh, Nima, Al Muhsen, Saleh, Alosaimi, Mohammed F., Alsohime, Fahad, Nourizadeh, Maryam, Moin, Mostafa, Arnaout, Rand, Alshareef, Saad, El-Baghdadi, Jamila, Genel, Ferah, Sherkat, Roya, Kiykim, Ayca, Yucel, Esra, Keles, Sevgi, Bustamante, Jacinta, Abel, Laurent, Casanova, Jean-Laurent, and Boisson-Dupuis, Stephanie

Abstract

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-alpha/beta (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-gamma is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.

Published
2022

15. Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations

Author

Seldin, Michael F., Alkhairy, Omar K., Lee, Annette T., Lamb, Janine A., Sussman, Jon, Pirskanen-Matell, Ritva, Piehl, Fredrik, Verschuuren, Jan J. G. M., Kostera-Pruszczyk, Anna, Szczudlik, Piotr, McKee, David, Maniaol, Angelina H., Harbo, Hanne F., Lie, Benedicte A., Melms, Arthur, Garchon, Henri-Jean, Willcox, Nicholas, Gregersen, Peter K., and Hammarstrom, Lennart

Published
2015
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16. The risk of COVID-19 death is much greater and age-dependent with type I IFN autoantibodies

Author

Manry, Jeremy, primary, Bastard, Paul, additional, Gervais, Adrian, additional, Voyer, Tom Le, additional, Rosain, Jérémie, additional, Philippot, Quentin, additional, Michailidis, Eleftherios, additional, Hoffmann, Hans-Heinrich, additional, Eto, Shohei, additional, Garcia-Prat, Marina, additional, Bizien, Lucy, additional, Parra-Martínez, Alba, additional, Yang, Rui, additional, Haljasmägi, Liis, additional, Migaud, Mélanie, additional, Särekannu, Karita, additional, Maslovskaja, Julia, additional, de Prost, Nicolas, additional, Tandjaoui-Lambiotte, Yacine, additional, Luyt, Charles-Edouard, additional, Amador-Borrero, Blanca, additional, Gaudet, Alexandre, additional, Poissy, Julien, additional, Morel, Pascal, additional, Richard, Pascale, additional, Cognasse, Fabrice, additional, Troya, Jesus, additional, Trouillet-Assant, Sophie, additional, Belot, Alexandre, additional, Saker, Kahina, additional, Garçon, Pierre, additional, Rivière, Jacques G., additional, Lagier, Jean-Christophe, additional, Gentile, Stéphanie, additional, Rosen, Lindsey, additional, Shaw, Elana, additional, Morio, Tomohiro, additional, Tanaka, Junko, additional, Dalmau, David, additional, Tharaux, Pierre-Louis, additional, Sene, Damien, additional, Stepanian, Alain, additional, Mégarbane, Bruno, additional, Triantafyllia, Vasiliki, additional, Fekkar, Arnaud, additional, Heath, James, additional, Franco, Jose, additional, Anaya, Juan-Manuel, additional, Solé-Violán, Jordi, additional, Imberti, Luisa, additional, Biondi, Andrea, additional, Bonfanti, Paolo, additional, Castagnoli, Riccardo, additional, Delmonte, Ottavia, additional, Zhang, Yu, additional, Snow, Andrew, additional, Holland, Steve, additional, Biggs, Catherine, additional, Moncada-Vélez, Marcela, additional, Arias, Andrés, additional, Lorenzo, Lazaro, additional, Boucherit, Soraya, additional, Anglicheau, Dany, additional, Planas, Anna, additional, Haerynck, Filomeen, additional, Duvlis, Sotirija, additional, Nussbaum, Robert, additional, Ozcelik, Tayfun, additional, Keles, Sevgi, additional, Bousfiha, Aziz, additional, Bakkouri, Jalila El, additional, Ramirez-Santana, Carolina, additional, Paul, Stéphane, additional, Pan-Hammarstrom, Qiang, additional, Hammarstrom, Lennart, additional, Dupont, Annabelle, additional, Kurolap, Alina, additional, Metz, Christine, additional, Aiuti, Alessandro, additional, Casari, Giorgio, additional, Lampasona, Vito, additional, Ciceri, Fabio, additional, Barreiros, Lucila, additional, Dominguez-Garrido, Elena, additional, Vidigal, Mateus, additional, Zatz, Mayana, additional, de Beek, Diederik van, additional, Sahanic, Sabina, additional, Tancevski, Ivan, additional, Stepanovskyy, Yurii, additional, Boyarchuk, Oksana, additional, Nukui, Yoko, additional, Tsumura, Miyuki, additional, Vidaur, Loreto, additional, Tangye, Stuart, additional, Burrel, Sonia, additional, Duffy, Darragh, additional, Quintana-Murci, Lluis, additional, Klocperk, Adam, additional, Kann, Nelli, additional, Shcherbina, Anna, additional, Lau, Yu-Lung, additional, Leung, Daniel, additional, Coulongeat, Matthieu, additional, Marlet, Julien, additional, Koning, Rutger, additional, Reyes, Luis, additional, Chauvineau-Grenier, Angélique, additional, Venet, Fabienne, additional, monneret, guillaume, additional, Nussenzweig, Michel, additional, Arrestier, Romain, additional, Boudhabhay, Idris, additional, Baris-Feldman, Hagit, additional, Hagin, David, additional, Wauters, Joost, additional, Meyts, Isabelle, additional, Dyer, Adam, additional, Kennelly, Sean, additional, Bourke, Nollaig, additional, Halwani, Rabih, additional, Sharif-Askari, Fatemeh, additional, Dorgham, Karim, additional, Sallette, Jérôme, additional, Mehlal-Sedkaoui, Souad, additional, AlKhater, Suzan, additional, Rigo-Bonnin, Raúl, additional, Morandeira, Francisco, additional, Roussel, Lucie, additional, Vinh, Donald, additional, Erikstrup, Christian, additional, Condino-Neto, Antonio, additional, Prando, Carolina, additional, Bondarenko, Anastasiia, additional, Spaan, András, additional, Gilardin, Laurent, additional, Fellay, Jacques, additional, Lyonnet, Stanislas, additional, Bilguvar, Kaya, additional, Lifton, Richard, additional, Mane, Shrikant, additional, Anderson, Mark, additional, Boisson, Bertrand, additional, Béziat, Vivien, additional, Zhang, Shen-Ying, additional, Andreakos, Evangelos, additional, Hermine, Olivier, additional, Pujol, Aurora, additional, Peterson, Pärt, additional, Mogensen, Trine Hyrup, additional, Rowen, Lee, additional, Mond, James, additional, Debette, Stéphanie, additional, deLamballerie, Xavier, additional, Burdet, Charles, additional, Bouadma, Lila, additional, Zins, Marie, additional, Soler-Palacin, Pere, additional, Colobran, Roger, additional, Gorochov, Guy, additional, Solanich, Xavier, additional, Susen, Sophie, additional, Martinez-Picado, Javier, additional, Raoult, Didier, additional, Vasse, Marc, additional, Gregersen, Peter, additional, Rodríguez-Gallego, Carlos, additional, Piemonti, Lorenzo, additional, Notarangelo, Luigi, additional, Su, Helen, additional, Kisand, Kai, additional, Okada, Satoshi, additional, Puel, Anne, additional, Jouanguy, Emmanuelle, additional, Rice, Charles, additional, Tiberghien, Pierre, additional, Zhang, Qian, additional, Casanova, Jean-Laurent, additional, Abel, Laurent, additional, and Cobat, Aurélie, additional

Published
2022
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17. CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding and Signaling Responses

Author

Block, Violeta, primary, Sevdali, Eirini, additional, Recher, Mike, additional, Abolhassani, Hassan, additional, Hammarstrom, Lennart, additional, Smulski, Cristian R., additional, Plebani, Alessandro, additional, Speletas, Matthaios, additional, Warnatz, Klaus, additional, Voll, Reinhard E., additional, Lougaris, Vassilios, additional, Schneider, Pascal, additional, and Eibel, Hermann, additional

Published
2021
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18. Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits

Author

Liu, Lili, primary, Khan, Atlas, additional, Sanchez-Rodriguez, Elena, additional, Zanoni, Francesca, additional, Li, Yifu, additional, Steers, Nicholas, additional, Balderes, Olivia, additional, Zhang, Junying, additional, Krithivasan, Priya, additional, LeDesma, Robert A., additional, Fischman, Clara, additional, Hebbring, Scott J., additional, Harley, John B., additional, Moncrieffe, Halima, additional, Kottyan, Leah C., additional, Namjou-Khales, Bahram, additional, Walunas, Theresa L., additional, Knevel, Rachel, additional, Raychaudhuri, Soumya, additional, Karlson, Elizabeth W., additional, Denny, Joshua C., additional, Stanaway, Ian B., additional, Crosslin, David, additional, Rauen, Thomas, additional, Floege, Jurgen, additional, Eitner, Frank, additional, Moldoveanu, Zina, additional, Reily, Colin, additional, Knoppova, Barbora, additional, Hall, Stacy, additional, Sheff, Justin T., additional, Julian, Bruce A., additional, Wyatt, Robert J., additional, Suzuki, Hitoshi, additional, Xie, Jingyuan, additional, Chen, Nan, additional, Zhou, Xujie, additional, Zhang, Hong, additional, Hammarstrom, Lennart, additional, Viktorin, Alexander, additional, Magnusson, Patrik K. E., additional, Shang, Ning, additional, Hripcsak, George, additional, Weng, Chunhua, additional, Rundek, Tatjana, additional, Elkind, Mitchell S. V., additional, Oelsner, Elizabeth C., additional, Barr, R. Graham, additional, Ionita-Laza, Iuliana, additional, Novak, Jan, additional, Gharavi, Ali G., additional, and Kiryluk, Krzysztof, additional

Published
2021
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19. X-linked recessive TLR7 deficiency in similar to 1% of men under 60 years old with life-threatening COVID-19

Author

Asano, Takaki, Boisson, Bertrand, Onodi, Fanny, Matuozzo, Daniela, Moncada-Velez, Marcela, Renkilaraj, Majistor Raj Luxman Maglorius, Zhang, Peng, Meertens, Laurent, Bolze, Alexandre, Materna, Marie, Korniotis, Sarantis, Gervais, Adrian, Talouarn, Estelle, Bigio, Benedetta, Seeleuthner, Yoann, Bilguvar, Kaya, Zhang, Yu, Neehus, Anna-Lena, Ogishi, Masato, Pelham, Simon J, Le Voyer, Tom, Rosain, Jeremie, Philippot, Quentin, Soler-Palacin, Pere, Colobran, Roger, Martin-Nalda, Andrea, Riviere, Jacques G, Tandjaoui-Lambiotte, Yacine, Chaibi, Khalil, Shahrooei, Mohammad, Darazam, Ilad Alavi, Olyaei, Nasrin Alipour, Mansouri, Davood, Palabiyik, Figen, Ozcelik, Tayfun, Novelli, Giuseppe, Novelli, Antonio, Casari, Giorgio, Aiuti, Alessandro, Carrera, Paola, Bondesan, Simone, Barzaghi, Federica, Rovere-Querini, Patrizia, Tresoldi, Cristina, Franco, Jose Luis, Rojas, Julian, Reyes, Luis Felipe, Bustos, Ingrid G, Arias, Andres Augusto, Morelle, Guillaume, Kyheng, Christele, Troya, Jesus, Planas-Serra, Laura, Schluter, Agatha, Gut, Marta, Pujol, Aurora, Allende, Luis M, Rodriguez-Gallego, Carlos, Flores, Carlos, Cabrera-Marante, Oscar, Pleguezuelo, Daniel E, de Diego, Rebeca Perez, Keles, Sevgi, Aytekin, Gokhan, Akcan, Ozge Metin, Bryceson, Yenan T, Bergman, Peter, Brodin, Petter, Smole, Daniel, Smith, CI Edvard, Norlin, Anna-Carin, Campbell, Tessa M, Covill, Laura E, Hammarstrom, Lennart, Pan-Hammarstrom, Qiang, Abolhassani, Hassan, Mane, Shrikant, Marr, Nico, Ata, Manar, Al Ali, Fatima, Khan, Taushif, Spaan, Andras N, Dalgard, Clifton L, Bonfanti, Paolo, Biondi, Andrea, Tubiana, Sarah, Burdet, Charles, Nussbaum, Robert, Kahn-Kirby, Amanda, Snow, Andrew L, Bustamante, Jacinta, Puel, Anne, Boisson-Dupuis, Stephanie, Zhang, Shen-Ying, Beziat, Vivien, Lifton, Richard P, Bastard, Paul, Notarangelo, Luigi D, Abel, Laurent, Su, Helen C, Jouanguy, Emmanuelle, Amara, Ali, Soumelis, Vassili, Cobat, Aurelie, Zhang, Qian, Casanova, Jean-Laurent, and Gunst, Jan

Subjects
TOLL-LIKE RECEPTORS, PYOGENIC BACTERIAL-INFECTIONS, Science & Technology, SUBSETS, Immunology, RECOGNITION, virus diseases, HUMANS, REDUNDANT, PROTECTIVE IMMUNITY, HOST-DEFENSE, PLASMACYTOID DENDRITIC CELLS, Life Sciences & Biomedicine, SINGLE-STRANDED RNA
Abstract

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract. ispartof: SCIENCE IMMUNOLOGY vol:6 issue:62 ispartof: location:United States status: published

Published
2021

21. Rice-based oral antibody fragment prophylaxis and therapy against rotavirus infection

Author

Tokuhara, Daisuke, Alvarez, Beatriz, Mejima, Mio, Hiroiwa, Tomoko, Takahashi, Yuko, Kurokawa, Shiho, Kuroda, Masaharu, Oyama, Masaaki, Kozuka-Hata, Hiroko, Nochi, Tomonori, Sagara, Hiroshi, Aladin, Farah, Marcotte, Harold, Frenken, Leon G.J., Iturriza-Gomara, Miren, Kiyono, Hiroshi, Hammarstrom, Lennart, and Yuki, Yoshikazu

Subjects
Diarrhea -- Research, Rotavirus infections -- Care and treatment, Health care industry
Abstract

Rotavirus-induced diarrhea is a life-threatening disease in immunocompromised individuals and in children in developing countries. We have developed a system for prophylaxis and therapy against rotavirus disease using transgenic rice expressing the neutralizing variable domain of a rotavirus-specific llama heavy-chain antibody fragment (MucoRice-ARP1). MucoRice-ARP1 was produced at high levels in rice seeds using an overexpression system and RNAi technology to suppress the production of major rice endogenous storage proteins. Orally administered MucoRice-ARP1 markedly decreased the viral load in immunocompetent and immunodeficient mice. The antibody retained in vitro neutralizing activity after long-term storage (>1 yr) and boiling and conferred protection in mice even after heat treatment at 94°C for 30 minutes. High-yield, water-soluble, and purification-free MucoRice-ARP1 thus forms the basis for orally administered prophylaxis and therapy against rotavirus infections., Introduction Rotavirus is the leading cause of diarrhea in infants and young children worldwide, causing more than 114 million episodes of diarrhea annually in children under the age of 5 [...]

Published
2013

23. 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

25. B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans

Author

Warnatz, Klaus, Salzer, Ulrich, Rizzi, Marta, Fischer, Beate, Gutenberger, Sylvia, Bohm, Joachim, Kienzler, Anne-Kathrin, Pan-Hammarstrom, Qiang, Hammarstrom, Lennart, Rakhmanov, Mirzokhid, Schlesier, Michael, Grimbacher, Bodo, Peter, Hans-Hartmut, and Eibel, Hermann

Subjects
Immunodeficiency -- Development and progression, Immunodeficiency -- Genetic aspects, B cells -- Health aspects, Science and technology
Abstract

B-cell survival depends on signals induced by B-cell activating factor (BAFF) binding to its receptor (BAFF-R). In mice, mutations in BAFF or BAFF-R cause B-cell lymphopenia and antibody deficiency. Analyzing BAFF-R expression and BAFF-binding to B cells in common variable immunodeficiency (CVID) patients, we identified two siblings carrying a homozygous deletion in the BAFF-R gene. Removing most of the BAFF-R transmembrane part, the deletion precludes BAFF-R expression. Without BAFF-R, B-cell development is arrested at the stage of transitional B cells and the numbers of all subsequent B-cell stages are severely reduced. Both siblings have lower IgG and IgM serum levels but, unlike most CVID patients, normal IgA concentrations. They also did not mount a T-independent immune response against pneumococcal cell wall polysaccharides but only one BAFF-R-deficient sibling developed recurrent infections. Therefore, deletion of the BAFF-R gene in humans causes a characteristic immunological phenotype but it does not necessarily lead to a clinically manifest immunodeficiency. B lymphopenia | primary immunodeficiency | recessive mutation

Published
2009

26. Global systematic review of primary immunodeficiency registries

Author

Abolhassani, Hassan, Azizi, Gholamreza, Sharifi, Laleh, Yazdani, Reza, Mohsenzadegan, Monireh, Delavari, Samaneh, Sohani, Mahsa, Shirmast, Paniz, Chavoshzadeh, Zahra, Mahdaviani, Seyed Alireza, Kalantari, Arash, Tavakol, Marzieh, Jabbari-Azad, Farahzad, Ahanchian, Hamid, Momen, Tooba, Sherkat, Roya, Sadeghi-Shabestari, Mahnaz, Aleyasin, Soheila, Esmaeilzadeh, Hossein, Al-Herz, Waleed, Bousfiha, Ahmed Aziz, Condino-Neto, Antonio, Seppänen, Mikko, Sullivan, Kathleen E., Hammarstrom, Lennart, Modell, Vicki, Modell, Fred, Quinn, Jessica, Orange, Jordan S., Aghamohammadi, Asghar, Children's Hospital, HUS Children and Adolescents, Clinicum, Department of Medicine, Infektiosairauksien yksikkö, HUS Inflammation Center, University of Helsinki, and Helsinki University Hospital Area

Subjects
Primary immunodeficiencies, DISORDERS, CLINICAL-FEATURES, prevalence, ANTIBODY DEFICIENCY, 1ST REPORT, RESEARCH DATABASE, CHILDREN, LATIN-AMERICA, burden of disease, DISEASES, 3121 General medicine, internal medicine and other clinical medicine, molecular diagnosis, GERMAN NATIONAL REGISTRY, ethnicity, INTERNET-BASED PATIENT
Abstract

Introduction During the last 4 decades, registration of patients with primary immunodeficiencies (PID) has played an essential role in different aspects of these diseases worldwide including epidemiological indexes, policymaking, quality controls of care/life, facilitation of genetic studies and clinical trials as well as improving our understanding about the natural history of the disease and the immune system function. However, due to the limitation of sustainable resources supporting these registries, inconsistency in diagnostic criteria and lack of molecular diagnosis as well as difficulties in the documentation and designing any universal platform, the global perspective of these diseases remains unclear. Areas covered Published and unpublished studies from January 1981 to June 2020 were systematically reviewed on PubMed, Web of Science and Scopus. Additionally, the reference list of all studies was hand-searched for additional studies. This effort identified a total of 104614 registered patients and suggests identification of at least 10590 additional PID patients, mainly from countries located in Asia and Africa. Molecular defects in genes known to cause PID were identified and reported in 13852 (13.2% of all registered) patients. Expert opinion Although these data suggest some progress in the identification and documentation of PID patients worldwide, achieving the basic requirement for the global PID burden estimation and registration of undiagnosed patients will require more reinforcement of the progress, involving both improved diagnostic facilities and neonatal screening.

Published
2020

27. 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

28. Role for Msh5 in the regulation of Ig class switch recombination

Author

Sekine, Hideharu, Ferreira, Ricardo C., Pan-Hammarstrom, Qiang, Graham, Robert R., Ziemba, Beth, de Vries, Sandra S., Liu, Jiabin, Hippen, Keli, Koeuth, Thearith, Ortmann, Ward, Iwahori, Akiko, Elliott, Margaret K., Offer, Steven, Skon, Cara, Du, Likun, Novitzke, Jill, Lee, Annette T., Zhao, Nianxi, Tompkins, Joshua D., Altshuler, David, Gregersen, Peter K., Cunningham-Rundles, Charlotte, Harris, Reuben S., Her, Chengtao, Nelson, David L., Hammarstrom, Lennart, Gilkeson, Gary S., and Behrens, Timothy W.

Subjects
Genetic regulation -- Research, Genetic recombination -- Research, DNA repair -- Research, Immunoglobulin A -- Research, Science and technology
Abstract

Ig class switch recombination (CSR) and somatic hypermutation serve to diversify antibody responses and are orchestrated by the activity of activation-induced cytidine deaminase and many proteins involved in DNA repair and genome surveillance. Msh5, a gene encoded in the central MHC class III region, and its obligate heterodimerization partner Msh4 have a critical role in regulating meiotic homologous recombination and have not been implicated in CSR. Here, we show that MRL/Ipr mice carrying a congenic [H-2.sup.b/b] MHC interval exhibit several abnormalities regarding CSR, including a profound deficiency of IgG3 in most mice and long micro-homologies at Ig switch (S) joints. We found that Msh5 is expressed at low levels on the [H-2.sup.b] haplotype and, importantly, a similar long S joint microhomology phenotype was observed in both Msh5 and Msh4-null mice. We also present evidence that genetic variation in MSH5 is associated with IgA deficiency and common variable immune deficiency (CVID) in humans. One of the human MSH5 alleles identified contains two nonsynonymous polymorphisms, and the variant protein encoded by this allele shows impaired binding to MSH4. Similar to the mice, Ig S joints from CVID and IgA deficiency patients carrying disease-associated MSH5 alleles show increased donor/acceptor microhomology, involving pentameric DNA repeat sequences and lower mutation rates than controls. Our findings suggest that Msh4/5 heterodimers contribute to CSR and support a model whereby Msh4/5 promotes the resolution of DNA breaks with low or no terminal microhomology by a classical nonhomologous end-joining mechanism while possibly suppressing an alternative microhomology-mediated pathway. immunoglobulin subclass deficiency | mismatch repair | Msh4

Published
2007

29. Newborn Screening for Presymptomatic Diagnosis of Complement and Phagocyte Deficiencies

Author

Dezfouli, Mahya, Bergström, Sofia, Skattum, Lillemor, Abolhassani, Hassan, Neiman, Maja, Torabi-Rahvar, Monireh, Franco Jarava, Clara, Martin-Nalda, Andrea, Ferrer Balaguer, Juana M., Slade, Charlotte A., Roos, Anja, Fernandez Pereira, Luis M., Lopez-Trascasa, Margarita, Gonzalez-Granado, Luis, I, Allende-Martinez, Luis M., Mizuno, Yumi, Yoshida, Yusuke, Friman, Vanda, Lundgren, Asa, Aghamohammadi, Asghar, Rezaei, Nima, Hernandez-Gonzalez, Manuel, von Dobeln, Ulrika, Truedsson, Lennart, Hara, Toshiro, Nonoyama, Shigeaki, Schwenk, Jochen M., Nilsson, Peter, Hammarstrom, Lennart, Dezfouli, Mahya, Bergström, Sofia, Skattum, Lillemor, Abolhassani, Hassan, Neiman, Maja, Torabi-Rahvar, Monireh, Franco Jarava, Clara, Martin-Nalda, Andrea, Ferrer Balaguer, Juana M., Slade, Charlotte A., Roos, Anja, Fernandez Pereira, Luis M., Lopez-Trascasa, Margarita, Gonzalez-Granado, Luis, I, Allende-Martinez, Luis M., Mizuno, Yumi, Yoshida, Yusuke, Friman, Vanda, Lundgren, Asa, Aghamohammadi, Asghar, Rezaei, Nima, Hernandez-Gonzalez, Manuel, von Dobeln, Ulrika, Truedsson, Lennart, Hara, Toshiro, Nonoyama, Shigeaki, Schwenk, Jochen M., Nilsson, Peter, and Hammarstrom, Lennart

Abstract

The clinical outcomes of primary immunodeficiencies (PIDs) are greatly improved by accurate diagnosis early in life. However, it is not common to consider PIDs before the manifestation of severe clinical symptoms. Including PIDs in the nation-wide newborn screening programs will potentially improve survival and provide better disease management and preventive care in PID patients. This calls for the detection of disease biomarkers in blood and the use of dried blood spot samples, which is a part of routine newborn screening programs worldwide. Here, we developed a newborn screening method based on multiplex protein profiling for parallel diagnosis of 22 innate immunodeficiencies affecting the complement system and respiratory burst function in phagocytosis. The proposed method uses a small fraction of eluted blood from dried blood spots and is applicable for population-scale performance. The diagnosis method is validated through a retrospective screening of immunodeficient patient samples. This diagnostic approach can pave the way for an earlier, more comprehensive and accurate diagnosis of complement and phagocytic disorders, which ultimately lead to a healthy and active life for the PID patients., QC 20200428

Published
2020
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30. Noncoding RNA transcription alters chromosomal topology to promote isotype-specific class switch recombination

Author

Rothschild, Gerson, Zhang, Wanwei, Lim, Junghyun, Giri, Pankaj Kumar, Laffleur, Brice, Chen, Yiyun, Fang, Mingyan, Chen, Yuling, Nair, Lekha, Liu, Zhi-Ping, Deng, Haiteng, Hammarstrom, Lennart, Wang, Jiguang, Basu, Uttiya, Rothschild, Gerson, Zhang, Wanwei, Lim, Junghyun, Giri, Pankaj Kumar, Laffleur, Brice, Chen, Yiyun, Fang, Mingyan, Chen, Yuling, Nair, Lekha, Liu, Zhi-Ping, Deng, Haiteng, Hammarstrom, Lennart, Wang, Jiguang, and Basu, Uttiya

Abstract

B cells undergo two types of genomic alterations to increase antibody diversity: introduction of point mutations into immunoglobulin heavy- and light-chain (IgH and IgL) variable regions by somatic hypermutation (SHM) and alteration of antibody effector functions by changing the expressed IgH constant region exons through IgH class switch recombination (CSR). SHM and CSR require the B cell-specific activation-induced cytidine deaminase (AID) protein, the transcription of germline noncoding RNAs, and the activity of the 3' regulatory region (3'RR) superenhancer. Although many transcription regulatory elements (e.g., promoters and enhancers) reside inside the IgH and IgL sequences, the question remains whether clusters of regulatory elements outside IgH control CSR. Using RNA exosome-deficient mouse B cells where long noncoding RNAs (lncRNAs) are easily detected, we identified a cluster of three RNA-expressing elements that includes IncCSR(IgA) (that expresses lncRNA-CSRIgA). B cells isolated from a mouse model lacking lncRNA-CSRIgA transcription fail to undergo normal levels of CSR to IgA both in B cells of the Peyer's patches and grown in ex vivo culture conditions. lncRNA-CSRIgA is expressed from an enhancer site (IncCSR(IgA)) to facilitate the recruitment of regulatory proteins to a nearby CTCF site (CTCF IncCSR) that alters the chromosomal interactions inside the TAD(IncCSRIgA) and long-range interactions with the 3'RR super-enhancer. Humans with IgA deficiency show polymorphisms in the IncCSR(IgA) locus compared with the normal population. Thus, we provide evidence for an evolutionarily conserved topologically associated domain (TAD(IncCSRIgA)) that coordinates IgA CSR in Peyer's patch B cells through an lncRNA (lncRNA-CSRIgA) transcription-dependent mechanism.

Published
2020

31. Identification of IgF, a hinge-region-containing Ig class, and IgD in Xenopus tropicalis

Author

Zhao, Yaofeng, Pan-Hammarstrom, Qiang, Yu, Shuyang, Wertz, Nancy, Zhang, Xiaofeng, Li, Ning, Butler, John E., and Hammarstrom, Lennart

Subjects
Amphibians -- Health aspects, Amphibians -- Research, Antibodies -- Origin, Viral antibodies -- Origin, Science and technology
Abstract

Only three Ig isotypes, IgM, IgX, and IgY, were previously known in amphibians. Here, we describe a heavy-chain isotype in Xenopus tropicalis, IgF (encoded by [C.sub.[phi]]), with only two constant region domains. IgF is similar to amphibian IgY in sequence, but the gene contains a hinge exon, making it the earliest example, in evolution, of an Ig isotype with a separately encoded genetic hinge. We also characterized a gene for the heavy chain of IgD, located immediately 3' of [C.sub.[mu]], that shares features with the [C.sub.[delta]] gene in fish and mammals. The latter gene contains eight constant-region-encoding exons and, unlike the chimeric splicing of [mu][C.sub.H]1 onto the IgD heavy chain in teleost fish, it is expressed as a unique IgD heavy chain. The IgH locus of X. tropicalis shows a 5' [V.sub.H]-[D.sub.H]-[J.sub.H]-[C.sub.[mu]]-[C.sub. [delta]]-[C.sub.x]-[C.sub.v]-[C.sub.[phi]], 3' organization, suggesting that the mammalian and amphibian Ig heavy-chain loci share a common ancestor. amphibians | antibody evolution

Published
2006

33. Risk for myasthenia gravis maps to a 151Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08

Author

Gregersen, Peter K., Kosoy, Roman, Lee, Annette T., Lamb, Janine, Sussman, Jon, McKee, David, Simpfendorfer, Kim R., Pirskanen-Matell, Ritva, Piehl, Frederik, Pan-Hammarstrom, Qiang, Verschuuren, Jan J. G. M., Titulaer, Maarten J., Niks, Erik H., Marx, Alexander, Ströbel, Philipp, Tackenberg, Björn, Pütz, Michael, Maniaol, Angelina, Elsais, Ahmed, Tallaksen, Chantal, Harbo, Hanne F., Lie, Benedicte A., Raychaudhuri, Soumya, de Bakker, Paul I. W., Melms, Arthur, Garchon, Henri-Jean, Willcox, Nicholas, Hammarstrom, Lennart, and Seldin, Michael F.

Published
2012
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34. Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation. (Research Article)

Author

Mahdavi, Jafar, Sonden, Berit, Hurtig, Marina, Olfat, Farzad O., Forsberg, Lina, Roche, Niamh, Angstrom, Jonas, Larsson, Thomas, Teneberg, Susann, Karlsson, Karl-Anders, Altraja, Siiri, Wadstrom, Torkel, Kersulyte, Dangeruta, Berg, Douglas E., Dubois, Andre, Petersson, Christoffer, Magnusson, Karl-Eric, Norberg, Thomas, Lindh, Frank, Lundskog, Bertil B., Arnqvist, Anna, Hammarstrom, Lennart, and Boren, Thomas

Subjects
Helicobacter pylori -- Research, Stomach cancer -- Causes of -- Research, Science and technology, Research, Causes of
Abstract

Helicobacter pylori adherence in the human gastric mucosa involves specific bacterial adhesins and cognate host receptors. Here, we identify sialyl-dimeric-Lewis x glycosphingolipid as a receptor for H. pylori and show that H. pylori infection induced formation of sialyl-Lewis x antigens in gastric epithelium in humans and in a Rhesus monkey. The corresponding sialic acid--binding adhesin (SabA) was isolated with the 'retagging' method, and the underlying sabA gene (JHP662/HP0725) was identified. The ability of many H. pylori strains to adhere to sialylated glycoconjugates expressed during chronic inflammation might thus contribute to virulence and the extraordinary chronicity of H. pylori infection., Helicobacter pylori persistently infects the gastric mucosa of more than half of all people worldwide, causes peptic ulcer disease, and is an early risk factor for gastric cancer (1). Many [...]

Published
2002

36. A Heterodimeric Antibody Fragment for Passive Immunotherapy Against Norovirus Infection

Author

Yuki, Yoshikazu, primary, Kurokawa, Shiho, primary, Sato, Shintaro, primary, Sasou, Ai, primary, Matsumoto, Naomi, primary, Suzuki, Akio, primary, Sakon, Naomi, primary, Goda, Yuki, primary, Takeyama, Natsumi, primary, Miyoshi, Tatsuya, primary, Marcotte, Harold, primary, Tanaka, Tomoyuki, primary, Hammarstrom, Lennart, primary, and Kiyono, Hiroshi, primary

Published
2020
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37. A common single nucleotide polymorphism impairs B-cell activating factor receptorʼs multimerization, contributing to common variable immunodeficiency

Author

Pieper, Kathrin, Rizzi, Marta, Speletas, Matthaios, Smulski, Cristian R., Sic, Heiko, Kraus, Helene, Salzer, Ulrich, Fiala, Gina J., Schamel, Wolfgang W., Lougaris, Vassilios, Plebani, Alessandro, Hammarstrom, Lennart, Recher, Mike, Germenis, Anastasios E., Grimbacher, Bodo, Warnatz, Klaus, Rolink, Antonius G., Schneider, Pascal, Notarangelo, Luigi D., and Eibel, Hermann

Published
2014
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38. Monozygotic Twins Concordant for Common Variable Immunodeficiency: Strikingly Similar Clinical and Immune Profile Associated With a Polygenic Burden

Author

Silva, Susana L., primary, Fonseca, Mariana, additional, Pereira, Marcelo L. M., additional, Silva, Sara P., additional, Barbosa, Rita R., additional, Serra-Caetano, Ana, additional, Blanco, Elena, additional, Rosmaninho, Pedro, additional, Pérez-Andrés, Martin, additional, Sousa, Ana Berta, additional, Raposo, Alexandre A. S. F., additional, Gama-Carvalho, Margarida, additional, Victorino, Rui M. M., additional, Hammarstrom, Lennart, additional, and Sousa, Ana E., additional

Published
2019
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39. Genetic linkage of IgA deficiency to the major histocompatibility complex: evidence for allele segregation distortion, parent-of-origin penetrance differences, and the role of anti-IgA antibodies in disease predisposition

Author

Vorechovsky, Igor, Webster, A David B., Plebani, Alessandro, and Hammarstrom, Lennart

Subjects
Immunoglobulin A -- Research, Immunoglobulins -- Research, Diseases -- Genetic aspects, Biological sciences
Abstract

Several pathogenic mechanisms have been identified that correlate immunoglobulin A deficiency (IgAD) and disease predisposition. Studies using transmission/disequilibrium testing indicates family-based associations, with affected mothers more likely to produce IgAD offspring than affected fathers. Anti-IgA-positive status also affects transmission, as does increased allele sharing at 6p21 witnessed in affected individuals.

Published
1999

43. Lactobacilli expressing variable domain of Llama heavy-chain antibody fragments (lactobodies) confer protection against rotavirus-induced diarrhea

Author

Pant, Neha, Hultberg, Anna, Zhao, Yaofeng, Svensson, Lennart, Pan-Hammarstrom, Qiang, Johansen, Kari, Pouwels, Peter H., Ruggeri, Franco M., Hermans, Pim, Frenken, Leon, Boren, Thomas, Marcotte, Harold, and Hammarstrom, Lennart

Subjects
Lactobacillus -- Research, Rotavirus infections -- Complications and side effects, Rotavirus infections -- Care and treatment, Viral diarrhea -- Care and treatment, Antibodies -- Analysis, Viral antibodies -- Analysis, Health
Published
2006

47. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases

Author

Vetrie, David, Vorechovsky, Igor, Sideras, Paschalis, Holland, Jill, Davies, Angela, Flinter, Frances, Hammarstrom, Lennart, Kinnon, Christine, Levinsky, Roland, Bobrow, Martin, Smith, C.I. Edvard, and Bentley, David R.

Subjects
Agammaglobulinemia -- Genetic aspects, B cells -- Abnormalities, Proto-oncogenes -- Research, Protein tyrosine kinase -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

A gene belonging to the src group of proto-oncogenes has been associated with X-linked agammaglobulinemia (XLA), a hereditary immunodeficiency disease occurring in males. The gene, which was isolated in yeast artificial chromosome using complementary DNA and which has been designated atk, probably produces the defective development of B cells in the bone marrow that causes XLA. Furthermore, atk also carries the genetic information for a protein-tyrosine kinase.

Published
1993

50. Clinical spectrum of X-linked hyper-IgM syndrome

Author

Levy, Jacov, Espanol-Boren, Teresa, Thomas, Carolin, Fischer, Alain, Tovo, Pierangelo, Bordigoni, Pierre, Resnick, Igor, Fasth, Anders, Baer, Maija, Gomez, Lina, Sanders, E. A.M., Tabone, Marie-Dominique, Plantaz, Dominique, Etzioni, Amos, Monafo, Virginia, Abinun, Mario, Hammarstrom, Lennart, Abrahamsen, Tore, Jones, Allison, Finn, Adam, Klemola, Timo, DeVries, Esther, Sanal, Ozden, Peitsch, Manuel C., and Notarangelo, Luigi D.

Published
1997

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