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1. Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Author

Medicina i Cirurgia, Universitat Rovira i Virgili, Matuozzo, D; Talouarn, E; Marchal, A; Zhang, P; Manry, J; Seeleuthner, Y; Zhang, Y; Bolze, A; Chaldebas, M; Milisavljevic, B; Gervais, A; Bastard, P; Asano, T; Bizien, L; Barzaghi, F; Abolhassani, H; Abou Tayoun, A; Aiuti, A; Alavi Darazam, I; Allende, LM; Alonso-Arias, R; Arias, AA; Aytekin, G; Bergman, P; Bondesan, S; Bryceson, YT; Bustos, IG; Cabrera-Marante, O; Carcel, S; Carrera, P; Casari, G; Chaïbi, K; Colobran, R; Condino-Neto, A; Covill, LE; Delmonte, OM; El Zein, L; Flores, C; Gregersen, PK; Gut, M; Haerynck, F; Halwani, R; Hancerli, S; Hammarström, L; Hatipoglu, N; Karbuz, A; Keles, S; Kyheng, C; Leon-Lopez, R; Franco, JL; Mansouri, D; Martinez-Picado, J; Metin Akcan, O; Migeotte, I; Morange, PE; Morelle, G; Martin-Nalda, A; Novelli, G; Novelli, A; Ozcelik, T; Palabiyik, F; Pan-Hammarström, Q; de Diego, RP; Planas-Serra, L; Pleguezuelo, DE; Prando, C; Pujol, A; Reyes, LF; Rivière, JG; Rodriguez-Gallego, C; Rojas, J; Rovere-Querini, P; Schlüter, A; Shahrooei, M; Sobh, A; Soler-Palacin, P; Tandjaoui-Lambiotte, Y; Tipu, I; Tresoldi, C; Troya, J; van de Beek, D; Zatz, M; Zawadzki, P; Al-Muhsen, SZ; Alosaimi, MF; Alsohime, FM; Baris-Feldman, H; Butte, MJ; Constantinescu, SN; Cooper, MA; Dalgard, CL; Fellay, J; Heath, JR; Lau, YL; Lifton, RP; Maniatis, T; Mogensen, TH; von Bernuth, H; Lermine, A; Vidaud, M; Boland, A; Deleuze, JF; Nussbaum, R; Kahn-Kirby, A; Mentre, F; Tubiana, S; Gorochov, G; Tubach, F; Hausfater, P; Effort, CHG; Meyts, I; Zhang, SY; Puel, A; Notarangelo, LD; Boisson-Dupuis, S; Su, HC; Boisson, B; Jouanguy, E; Casanova, JL; Zhang, Q; Abel, L; Cobat, A, Medicina i Cirurgia, Universitat Rovira i Virgili, and Matuozzo, D; Talouarn, E; Marchal, A; Zhang, P; Manry, J; Seeleuthner, Y; Zhang, Y; Bolze, A; Chaldebas, M; Milisavljevic, B; Gervais, A; Bastard, P; Asano, T; Bizien, L; Barzaghi, F; Abolhassani, H; Abou Tayoun, A; Aiuti, A; Alavi Darazam, I; Allende, LM; Alonso-Arias, R; Arias, AA; Aytekin, G; Bergman, P; Bondesan, S; Bryceson, YT; Bustos, IG; Cabrera-Marante, O; Carcel, S; Carrera, P; Casari, G; Chaïbi, K; Colobran, R; Condino-Neto, A; Covill, LE; Delmonte, OM; El Zein, L; Flores, C; Gregersen, PK; Gut, M; Haerynck, F; Halwani, R; Hancerli, S; Hammarström, L; Hatipoglu, N; Karbuz, A; Keles, S; Kyheng, C; Leon-Lopez, R; Franco, JL; Mansouri, D; Martinez-Picado, J; Metin Akcan, O; Migeotte, I; Morange, PE; Morelle, G; Martin-Nalda, A; Novelli, G; Novelli, A; Ozcelik, T; Palabiyik, F; Pan-Hammarström, Q; de Diego, RP; Planas-Serra, L; Pleguezuelo, DE; Prando, C; Pujol, A; Reyes, LF; Rivière, JG; Rodriguez-Gallego, C; Rojas, J; Rovere-Querini, P; Schlüter, A; Shahrooei, M; Sobh, A; Soler-Palacin, P; Tandjaoui-Lambiotte, Y; Tipu, I; Tresoldi, C; Troya, J; van de Beek, D; Zatz, M; Zawadzki, P; Al-Muhsen, SZ; Alosaimi, MF; Alsohime, FM; Baris-Feldman, H; Butte, MJ; Constantinescu, SN; Cooper, MA; Dalgard, CL; Fellay, J; Heath, JR; Lau, YL; Lifton, RP; Maniatis, T; Mogensen, TH; von Bernuth, H; Lermine, A; Vidaud, M; Boland, A; Deleuze, JF; Nussbaum, R; Kahn-Kirby, A; Mentre, F; Tubiana, S; Gorochov, G; Tubach, F; Hausfater, P; Effort, CHG; Meyts, I; Zhang, SY; Puel, A; Notarangelo, LD; Boisson-Dupuis, S; Su, HC; Boisson, B; Jouanguy, E; Casanova, JL; Zhang, Q; Abel, L; Cobat, A

Abstract

Abstract Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in?~?80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P?=?1.1?×?10?4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR?=?3.70[95%CI 1.3–8.2], P?=?2.1?×?10?4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR?

Published
2023

2. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Author

Zhang, Q, Liu, Z, Moncada-Velez, M, Chen, J, Ogishi, M, Bigio, B, Yang, R, Arias, AA, Zhou, Q, Han, JE, Ugurbil, AC, Zhang, P, Rapaport, F, Li, J, Spaan, AN, Boisson, B, Boisson-Dupuis, S, Bustamante, J, Puel, A, Ciancanelli, MJ, Zhang, SY, Béziat, V, Jouanguy, E, Abel, L, Cobat, A, Casanova, JL, Bastard, P, Korol, C, Rosain, J, Philippot, Q, Chbihi, M, Lorenzo, L, Bizien, L, Neehus, AL, Kerner, G, Seeleuthner, Y, Manry, J, Le Voyer, T, Le Pen, J, Schneider, WM, Razooky, BS, Hoffmann, HH, Michailidis, E, Rice, CM, Sabli, IKD, Hodeib, S, Sancho-Shimizu, V, Bilguvar, K, Ye, J, Maniatis, T, Bolze, A, Zhang, Y, Notarangelo, LD, Su, HC, Onodi, F, Korniotis, S, Karpf, L, Soumelis, V, Bonnet-Madin, L, Amara, A, Dorgham, K, Gorochov, G, Smith, N, Duffy, D, Moens, L, Meyts, I, Zhang, Q, Liu, Z, Moncada-Velez, M, Chen, J, Ogishi, M, Bigio, B, Yang, R, Arias, AA, Zhou, Q, Han, JE, Ugurbil, AC, Zhang, P, Rapaport, F, Li, J, Spaan, AN, Boisson, B, Boisson-Dupuis, S, Bustamante, J, Puel, A, Ciancanelli, MJ, Zhang, SY, Béziat, V, Jouanguy, E, Abel, L, Cobat, A, Casanova, JL, Bastard, P, Korol, C, Rosain, J, Philippot, Q, Chbihi, M, Lorenzo, L, Bizien, L, Neehus, AL, Kerner, G, Seeleuthner, Y, Manry, J, Le Voyer, T, Le Pen, J, Schneider, WM, Razooky, BS, Hoffmann, HH, Michailidis, E, Rice, CM, Sabli, IKD, Hodeib, S, Sancho-Shimizu, V, Bilguvar, K, Ye, J, Maniatis, T, Bolze, A, Zhang, Y, Notarangelo, LD, Su, HC, Onodi, F, Korniotis, S, Karpf, L, Soumelis, V, Bonnet-Madin, L, Amara, A, Dorgham, K, Gorochov, G, Smith, N, Duffy, D, Moens, L, and Meyts, I

Abstract

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

Published
2020

3. Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Author

Bastard, P, Rosen, LB, Zhang, Q, Michailidis, E, Hoffmann, HH, Zhang, Y, Dorgham, K, Philippot, Q, Rosain, J, Béziat, V, Manry, J, Shaw, E, Haljasmägi, L, Peterson, P, Lorenzo, L, Bizien, L, Trouillet-Assant, S, Dobbs, K, de Jesus, AA, Belot, A, Kallaste, A, Catherinot, E, Tandjaoui-Lambiotte, Y, Le Pen, J, Kerner, G, Bigio, B, Seeleuthner, Y, Yang, R, Bolze, A, Spaan, AN, Delmonte, OM, Abers, MS, Aiuti, A, Casari, G, Lampasona, V, Piemonti, L, Ciceri, F, Bilguvar, K, Lifton, RP, Vasse, M, Smadja, DM, Migaud, M, Hadjadj, J, Terrier, B, Duffy, D, Quintana-Murci, L, van de Beek, D, Roussel, L, Vinh, DC, Tangye, SG, Haerynck, F, Dalmau, D, Martinez-Picado, J, Brodin, P, Nussenzweig, MC, Boisson-Dupuis, S, Rodríguez-Gallego, C, Vogt, G, Mogensen, TH, Oler, AJ, Gu, J, Burbelo, PD, Cohen, JI, Biondi, A, Bettini, LR, DÁngio, M, Bonfanti, P, Rossignol, P, Mayaux, J, Rieux-Laucat, F, Husebye, ES, Fusco, F, Ursini, MV, Imberti, L, Sottini, A, Paghera, S, Quiros-Roldan, E, Rossi, C, Castagnoli, R, Montagna, D, Licari, A, Marseglia, GL, Duval, X, Ghosn, J, Tsang, JS, Goldbach-Mansky, R, Kisand, K, Lionakis, MS, Puel, A, Zhang, SY, Holland, SM, Gorochov, G, Jouanguy, E, Rice, CM, Cobat, A, Notarangelo, LD, Abel, L, Su, HC, Casanova, JL, Arias, AA, Bastard, P, Rosen, LB, Zhang, Q, Michailidis, E, Hoffmann, HH, Zhang, Y, Dorgham, K, Philippot, Q, Rosain, J, Béziat, V, Manry, J, Shaw, E, Haljasmägi, L, Peterson, P, Lorenzo, L, Bizien, L, Trouillet-Assant, S, Dobbs, K, de Jesus, AA, Belot, A, Kallaste, A, Catherinot, E, Tandjaoui-Lambiotte, Y, Le Pen, J, Kerner, G, Bigio, B, Seeleuthner, Y, Yang, R, Bolze, A, Spaan, AN, Delmonte, OM, Abers, MS, Aiuti, A, Casari, G, Lampasona, V, Piemonti, L, Ciceri, F, Bilguvar, K, Lifton, RP, Vasse, M, Smadja, DM, Migaud, M, Hadjadj, J, Terrier, B, Duffy, D, Quintana-Murci, L, van de Beek, D, Roussel, L, Vinh, DC, Tangye, SG, Haerynck, F, Dalmau, D, Martinez-Picado, J, Brodin, P, Nussenzweig, MC, Boisson-Dupuis, S, Rodríguez-Gallego, C, Vogt, G, Mogensen, TH, Oler, AJ, Gu, J, Burbelo, PD, Cohen, JI, Biondi, A, Bettini, LR, DÁngio, M, Bonfanti, P, Rossignol, P, Mayaux, J, Rieux-Laucat, F, Husebye, ES, Fusco, F, Ursini, MV, Imberti, L, Sottini, A, Paghera, S, Quiros-Roldan, E, Rossi, C, Castagnoli, R, Montagna, D, Licari, A, Marseglia, GL, Duval, X, Ghosn, J, Tsang, JS, Goldbach-Mansky, R, Kisand, K, Lionakis, MS, Puel, A, Zhang, SY, Holland, SM, Gorochov, G, Jouanguy, E, Rice, CM, Cobat, A, Notarangelo, LD, Abel, L, Su, HC, Casanova, JL, and Arias, AA

Abstract

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

Published
2020

4. The Clinical and Genetic Spectrum of 82 Patients WithRAGDeficiency Including a c.256_257delAA Founder Variant in Slavic Countries

Author

Sharapova, SO, Skomska-Pawliszak, M, Rodina, YA, Wolska-Kusnierz, B, Dabrowska-Leonik, N, Mikoluc, B, Pashchenko, OE, Pasic, S, Freiberger, T, Milota, T, Formankova, R, Szaflarska, A, Siedlar, M, Avcin, T, Markelj, G, Ciznar, P, Kalwak, K, Kottan, S, Jackowska, T, Drabko, K, Gagro, A, Pac, M, Naumova, E, Kandilarova, S, Babol-Pokora, K, Varabyou, DS, Barendregt, Barbara, Raykina, EV, Varlamova, TV, Pavlova, AV, Grombirikova, H, Debeljak, M, Mersiyanova, IV, Bondarenko, AV, Chernyshova, LI, Kostyuchenko, LV, Guseva, MN, Rascon, J, Muleviciene, A, Preiksaitiene, E, Geier, CB, Leiss-Piller, A, Yamazaki, Y, Kawai, T, Walter, JE, Kondratenko, IV, Sediva, A, van der Burg, Mirjam, Kuzmenko, NB, Notarangelo, LD, Bernatowska, E, Aleinikova, OV, Sharapova, SO, Skomska-Pawliszak, M, Rodina, YA, Wolska-Kusnierz, B, Dabrowska-Leonik, N, Mikoluc, B, Pashchenko, OE, Pasic, S, Freiberger, T, Milota, T, Formankova, R, Szaflarska, A, Siedlar, M, Avcin, T, Markelj, G, Ciznar, P, Kalwak, K, Kottan, S, Jackowska, T, Drabko, K, Gagro, A, Pac, M, Naumova, E, Kandilarova, S, Babol-Pokora, K, Varabyou, DS, Barendregt, Barbara, Raykina, EV, Varlamova, TV, Pavlova, AV, Grombirikova, H, Debeljak, M, Mersiyanova, IV, Bondarenko, AV, Chernyshova, LI, Kostyuchenko, LV, Guseva, MN, Rascon, J, Muleviciene, A, Preiksaitiene, E, Geier, CB, Leiss-Piller, A, Yamazaki, Y, Kawai, T, Walter, JE, Kondratenko, IV, Sediva, A, van der Burg, Mirjam, Kuzmenko, NB, Notarangelo, LD, Bernatowska, E, and Aleinikova, OV

Published
2020

5. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19

Author

Universitat Rovira i Virgili, Bastard P; Rosen LB; Zhang Q; Michailidis E; Hoffmann HH; Zhang Y; Dorgham K; Philippot Q; Rosain J; Béziat V; Manry J; Shaw E; Haljasmägi L; Peterson P; Lorenzo L; Bizien L; Trouillet-Assant S; Dobbs K; de Jesus AA; Belot A; Kallaste A; Catherinot E; Tandjaoui-Lambiotte Y; Le Pen J; Kerner G; Bigio B; Seeleuthner Y; Yang R; Bolze A; Spaan AN; Delmonte OM; Abers MS; Aiuti A; Casari G; Lampasona V; Piemonti L; Ciceri F; Bilguvar K; Lifton RP; Vasse M; Smadja DM; Migaud M; Hadjadj J; Terrier B; Duffy D; Quintana-Murci L; van de Beek D; Roussel L; Vinh DC; Tangye SG; Haerynck F; Dalmau D; Martinez-Picado J; Brodin P; Nussenzweig MC; Boisson-Dupuis S; Rodríguez-Gallego C; Vogt G; Mogensen TH; Oler AJ; Gu J; Burbelo PD; Cohen J; Biondi A; Bettini LR; D'Angio M; Bonfanti P; Rossignol P; Mayaux J; Rieux-Laucat F; Husebye ES; Fusco F; Ursini MV; Imberti L; Sottini A; Paghera S; Quiros-Roldan E; Rossi C; Castagnoli R; Montagna D; Licari A; Marseglia GL; Duval X; Ghosn J; HGID Lab; NIAID-USUHS Immune Response to COVID Group; COVID Clinicians; COVID-STORM Clinicians; Imagine COVID Group; French COVID Cohort Study Group; Milieu Intérieur Consortium; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank; COVID Human Genetic Effort; Tsang JS; Goldbach-Mansky R; Kisand K; Lionakis MS; Puel A; Zhang SY; Holland SM; Gorochov G; Jouanguy E; Rice CM; Cobat A; Notarangelo LD; Abel L; Su HC; Casanova JL, Universitat Rovira i Virgili, and Bastard P; Rosen LB; Zhang Q; Michailidis E; Hoffmann HH; Zhang Y; Dorgham K; Philippot Q; Rosain J; Béziat V; Manry J; Shaw E; Haljasmägi L; Peterson P; Lorenzo L; Bizien L; Trouillet-Assant S; Dobbs K; de Jesus AA; Belot A; Kallaste A; Catherinot E; Tandjaoui-Lambiotte Y; Le Pen J; Kerner G; Bigio B; Seeleuthner Y; Yang R; Bolze A; Spaan AN; Delmonte OM; Abers MS; Aiuti A; Casari G; Lampasona V; Piemonti L; Ciceri F; Bilguvar K; Lifton RP; Vasse M; Smadja DM; Migaud M; Hadjadj J; Terrier B; Duffy D; Quintana-Murci L; van de Beek D; Roussel L; Vinh DC; Tangye SG; Haerynck F; Dalmau D; Martinez-Picado J; Brodin P; Nussenzweig MC; Boisson-Dupuis S; Rodríguez-Gallego C; Vogt G; Mogensen TH; Oler AJ; Gu J; Burbelo PD; Cohen J; Biondi A; Bettini LR; D'Angio M; Bonfanti P; Rossignol P; Mayaux J; Rieux-Laucat F; Husebye ES; Fusco F; Ursini MV; Imberti L; Sottini A; Paghera S; Quiros-Roldan E; Rossi C; Castagnoli R; Montagna D; Licari A; Marseglia GL; Duval X; Ghosn J; HGID Lab; NIAID-USUHS Immune Response to COVID Group; COVID Clinicians; COVID-STORM Clinicians; Imagine COVID Group; French COVID Cohort Study Group; Milieu Intérieur Consortium; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank; COVID Human Genetic Effort; Tsang JS; Goldbach-Mansky R; Kisand K; Lionakis MS; Puel A; Zhang SY; Holland SM; Gorochov G; Jouanguy E; Rice CM; Cobat A; Notarangelo LD; Abel L; Su HC; Casanova JL

Abstract

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-omega (IFN-omega) (13 patients), against the 13 types of IFN-alpha (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for lifethreatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

Published
2020

6. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Author

Universitat Rovira i Virgili, Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, Ogishi M, Sabli IKD, Hodeib S, Korol C, Rosain J, Bilguvar K, Ye J, Bolze A, Bigio B, Yang R, Arias AA, Zhou Q, Zhang Y, Onodi F, Korniotis S, Karpf L, Philippot Q, Chbihi M, Bonnet-Madin L, Dorgham K, Smith N, Schneider WM, Razooky BS, Hoffmann HH, Michailidis E, Moens L, Han JE, Lorenzo L, Bizien L, Meade P, Neehus AL, Ugurbil AC, Corneau A, Kerner G, Zhang P, Rapaport F, Seeleuthner Y, Manry J, Masson C, Schmitt Y, Schlüter A, Le Voyer T, Khan T, Li J, Fellay J, Roussel L, Shahrooei M, Alosaimi MF, Mansouri D, Al-Saud H, Al-Mulla F, Almourfi F, Al-Muhsen SZ, Alsohime F, Al Turki S, Hasanato R, van de Beek D, Biondi A, Bettini LR, D'Angio M, Bonfanti P, Imberti L, Sottini A, Paghera S, Quiros-Roldan E, Rossi C, Oler AJ, Tompkins MF, Alba C, Vandernoot I, Goffard JC, Smits G, Migeotte I, Haerynck F, Soler-Palacin P, Martin-Nalda A, Colobran R, Morange PE, Keles S, Çölkesen F, Ozcelik T, Yasar KK, Senoglu S, Karabela ?N, Gallego CR, Novelli G, Hraiech S, Tandjaoui-Lambiotte Y, Duval X, Laouénan C,, Snow AL, Dalgard CL, Milner J, Vinh DC, Mogensen TH, Marr N, Spaan AN, Boisson B, Boisson-Dupuis S, Bustamante J, Puel A, Ciancanelli M, Meyts I, Maniatis T, Soumelis V, Amara A, Nussenzweig M, García-Sastre A, Krammer F, Pujol A, Duffy D, Lifton R, Zhang SY, Gorochov G, Béziat V, Jouanguy E, Sancho-Shimizu V, Rice CM, Abel L, Notarangelo LD, Cobat A, Su HC, Casanova JL COVID-STORM Clinicians, COVID Clinicians, Imagine COVID Group, French COVID Cohort Study Group, CoV-Contact Cohort, Amsterdam UMC Covid-19, Biobank, COVID Human Genetic Effort, NIAID-USUHS, TAGC COVID Immunity Group, Universitat Rovira i Virgili, and Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, Ogishi M, Sabli IKD, Hodeib S, Korol C, Rosain J, Bilguvar K, Ye J, Bolze A, Bigio B, Yang R, Arias AA, Zhou Q, Zhang Y, Onodi F, Korniotis S, Karpf L, Philippot Q, Chbihi M, Bonnet-Madin L, Dorgham K, Smith N, Schneider WM, Razooky BS, Hoffmann HH, Michailidis E, Moens L, Han JE, Lorenzo L, Bizien L, Meade P, Neehus AL, Ugurbil AC, Corneau A, Kerner G, Zhang P, Rapaport F, Seeleuthner Y, Manry J, Masson C, Schmitt Y, Schlüter A, Le Voyer T, Khan T, Li J, Fellay J, Roussel L, Shahrooei M, Alosaimi MF, Mansouri D, Al-Saud H, Al-Mulla F, Almourfi F, Al-Muhsen SZ, Alsohime F, Al Turki S, Hasanato R, van de Beek D, Biondi A, Bettini LR, D'Angio M, Bonfanti P, Imberti L, Sottini A, Paghera S, Quiros-Roldan E, Rossi C, Oler AJ, Tompkins MF, Alba C, Vandernoot I, Goffard JC, Smits G, Migeotte I, Haerynck F, Soler-Palacin P, Martin-Nalda A, Colobran R, Morange PE, Keles S, Çölkesen F, Ozcelik T, Yasar KK, Senoglu S, Karabela ?N, Gallego CR, Novelli G, Hraiech S, Tandjaoui-Lambiotte Y, Duval X, Laouénan C,, Snow AL, Dalgard CL, Milner J, Vinh DC, Mogensen TH, Marr N, Spaan AN, Boisson B, Boisson-Dupuis S, Bustamante J, Puel A, Ciancanelli M, Meyts I, Maniatis T, Soumelis V, Amara A, Nussenzweig M, García-Sastre A, Krammer F, Pujol A, Duffy D, Lifton R, Zhang SY, Gorochov G, Béziat V, Jouanguy E, Sancho-Shimizu V, Rice CM, Abel L, Notarangelo LD, Cobat A, Su HC, Casanova JL COVID-STORM Clinicians, COVID Clinicians, Imagine COVID Group, French COVID Cohort Study Group, CoV-Contact Cohort, Amsterdam UMC Covid-19, Biobank, COVID Human Genetic Effort, NIAID-USUHS, TAGC COVID Immunity Group

Abstract

Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal COVID-19. We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally define LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies. We show that human fibroblasts with mutations affecting this pathway are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.Copyright © 2020, American Association for the Advancement of Science.

Published
2020

8. Human Fibrinogen Concentrate and Fresh Frozen Plasma in the Management of Severe Acquired Hypofibrinogenemia in Children with Acute Lymphoblastic Leukemia: Results of a Retrospective Survey

Author

Giordano, P, Grassi, M, Saracco, P, Luciani, M, Colombini, A, Testi, A, Micalizzi, C, Petruzziello, F, Putti, M, Casale, F, Consarino, C, Mura, R, Mastrodicasa, E, Notarangelo, L, Onofrillo, D, Pollio, B, Rizzari, C, Tafuri, S, De Leonardis, F, Corallo, P, Santoro, N, Testi, AM, Putti, MC, Mura, RM, Notarangelo, LD, Corallo, PC, Giordano, P, Grassi, M, Saracco, P, Luciani, M, Colombini, A, Testi, A, Micalizzi, C, Petruzziello, F, Putti, M, Casale, F, Consarino, C, Mura, R, Mastrodicasa, E, Notarangelo, L, Onofrillo, D, Pollio, B, Rizzari, C, Tafuri, S, De Leonardis, F, Corallo, P, Santoro, N, Testi, AM, Putti, MC, Mura, RM, Notarangelo, LD, and Corallo, PC

Abstract

Objective of the Study:In this study we aimed to retrospectively evaluate how centers, belonging to the Associazione Italiana Ematologia e Oncologia Pediatrica (AIEOP), manage severe acquired hypofibrinogenemia in children with acute lymphoblastic leukemia, particularly evaluating the therapeutic role of human fibrinogen concentrate (HFC) and fresh frozen plasma (FFP).Methods:We conducted a survey among AIEOP centers; thereafter, we collected and analyzed data with regard to the treatment of episodes of severe acquired hypofibrinogenemia occurring during the induction and reinduction phases of the AIEOP-BFM ALL 2009 protocol.Results:In total, 15 of the 37 AIEOP centers invited to join the survey agreed to collect the data, with 10 and 5 centers declaring to react to severe acquired hypofibrinogenemia (<70 mg/dL) by administering HFC or FFP, respectively. Of the 150 episodes of severe hypofibrinogenemia occurring in 101 patients, 47.3% were treated with HFC and 52.7% with FFP, with a normalization of fibrinogen levels achieved in greater proportion and in a shorter amount of time in the HFC group as compared with the FFP group. None of the patients presented with bleeding or thrombosis during the observation period.Conclusions:Even with the limitations of the retrospective nature of this study, HFC seems to be a safe and effective alternative to FFP for replacement therapy in case of severe hypofibrinogenemia in children with acute lymphoblastic leukemia.

Published
2019

9. Efficacy of lentivirus-mediated gene therapy in an Omenn syndrome recombination-activating gene 2 mouse model is not hindered by inflammation and immune dysregulation

Author

Capo, V, Castiello, M, Fontana, E, Penna, S, Bosticardo, M, Draghici, E, Poliani, L, Sergi Sergi, L, Rigoni, R, Cassani, B, Zanussi, M, Carrera, P, Uva, P, Dobbs, K, Sacchetti, N, Notarangelo, L, van Til, N, Wagemaker, G, Villa, A, Castiello, MC, Poliani, LP, Notarangelo, LD, van Til N. P., Capo, V, Castiello, M, Fontana, E, Penna, S, Bosticardo, M, Draghici, E, Poliani, L, Sergi Sergi, L, Rigoni, R, Cassani, B, Zanussi, M, Carrera, P, Uva, P, Dobbs, K, Sacchetti, N, Notarangelo, L, van Til, N, Wagemaker, G, Villa, A, Castiello, MC, Poliani, LP, Notarangelo, LD, and van Til N. P.

Abstract

Background: Omenn syndrome (OS) is a rare severe combined immunodeficiency associated with autoimmunity and caused by defects in lymphoid-specific V(D)J recombination. Most patients carry hypomorphic mutations in recombination-activating gene (RAG) 1 or 2. Hematopoietic stem cell transplantation is the standard treatment; however, gene therapy (GT) might represent a valid alternative, especially for patients lacking a matched donor. Objective: We sought to determine the efficacy of lentiviral vector (LV)–mediated GT in the murine model of OS (Rag2 R229Q/R229Q ) in correcting immunodeficiency and autoimmunity. Methods: Lineage-negative cells from mice with OS were transduced with an LV encoding the human RAG2 gene and injected into irradiated recipients with OS. Control mice underwent transplantation with wild-type or OS-untransduced lineage-negative cells. Immunophenotyping, T-dependent and T-independent antigen challenge, immune spectratyping, autoantibody detection, and detailed tissue immunohistochemical analyses were performed. Results: LV-mediated GT allowed immunologic reconstitution, although it was suboptimal compared with that seen in wild-type bone marrow (BM)−transplanted OS mice in peripheral blood and hematopoietic organs, such as the BM, thymus, and spleen. We observed in vivo variability in the efficacy of GT correlating with the levels of transduction achieved. Immunoglobulin levels and T-cell repertoire normalized, and gene-corrected mice responded properly to challenges in vivo. Autoimmune manifestations, such as skin infiltration and autoantibodies, dramatically improved in GT mice with a vector copy number/genome higher than 1 in the BM and 2 in the thymus. Conclusions: Our data show that LV-mediated GT for patients with OS significantly ameliorates the immunodeficiency, even in an inflammatory environment.

Published
2018

11. Comparison of outcomes of hematopoietic stem cell transplantation without chemotherapy conditioning by using matched sibling and unrelated donors for treatment of severe combined immunodeficiency

Author

Dvorak, CC, Dvorak, CC, Hassan, A, Slatter, MA, Hönig, M, Lankester, AC, Buckley, RH, Pulsipher, MA, Davis, JH, Güngör, T, Gabriel, M, Bleesing, JH, Bunin, N, Sedlacek, P, Connelly, JA, Crawford, DF, Notarangelo, LD, Pai, SY, Hassid, J, Veys, P, Gennery, AR, Cowan, MJ, Dvorak, CC, Dvorak, CC, Hassan, A, Slatter, MA, Hönig, M, Lankester, AC, Buckley, RH, Pulsipher, MA, Davis, JH, Güngör, T, Gabriel, M, Bleesing, JH, Bunin, N, Sedlacek, P, Connelly, JA, Crawford, DF, Notarangelo, LD, Pai, SY, Hassid, J, Veys, P, Gennery, AR, and Cowan, MJ

Abstract

Background Patients with severe combined immunodeficiency disease who have matched sibling donors (MSDs) can proceed to hematopoietic cell transplantation (HCT) without conditioning chemotherapy. Objective We sought to determine whether the results of HCT without chemotherapy-based conditioning from matched unrelated donors (URDs), either from volunteer adults or umbilical cord blood, are comparable with those from MSDs.

Published
2014

12. Comparison of outcomes of hematopoietic stem cell transplantation without chemotherapy conditioning by using matched sibling and unrelated donors for treatment of severe combined immunodeficiency

Author

Dvorak, CC, Dvorak, CC, Hassan, A, Slatter, MA, Hönig, M, Lankester, AC, Buckley, RH, Pulsipher, MA, Davis, JH, Güngör, T, Gabriel, M, Bleesing, JH, Bunin, N, Sedlacek, P, Connelly, JA, Crawford, DF, Notarangelo, LD, Pai, SY, Hassid, J, Veys, P, Gennery, AR, Cowan, MJ, Dvorak, CC, Dvorak, CC, Hassan, A, Slatter, MA, Hönig, M, Lankester, AC, Buckley, RH, Pulsipher, MA, Davis, JH, Güngör, T, Gabriel, M, Bleesing, JH, Bunin, N, Sedlacek, P, Connelly, JA, Crawford, DF, Notarangelo, LD, Pai, SY, Hassid, J, Veys, P, Gennery, AR, and Cowan, MJ

Abstract

Background Patients with severe combined immunodeficiency disease who have matched sibling donors (MSDs) can proceed to hematopoietic cell transplantation (HCT) without conditioning chemotherapy. Objective We sought to determine whether the results of HCT without chemotherapy-based conditioning from matched unrelated donors (URDs), either from volunteer adults or umbilical cord blood, are comparable with those from MSDs.

Published
2014

13. Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders

Author

Noris, P, Biino, G, Pecci, A, Civaschi, E, Savoia, A, Seri, M, Melazzini, F, Loffredo, G, Russo, G, Bozzi, V, Notarangelo, Ld, Gresele, P, Heller, Pg, Pujol Moix, N, Kunishima, S, Cattaneo, M, Bussel, J, De Candia, Erica, Cagioni, C, Ramenghi, U, Barozzi, S, Fabris, F, Balduini, Cl, De Candia, Erica (ORCID:0000-0003-0942-2819), Noris, P, Biino, G, Pecci, A, Civaschi, E, Savoia, A, Seri, M, Melazzini, F, Loffredo, G, Russo, G, Bozzi, V, Notarangelo, Ld, Gresele, P, Heller, Pg, Pujol Moix, N, Kunishima, S, Cattaneo, M, Bussel, J, De Candia, Erica, Cagioni, C, Ramenghi, U, Barozzi, S, Fabris, F, Balduini, Cl, and De Candia, Erica (ORCID:0000-0003-0942-2819)

Abstract

Abnormalities of platelet size are one of the distinguishing features of inherited thrombocytopenias (ITs), and evaluation of blood films is recommended as an essential step for differential diagnosis of these disorders. Nevertheless, what we presently know about this subject is derived mainly from anecdotal evidence. To improve knowledge in this field, we evaluated platelet size on blood films obtained from 376 patients with all 19 forms of IT identified so far and found that these conditions differ not only in mean platelet diameter, but also in platelet diameter distribution width and the percentage of platelets with increased or reduced diameters. On the basis of these findings, we propose a new classification of ITs according to platelet size. It distinguishes forms with giant platelets, with large platelets, with normal or slightly increased platelet size, and with normal or slightly decreased platelet size. We also measured platelet diameters in 87 patients with immune thrombocytopenia and identified cutoff values for mean platelet diameter and the percentage of platelets with increased or reduced size that have good diagnostic accuracy in differentiating ITs with giant platelets and with normal or slightly decreased platelet size from immune thrombocytopenia and all other forms of IT

Published
2014

14. Wiskott-Aldrich syndrome protein-mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells

Author

Prete, F, Catucci, M, Labrada, M, Gobessi, S, Castiello, MC, Bonomi, E, Aiuti, A, Vermi, W, Cancrini, C, Metin, A, Hambleton, S, Bredius, R, Notarangelo, LD, van der Burg, Mirjam, Kalinke, U, Villa, A, Benvenuti, F, Prete, F, Catucci, M, Labrada, M, Gobessi, S, Castiello, MC, Bonomi, E, Aiuti, A, Vermi, W, Cancrini, C, Metin, A, Hambleton, S, Bredius, R, Notarangelo, LD, van der Burg, Mirjam, Kalinke, U, Villa, A, and Benvenuti, F

Published
2013

15. Primary immunodefciency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Priary Immunodeficiency

Author

Al-Herz, W, Bousfiha, A, Casanova, J-L, Chapel, H, Conley, ME, Cunningham-Rundles, C, Etzioni, A, Fischer, A, Luis Franco, J, Geha, RS, Hammarstrom, L, Nonoyama, S, Notarangelo, LD, Ochs, HD, Puck, JM, Roifman, CM, Seger, R, Tang, MLK, Al-Herz, W, Bousfiha, A, Casanova, J-L, Chapel, H, Conley, ME, Cunningham-Rundles, C, Etzioni, A, Fischer, A, Luis Franco, J, Geha, RS, Hammarstrom, L, Nonoyama, S, Notarangelo, LD, Ochs, HD, Puck, JM, Roifman, CM, Seger, R, and Tang, MLK

Abstract

We report the updated classification of primary immunodeficiency diseases, compiled by the ad hoc Expert Committee of the International Union of Immunological Societies. As compared to the previous edition, more than 15 novel disease entities have been added in the updated version. For each disorders, the key clinical and laboratory features are provided. This updated classification is meant to help in the diagnostic approach to patients with these diseases.

Published
2011

16. Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis

Author

UCL, Frattini, A, Pangrazio, A, Susani, L, Sobacchi, C, Mirolo, M, Abinun, M., Andolina, M, Flanagan, A, Horwitz, EM, Mihci, E, Notarangelo, LD, Ramenghi, U, Teti, A, Van Hove, J, Vujic, D, Young, T, Albertini, A, Orchard, PJ, Vezzoni, P, Villa, A, UCL, Frattini, A, Pangrazio, A, Susani, L, Sobacchi, C, Mirolo, M, Abinun, M., Andolina, M, Flanagan, A, Horwitz, EM, Mihci, E, Notarangelo, LD, Ramenghi, U, Teti, A, Van Hove, J, Vujic, D, Young, T, Albertini, A, Orchard, PJ, Vezzoni, P, and Villa, A

Abstract

Among 94 osteopetrotic patients presenting with a severe clinical picture and diagnosed early in life, 12 bore mutations in the ClCN7 gene, but only 7 of them had the expected two recessive mutations. The remaining five patients seem to be heterozygous for a ClCN7 mutation, and significant variations were observed in the clinical manifestations of their disease, even within the same family. Introduction: Human osteopetroses are a heterogeneous group of diseases that include both infantile severe, autosomal recessive (ARO) and adult autosomal dominant (ADO) forms. Two genes, Atp6a3 (TCIRG1) and ClCN7, have been shown to be associated with human ARO, the latter of which is also thought to be responsible for ADO-II. However, patients with an intermediate phenotype have been described: the genetic basis of these observances is unknown. Materials and Methods: In this study, we report the clinical and molecular analysis of 94 patients in which a diagnosis of severe osteopetrosis was made within the first 2 years of age. Both TCIRG1 and CLCN7 genes were sequenced in all patients and the molecular findings were correlated to clinical parameters. Results and Conclusions: In 56 of 94 patients with a classical picture of ARO, TCIRG1-dependent recessive mutations were found. In contrast, ClCN7 mutations were found in 12 cases (13%) of severe osteopetrosis, but only 7 of them had two recessive mutations identified: in 6 of these 7 cases, central nervous system manifestations were noted, and these patients had a poor prognosis. The remaining five cases were heterozygous for a ClCN7 mutation, including two brothers from a large family with a history of ADO-II in which the presence of a second ClCN7 mutation was formally excluded. Despite an early and severe clinical presentation, these five patients all reached adulthood, suggesting that the degree of dominant interference with chloride channel function can vary widely. Our findings suggest that recessive ClCN7-dependent ARO may b

Published
2003

17. Congenital Agammaglobulinemia in a Female Child

Author

Calabri, G, Salvi, G, Nieri, Rm, Rossi, Me, Parolini, Ornella, Notarangelo, Ld, Giovannucci, Ml, Cocchi, P., Parolini, Ornella (ORCID:0000-0002-5211-6430), Calabri, G, Salvi, G, Nieri, Rm, Rossi, Me, Parolini, Ornella, Notarangelo, Ld, Giovannucci, Ml, Cocchi, P., and Parolini, Ornella (ORCID:0000-0002-5211-6430)

Abstract

We report a case of congenital agammaglobulinemia in a female child. This immunodeficiency usually affects males since it is a X-linked immunological disorder. Personal and family history of the little girl let us suspect that the genetic defect is not X-linked but probably an autosomic recessive disorder.

Published
1995

18. Molecular Bases of primary immunodeficiencies

Author

Notarangelo, Ld, Giliani, S, Parolini, Ornella, Candotti, F., Parolini, Ornella (ORCID:0000-0002-5211-6430), Notarangelo, Ld, Giliani, S, Parolini, Ornella, Candotti, F., and Parolini, Ornella (ORCID:0000-0002-5211-6430)

Abstract

NOT AVAILABLE

Published
1994

19. The Wiskott-Aldrich syndrome (WAS) gene is expressed prior to the granulocyte-macrophage colony forming unit (GM-CFU) stage of hematopoietic differentiation

Author

Mantuano, E, Notarangelo, Ld, Candotti, F, Giliani, S, Lusardi, M, Parolini, Ornella, Porta, F, Ugazio, Ag, Parolini, Ornella (ORCID:0000-0002-5211-6430), Mantuano, E, Notarangelo, Ld, Candotti, F, Giliani, S, Lusardi, M, Parolini, Ornella, Porta, F, Ugazio, Ag, and Parolini, Ornella (ORCID:0000-0002-5211-6430)

Abstract

not available

Published
1993

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