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1. Lentiviral correction of enzymatic activity restrains macrophage inflammation in adenosine deaminase 2 deficiency

Author

Zoccolillo, Matteo, Brigida, Immacolata, Barzaghi, Federica, Scala, Serena, Hernández, Raisa Jofra, Basso-Ricci, Luca, Colantuoni, Mariasilvia, Pettinato, Emanuela, Sergi, Lucia Sergi, Milardi, Giulia, Capasso, Paola, Lombardo, Angelo, Gregori, Silvia, Sanvito, Francesca, Schena, Francesca, Cesaro, Simone, Conti, Francesca, Pession, Andrea, Benedetti, Fabio, Gattorno, Marco, Lee, Pui Y., Naldini, Luigi, Cicalese, Maria Pia, Aiuti, Alessandro, and Mortellaro, Alessandra

Published
2021
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2. Antimicrobial Synergistic Effects of Linezolid and Vancomycin with a Small Synthesized 2-Mercaptobenzothiazole Derivative: A Challenge for MRSA Solving

Author

Marilena Muraglia, Brigida Immacolata Pia Schiavone, Antonio Rosato, Maria Lisa Clodoveo, and Filomena Corbo

Subjects
Staphylococcus aureus, synergism, antibiotic resistance, anti-biofilm, MRSA and MRSE, benzothiazole, Organic chemistry, QD241-441
Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) emerged as one of the leading causes of persistent human infections and makes it difficult to treat bacteremia, especially with biofilm formation. In this work, we investigated the in vitro synergism between Linezolid (LNZ) and Vancomycin (VAN) with a 2-mercaptobenzothiazole derivative, resulting in a new small-molecule antibacterial compound that we named BTZ2e, on several clinical MRSA, MRSE (methicillin-resistant Staphylococcus epidermidis) and control (ATCC Collection) strains in their planktonic and biofilms cultures. The broth microdilution method evaluated the susceptibility of planktonic cells to each investigated antibiotic combined with BTZ2e. The biofilm’s metabolic activity was studied with the XTT reduction assay. As a result, in this study, biofilm formation was significantly suppressed by the BTZ2e treatment. In terms of minimal biofilm inhibitory concentration (MBIC), BTZ2e revealed an MBIC50 value of 32 μg/mL against methicillin-susceptible S. aureus (MSSA) and 16 μg/mL against methicillin-resistant S. aureus ATCC 43300 biofilms. An inhibition range of 32 μg/mL and 256 μg/mL was registered for the clinical isolates. Interestingly, a synergistic effect (FICI ≤ 0.5) was encountered for the combination of BTZ2e with LNZ and VAN on several planktonic and sessile strains. In particular, the best result against planktonic cells emerged as a result of the synergistic association between LNZ and BTZ2e, while against sessile cells, the best synergistic association resulted from VAN and BTZ2e. The consistent results indicate BTZ2e as a promising adjuvant against multi-resistant strains such as MRSA and MRSE.

Published
2023
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3. B-cell development and functions and therapeutic options in adenosine deaminase–deficient patients

Author

Brigida, Immacolata, Sauer, Aisha V, Ferrua, Francesca, Giannelli, Stefania, Scaramuzza, Samantha, Pistoia, Valentina, Castiello, Maria Carmina, Barendregt, Barbara H, Cicalese, Maria Pia, Casiraghi, Miriam, Brombin, Chiara, Puck, Jennifer, Müller, Klaus, Notarangelo, Lucia Dora, Montin, Davide, van Montfrans, Joris M, Roncarolo, Maria Grazia, Traggiai, Elisabetta, van Dongen, Jacques JM, van der Burg, Mirjam, and Aiuti, Alessandro

Subjects
Regenerative Medicine, Genetics, Pediatric, Stem Cell Research, Transplantation, Stem Cell Research - Nonembryonic - Non-Human, Gene Therapy, 2.1 Biological and endogenous factors, 5.2 Cellular and gene therapies, Aetiology, Development of treatments and therapeutic interventions, Inflammatory and immune system, Adenosine Deaminase, Adolescent, B-Cell Activating Factor, B-Lymphocytes, Child, Child, Preschool, Enzyme Replacement Therapy, Genetic Therapy, Hematopoietic Stem Cell Transplantation, Humans, Infant, Gene therapy, adenosine deaminase-deficient severe combined immunodeficiency, B-cell development, antibodies, adenosine deaminase–deficient severe combined immunodeficiency, Immunology, Allergy
Abstract

BackgroundAdenosine deaminase (ADA) deficiency causes severe cellular and humoral immune defects and dysregulation because of metabolic toxicity. Alterations in B-cell development and function have been poorly studied. Enzyme replacement therapy (ERT) and hematopoietic stem cell (HSC) gene therapy (GT) are therapeutic options for patients lacking a suitable bone marrow (BM) transplant donor.ObjectiveWe sought to study alterations in B-cell development in ADA-deficient patients and investigate the ability of ERT and HSC-GT to restore normal B-cell differentiation and function.MethodsFlow cytometry was used to characterize B-cell development in BM and the periphery. The percentage of gene-corrected B cells was measured by using quantitative PCR. B cells were assessed for their capacity to proliferate and release IgM after stimulation.ResultsDespite the severe peripheral B-cell lymphopenia, patients with ADA-deficient severe combined immunodeficiency showed a partial block in central BM development. Treatment with ERT or HSC-GT reverted most BM alterations, but ERT led to immature B-cell expansion. In the periphery transitional B cells accumulated under ERT, and the defect in maturation persisted long-term. HSC-GT led to a progressive improvement in B-cell numbers and development, along with increased levels of gene correction. The strongest selective advantage for ADA-transduced cells occurred at the transition from immature to naive cells. B-cell proliferative responses and differentiation to immunoglobulin secreting IgM after B-cell receptor and Toll-like receptor triggering were severely impaired after ERT and improved significantly after HSC-GT.ConclusionsADA-deficient patients show specific defects in B-cell development and functions that are differently corrected after ERT and HSC-GT.

Published
2014

4. T-cell defects in patients with ARPC1B germline mutations account for combined immunodeficiency

Author

Brigida, Immacolata, Zoccolillo, Matteo, Cicalese, Maria Pia, Pfajfer, Laurène, Barzaghi, Federica, Scala, Serena, Oleaga-Quintas, Carmen, Álvarez-Álvarez, Jesus A., Sereni, Lucia, Giannelli, Stefania, Sartirana, Claudia, Dionisio, Francesca, Pavesi, Luca, Benavides-Nieto, Marta, Basso-Ricci, Luca, Capasso, Paola, Mazzi, Benedetta, Rosain, Jeremie, Marcus, Nufar, Lee, Yu Nee, Somech, Raz, Degano, Massimo, Raiola, Giuseppe, Caorsi, Roberta, Picco, Paolo, Moncada Velez, Marcela, Khourieh, Joelle, Arias, Andrés Augusto, Bousfiha, Aziz, Issekutz, Thomas, Issekutz, Andrew, Boisson, Bertrand, Dobbs, Kerry, Villa, Anna, Lombardo, Angelo, Neven, Benedicte, Moshous, Despina, Casanova, Jean-Laurent, Franco, José Luis, Notarangelo, Luigi D., Scielzo, Cristina, Volpi, Stefano, Dupré, Loïc, Bustamante, Jacinta, Gattorno, Marco, and Aiuti, Alessandro

Published
2018
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6. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency

Author

Cicalese, Maria Pia, Ferrua, Francesca, Castagnaro, Laura, Pajno, Roberta, Barzaghi, Federica, Giannelli, Stefania, Dionisio, Francesca, Brigida, Immacolata, Bonopane, Marco, Casiraghi, Miriam, Tabucchi, Antonella, Carlucci, Filippo, Grunebaum, Eyal, Adeli, Mehdi, Bredius, Robbert G., Puck, Jennifer M., Stepensky, Polina, Tezcan, Ilhan, Rolfe, Katie, De Boever, Erika, Reinhardt, Rickey R., Appleby, Jonathan, Ciceri, Fabio, Roncarolo, Maria Grazia, and Aiuti, Alessandro

Published
2016
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7. Case Report: Consistent disease manifestations with a staggered time course in two identical twins affected by adenosine deaminase 2 deficiency

Author

Barzaghi, Federica, primary, Cicalese, Maria Pia, additional, Zoccolillo, Matteo, additional, Brigida, Immacolata, additional, Barcella, Matteo, additional, Merelli, Ivan, additional, Sartirana, Claudia, additional, Zanussi, Monica, additional, Calbi, Valeria, additional, Bernardo, Maria Ester, additional, Tucci, Francesca, additional, Migliavacca, Maddalena, additional, Giglio, Fabio, additional, Doglio, Matteo, additional, Canarutto, Daniele, additional, Ferrua, Francesca, additional, Consiglieri, Giulia, additional, Prunotto, Giulia, additional, Saettini, Francesco, additional, Bonanomi, Sonia, additional, Rovere-Querini, Patrizia, additional, Di Colo, Giulia, additional, Jofra, Tatiana, additional, Fousteri, Georgia, additional, Penco, Federica, additional, Gattorno, Marco, additional, Hershfield, Michael S., additional, Bongiovanni, Lucia, additional, Ponzoni, Maurilio, additional, Marktel, Sarah, additional, Milani, Raffaella, additional, Peccatori, Jacopo, additional, Ciceri, Fabio, additional, Mortellaro, Alessandra, additional, and Aiuti, Alessandro, additional

Published
2022
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8. T-cell suicide gene therapy prompts thymic renewal in adults after hematopoietic stem cell transplantation

Author

Vago, Luca, Oliveira, Giacomo, Bondanza, Attilio, Noviello, Maddalena, Soldati, Corrado, Ghio, Domenico, Brigida, Immacolata, Greco, Raffaella, Lupo Stanghellini, Maria Teresa, Peccatori, Jacopo, Fracchia, Sergio, Del Fiacco, Matteo, Traversari, Catia, Aiuti, Alessandro, Del Maschio, Alessandro, Bordignon, Claudio, Ciceri, Fabio, and Bonini, Chiara

Published
2012
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10. Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID

Author

Sauer, Aisha V., Brigida, Immacolata, Carriglio, Nicola, Jofra Hernandez, Raisa, Scaramuzza, Samantha, Clavenna, Daniela, Sanvito, Francesca, Poliani, Pietro L., Gagliani, Nicola, Carlucci, Filippo, Tabucchi, Antonella, Roncarolo, Maria Grazia, Traggiai, Elisabetta, Villa, Anna, and Aiuti, Alessandro

Published
2012
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11. Lentiviral-Mediated Gene Therapy for the Treatment of Adenosine Deaminase 2 Deficiency

Author

Mortellaro, Alessandra, primary, Zoccolillo, Matteo, additional, Mesa Nuñez, Cristina, additional, Brix, Alessia, additional, Brigida, Immacolata, additional, Barzaghi, Federica, additional, Scala, Serena, additional, Jofra Hernández, Raisa, additional, Basso-Ricci, Luca, additional, Colantuoni, Mariasilvia, additional, Cesaro, Simone, additional, Conti, Francesca, additional, Pession, Andrea, additional, Benedetti, Fabio, additional, Gattorno, Marco, additional, Naldini, Luigi, additional, Cicalese, Maria Pia, additional, Pistocchi, Anna, additional, and Aiuti, Alessandro, additional

Published
2021
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12. Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy

Author

Sauer, Aisha V., Morbach, Henner, Brigida, Immacolata, Ng, Yen-Shing, Aiuti, Alessandro, and Meffre, Eric

Subjects
Gene therapy -- Patient outcomes, B cells -- Genetic aspects, Adenosine deaminase deficiency -- Diagnosis -- Care and treatment, Health care industry
Abstract

Adenosine deaminase (ADA) gene defects are among the most common causes of SCID. Restoration of purine metabolism and immune functions can be achieved by enzyme replacement therapy, or more effectively by bone marrow transplant or HSC gene therapy (HSC-GT). However, autoimmune complications and autoantibody production, including anti-nuclear antibodies (ANAs), frequently occur in ADA-SCID patients after treatment. To assess whether ADA deficiency affects the establishment of B cell tolerance, we tested the reactivity of recombinant antibodies isolated from single B cells of ADA-SCID patients before and after HSC-GT. We found that before HSC-GT, new emigrant/transitional and mature naive B cells from ADA-SCID patients contained more autoreactive and ANA-expressing clones, indicative of defective central and peripheral B cell tolerance checkpoints. We further observed impaired B cell receptor (BCR) and TLR functions in B cells after ADA inhibition, which may underlie the defects in B cell tolerance. Strikingly, after HSC-GT, ADA-SCID patients displayed quasi-normal early B cell tolerance checkpoints, as evidenced by restored removal of developing autoreactive and ANA-expressing B cells. Hence, ADA plays an essential role in controlling autoreactive B cell counterselection by regulating BCR and TLR functions., Introduction Genetic defects in the adenosine deaminase (ADA) gene are among the most common causes of SCID (1). Immunological defects associated with this disease include impaired T, B, and NK [...]

Published
2012
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14. A combined immunodeficiency with severe infections, inflammation, and allergy caused by ARPC1B deficiency

Author

Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Volpi, Stefano, Cicalese, Maria Pia, Tuijnenburg, Paul, Tool, Anton T J, Cuadrado, Eloy, Abu-Halaweh, Marwan, Ahanchian, Hamid, Alzyoud, Raed, Akdemir, Zeynep Coban, Barzaghi, Federica, Blank, Alexander, Boisson, Bertrand, Bottino, Cristina, Brigida, Immacolata, Caorsi, Roberta, Casanova, Jean-Laurent, Chiesa, Sabrina, Chinn, Ivan Kingyue, Dückers, Gregor, Enders, Anselm, Erichsen, Hans Christian, Forbes, Lisa R, Gambin, Tomasz, Gattorno, Marco, Karimiani, Ehsan Ghayoor, Giliani, Silvia, Gold, Michael S, Jacobsen, Eva-Maria, Jansen, Machiel H, King, Jovanka R, Laxer, Ronald M, Lupski, James R, Mace, Emily, Marcenaro, Stefania, Maroofian, Reza, Meijer, Alexander B, Niehues, Tim, Notarangelo, Luigi D, Orange, Jordan, Pannicke, Ulrich, Pearson, Chris, Picco, Paolo, Quinn, Patrick J, Schulz, Ansgar, Seeborg, Filiz, Stray-Pedersen, Asbjørg, Tawamie, Hasan, van Leeuwen, Ester M M, Aiuti, Alessandro, Yeung, Rae, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Volpi, Stefano, Cicalese, Maria Pia, Tuijnenburg, Paul, Tool, Anton T J, Cuadrado, Eloy, Abu-Halaweh, Marwan, Ahanchian, Hamid, Alzyoud, Raed, Akdemir, Zeynep Coban, Barzaghi, Federica, Blank, Alexander, Boisson, Bertrand, Bottino, Cristina, Brigida, Immacolata, Caorsi, Roberta, Casanova, Jean-Laurent, Chiesa, Sabrina, Chinn, Ivan Kingyue, Dückers, Gregor, Enders, Anselm, Erichsen, Hans Christian, Forbes, Lisa R, Gambin, Tomasz, Gattorno, Marco, Karimiani, Ehsan Ghayoor, Giliani, Silvia, Gold, Michael S, Jacobsen, Eva-Maria, Jansen, Machiel H, King, Jovanka R, Laxer, Ronald M, Lupski, James R, Mace, Emily, Marcenaro, Stefania, Maroofian, Reza, Meijer, Alexander B, Niehues, Tim, Notarangelo, Luigi D, Orange, Jordan, Pannicke, Ulrich, Pearson, Chris, Picco, Paolo, Quinn, Patrick J, Schulz, Ansgar, Seeborg, Filiz, Stray-Pedersen, Asbjørg, Tawamie, Hasan, van Leeuwen, Ester M M, Aiuti, Alessandro, and Yeung, Rae

Published
2019

15. A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function

Author

Lam, Michael T., primary, Coppola, Simona, additional, Krumbach, Oliver H.F., additional, Prencipe, Giusi, additional, Insalaco, Antonella, additional, Cifaldi, Cristina, additional, Brigida, Immacolata, additional, Zara, Erika, additional, Scala, Serena, additional, Di Cesare, Silvia, additional, Martinelli, Simone, additional, Di Rocco, Martina, additional, Pascarella, Antonia, additional, Niceta, Marcello, additional, Pantaleoni, Francesca, additional, Ciolfi, Andrea, additional, Netter, Petra, additional, Carisey, Alexandre F., additional, Diehl, Michael, additional, Akbarzadeh, Mohammad, additional, Conti, Francesca, additional, Merli, Pietro, additional, Pastore, Anna, additional, Levi Mortera, Stefano, additional, Camerini, Serena, additional, Farina, Luciapia, additional, Buchholzer, Marcel, additional, Pannone, Luca, additional, Cao, Tram N., additional, Coban-Akdemir, Zeynep H., additional, Jhangiani, Shalini N., additional, Muzny, Donna M., additional, Gibbs, Richard A., additional, Basso-Ricci, Luca, additional, Chiriaco, Maria, additional, Dvorsky, Radovan, additional, Putignani, Lorenza, additional, Carsetti, Rita, additional, Janning, Petra, additional, Stray-Pedersen, Asbjorg, additional, Erichsen, Hans Christian, additional, Horne, AnnaCarin, additional, Bryceson, Yenan T., additional, Torralba-Raga, Lamberto, additional, Ramme, Kim, additional, Rosti, Vittorio, additional, Bracaglia, Claudia, additional, Messia, Virginia, additional, Palma, Paolo, additional, Finocchi, Andrea, additional, Locatelli, Franco, additional, Chinn, Ivan K., additional, Lupski, James R., additional, Mace, Emily M., additional, Cancrini, Caterina, additional, Aiuti, Alessandro, additional, Ahmadian, Mohammad R., additional, Orange, Jordan S., additional, De Benedetti, Fabrizio, additional, and Tartaglia, Marco, additional

Published
2019
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16. Corrigendum: Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

Author

Cifaldi, Cristina, primary, Brigida, Immacolata, additional, Barzaghi, Federica, additional, Zoccolillo, Matteo, additional, Ferradini, Valentina, additional, Petricone, Davide, additional, Cicalese, Maria Pia, additional, Lazarevic, Dejan, additional, Cittaro, Davide, additional, Omrani, Maryam, additional, Attardi, Enrico, additional, Conti, Francesca, additional, Scarselli, Alessia, additional, Chiriaco, Maria, additional, Di Cesare, Silvia, additional, Licciardi, Francesco, additional, Davide, Montin, additional, Ferrua, Francesca, additional, Canessa, Clementina, additional, Pignata, Claudio, additional, Giliani, Silvia, additional, Ferrari, Simona, additional, Fousteri, Georgia, additional, Barera, Graziano, additional, Merli, Pietro, additional, Palma, Paolo, additional, Cesaro, Simone, additional, Gattorno, Marco, additional, Trizzino, Antonio, additional, Moschese, Viviana, additional, Chini, Loredana, additional, Villa, Anna, additional, Azzari, Chiara, additional, Finocchi, Andrea, additional, Locatelli, Franco, additional, Rossi, Paolo, additional, Sangiuolo, Federica, additional, Aiuti, Alessandro, additional, Cancrini, Caterina, additional, and Di Matteo, Gigliola, additional

Published
2019
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17. Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

Author

Cifaldi, Cristina, primary, Brigida, Immacolata, additional, Barzaghi, Federica, additional, Zoccolillo, Matteo, additional, Ferradini, Valentina, additional, Petricone, Davide, additional, Cicalese, Maria Pia, additional, Lazarevic, Dejan, additional, Cittaro, Davide, additional, Omrani, Maryam, additional, Attardi, Enrico, additional, Conti, Francesca, additional, Scarselli, Alessia, additional, Chiriaco, Maria, additional, Di Cesare, Silvia, additional, Licciardi, Francesco, additional, Davide, Montin, additional, Ferrua, Francesca, additional, Canessa, Clementina, additional, Pignata, Claudio, additional, Giliani, Silvia, additional, Ferrari, Simona, additional, Fousteri, Georgia, additional, Barera, Graziano, additional, Merli, Pietro, additional, Palma, Paolo, additional, Cesaro, Simone, additional, Gattorno, Marco, additional, Trizzino, Antonio, additional, Moschese, Viviana, additional, Chini, Loredana, additional, Villa, Anna, additional, Azzari, Chiara, additional, Finocchi, Andrea, additional, Locatelli, Franco, additional, Rossi, Paolo, additional, Sangiuolo, Federica, additional, Aiuti, Alessandro, additional, Cancrini, Caterina, additional, and Di Matteo, Gigliola, additional

Published
2019
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18. First Case of Patient With Two Homozygous Mutations in MYD88 and CARD9 Genes Presenting With Pyogenic Bacterial Infections, Elevated IgE, and Persistent EBV Viremia

Author

Chiriaco, Maria, primary, Di Matteo, Gigliola, additional, Conti, Francesca, additional, Petricone, Davide, additional, De Luca, Maia, additional, Di Cesare, Silvia, additional, Cifaldi, Cristina, additional, De Vito, Rita, additional, Zoccolillo, Matteo, additional, Serafinelli, Jessica, additional, Poerio, Noemi, additional, Fraziano, Maurizio, additional, Brigida, Immacolata, additional, Cardinale, Fabio, additional, Rossi, Paolo, additional, Aiuti, Alessandro, additional, Cancrini, Caterina, additional, and Finocchi, Andrea, additional

Published
2019
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19. ALPS-Like Phenotype Caused by ADA2 Deficiency Rescued by Allogeneic Hematopoietic Stem Cell Transplantation

Author

Barzaghi, Federica, primary, Minniti, Federica, additional, Mauro, Margherita, additional, Bortoli, Massimiliano De, additional, Balter, Rita, additional, Bonetti, Elisa, additional, Zaccaron, Ada, additional, Vitale, Virginia, additional, Omrani, Maryam, additional, Zoccolillo, Matteo, additional, Brigida, Immacolata, additional, Cicalese, Maria Pia, additional, Degano, Massimo, additional, Hershfield, Michael S., additional, Aiuti, Alessandro, additional, Bondarenko, Anastasiia V., additional, Chinello, Matteo, additional, and Cesaro, Simone, additional

Published
2019
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20. First Occurrence of Plasmablastic Lymphoma in Adenosine Deaminase-Deficient Severe Combined Immunodeficiency Disease Patient and Review of the Literature

Author

Migliavacca, Maddalena, primary, Assanelli, Andrea, additional, Ponzoni, Maurilio, additional, Pajno, Roberta, additional, Barzaghi, Federica, additional, Giglio, Fabio, additional, Ferrua, Francesca, additional, Frittoli, Marta, additional, Brigida, Immacolata, additional, Dionisio, Francesca, additional, Nicoletti, Roberto, additional, Casiraghi, Miriam, additional, Roncarolo, Maria Grazia, additional, Doglioni, Claudio, additional, Peccatori, Jacopo, additional, Ciceri, Fabio, additional, Cicalese, Maria Pia, additional, and Aiuti, Alessandro, additional

Published
2018
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21. Biological and functional characterization of bone marrow-derived mesenchymal stromal cells from patients affected by primary immunodeficiency

Author

Starc, Nadia, primary, Ingo, Daniela, additional, Conforti, Antonella, additional, Rossella, Valeria, additional, Tomao, Luigi, additional, Pitisci, Angela, additional, De Mattia, Fabiola, additional, Brigida, Immacolata, additional, Algeri, Mattia, additional, Montanari, Mauro, additional, Palumbo, Giuseppe, additional, Merli, Pietro, additional, Rossi, Paolo, additional, Aiuti, Alessandro, additional, Locatelli, Franco, additional, and Bernardo, Maria Ester, additional

Published
2017
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22. Altered B cell development and fuctions in Adenosine Deaminase deficient patients

Author

Aiuti Alessandro, Giannelli Stefania, Scaramuzza Samantha, Brigida Immacolata, Van Der Burg Mirjam, Casiraghi Miriam, Traggiai Elisabetta, Ferrua Francesca, Sauer Aisha, and Cicalese Maria Pia

Subjects
medicine.anatomical_structure, Adenosine deaminase, biology, Chemistry, Immunology, medicine, biology.protein, Immunology and Allergy, Molecular biology, B cell
Published
2013
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23. T-cell defects in patients with ARPC1Bgermline mutations account for combined immunodeficiency

Author

Brigida, Immacolata, Zoccolillo, Matteo, Cicalese, Maria Pia, Pfajfer, Laurène, Barzaghi, Federica, Scala, Serena, Oleaga-Quintas, Carmen, Álvarez-Álvarez, Jesus A., Sereni, Lucia, Giannelli, Stefania, Sartirana, Claudia, Dionisio, Francesca, Pavesi, Luca, Benavides-Nieto, Marta, Basso-Ricci, Luca, Capasso, Paola, Mazzi, Benedetta, Rosain, Jeremie, Marcus, Nufar, Lee, Yu Nee, Somech, Raz, Degano, Massimo, Raiola, Giuseppe, Caorsi, Roberta, Picco, Paolo, Moncada Velez, Marcela, Khourieh, Joelle, Arias, Andrés Augusto, Bousfiha, Aziz, Issekutz, Thomas, Issekutz, Andrew, Boisson, Bertrand, Dobbs, Kerry, Villa, Anna, Lombardo, Angelo, Neven, Benedicte, Moshous, Despina, Casanova, Jean-Laurent, Franco, José Luis, Notarangelo, Luigi D., Scielzo, Cristina, Volpi, Stefano, Dupré, Loïc, Bustamante, Jacinta, Gattorno, Marco, and Aiuti, Alessandro

Abstract

ARPC1B is a key factor for the assembly and maintenance of the ARP2/3 complex that is involved in actin branching from an existing filament. Germline biallelic mutations in ARPC1Bhave been recently described in 6 patients with clinical features of combined immunodeficiency (CID), whose neutrophils and platelets but not T lymphocytes were studied. We hypothesized that ARPC1B deficiency may also lead to cytoskeleton and functional defects in T cells. We have identified biallelic mutations in ARPC1Bin 6 unrelated patients with early onset disease characterized by severe infections, autoimmune manifestations, and thrombocytopenia. Immunological features included T-cell lymphopenia, low numbers of naïve T cells, and hyper–immunoglobulin E. Alteration in ARPC1B protein structure led to absent/low expression by flow cytometry and confocal microscopy. This molecular defect was associated with the inability of patient-derived T cells to extend an actin-rich lamellipodia upon T-cell receptor (TCR) stimulation and to assemble an immunological synapse. ARPC1B-deficient T cells additionally displayed impaired TCR-mediated proliferation and SDF1-α−directed migration. Gene transfer of ARPC1Bin patients' T cells using a lentiviral vector restored both ARPC1B expression and T-cell proliferation in vitro. In 2 of the patients, in vivo somatic reversion restored ARPC1B expression in a fraction of lymphocytes and was associated with a skewed TCR repertoire. In 1 revertant patient, memory CD8+T cells expressing normal levels of ARPC1B displayed improved T-cell migration. Inherited ARPC1B deficiency therefore alters T-cell cytoskeletal dynamics and functions, contributing to the clinical features of CID.

Published
2018
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24. Gene therapy for immunodeficiency due to adenosine deaminase deficiency.

Author

Aiuti, Alessandro, Cattaneo, Federica, Galimberti, Stefania, Benninghoff, Ulrike, Cassani, Barbara, Callegaro, Luciano, Scaramuzza, Samantha, Andolfi, Grazia, Mirolo, Massimiliano, Brigida, Immacolata, Tabucchi, Antonella, Carlucci, Filippo, Eibl, Martha, Aker, Memet, Slavin, Shimon, Al-Mousa, Hamoud, Al Ghonaium, Abdulaziz, Ferster, Alina, Duppenthaler, Andrea, Notarangelo, Luigi, Wintergerst, Uwe, Buckley, Rebecca H, Bregni, Marco, Marktel, Sarah, Valsecchi, Maria Grazia, Rossi, Pier Luca, Ciceri, Fabio, Miniero, Roberto, Bordignon, Claudio, Roncarolo, Maria-Grazia, Aiuti, Alessandro, Cattaneo, Federica, Galimberti, Stefania, Benninghoff, Ulrike, Cassani, Barbara, Callegaro, Luciano, Scaramuzza, Samantha, Andolfi, Grazia, Mirolo, Massimiliano, Brigida, Immacolata, Tabucchi, Antonella, Carlucci, Filippo, Eibl, Martha, Aker, Memet, Slavin, Shimon, Al-Mousa, Hamoud, Al Ghonaium, Abdulaziz, Ferster, Alina, Duppenthaler, Andrea, Notarangelo, Luigi, Wintergerst, Uwe, Buckley, Rebecca H, Bregni, Marco, Marktel, Sarah, Valsecchi, Maria Grazia, Rossi, Pier Luca, Ciceri, Fabio, Miniero, Roberto, Bordignon, Claudio, and Roncarolo, Maria-Grazia

Abstract

We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency., Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2009

26. T Cell Suicide Gene Therapy Prompts Thymic Renewal in Adults After Haploidentical Hematopoietic Stem Cell Transplantation in the Absence of Post-Transplant Immunesuppression

Author

Vago, Luca, primary, Oliveira, Giacomo, additional, Bondanza, Attilio, additional, Noviello, Maddalena, additional, Soldati, Corrado, additional, Ghio, Domenico, additional, Brigida, Immacolata, additional, Greco, Raffaella, additional, Stanghellini, Maria Teresa Lupo, additional, Peccatori, Jacopo, additional, Fracchia, Sergio, additional, Fiacco, Matteo Del, additional, Traversari, Catia, additional, Aiuti, Alessandro, additional, Lambiase, Antonio, additional, Maschio, Alessandro Del, additional, Bordignon, Claudio, additional, Ciceri, Fabio, additional, and Bonini, Chiara, additional

Published
2011
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27. Thymic Renewal and Anti-Leukemic Effect In Adults After Haploidentical Transplantation and Donor T Cell Suicide Gene Therapy

Author

Vago, Luca, primary, Oliveira, Giacomo, additional, Noviello, Maddalena, additional, Soldati, Corrado, additional, Ghio, Domenico, additional, Nicoletti, Roberto, additional, Brigida, Immacolata, additional, Aiuti, Alessandro, additional, Stanghellini, Maria Teresa Lupo, additional, Mastaglio, Sara, additional, Greco, Raffaella, additional, Lambiase, Antonio, additional, Peccatori, Jacopo, additional, Bondanza, Attilio, additional, Fleischhauer, Katharina, additional, Bordignon, Claudio, additional, Ciceri, Fabio, additional, and Bonini, Chiara, additional

Published
2010
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28. HIV-1 envelope-dependent restriction of CXCR4-using viruses in child but not adult untransformed CD4+ T-lymphocyte lines.

Author

Mariani, Samanta A., Brigida, Immacolata, Kajaste-Rudnitski, Anna, Ghezzi, Silvia, Rocchi, Alessia, Plebani, Anna, Vicenzi, Elisa, Aiuti, Alessandro, and Poli, Guido

Subjects
*HIV, *T cells, *PHYTOHEMAGGLUTININS, *LEUCOCYTES, *VIRAL replication, *CELL culture, *DNA synthesis
Abstract

Phytohemagglutin-stimulated child and adult leukocytes equally supported CCR5-dependent (R5) and CXCR4-dependent (X4) HIV-1 replication. In contrast, when phytohemagglutin-stimulated leukocytes from either healthy or congenitally immu-nodeficient children were cultured on feeder cells, they well supported R5, but not X4 HIV-1 replication, whereas both viruses equally spread in adult cells maintained in similar conditions. Both child and adult cells showed similar levels of proliferation and surface expression of CD4, CCR5, CXCR4, CD25, CD69, and HLA-DR. Lack of X4 HIV-1 replication in child versus adult ceils was not caused by a differential expression of several known HIV-1 restriction factors. Similar levels of HIV DNA synthesis occurred in child cells infected with R5 and X4 viruses up to 48 hours after infection when R5 HIV-1 showed a significantly superior capacity to spread in culture than X4 virus. Cultured child cells well supported single round vescicular stomatitis vi-rus-G pseudotyped virus replication, whereas superinfection of R5-infected cells with X4 HIV-1 (or vice versa) rescued the replication of this latter virus. Thus, child cells exposed to feeder cell culture represent a novel model system in which the superior capacity of R5 versus X4 viruses to spread can be investigated in primary, untransformed CD4+ cells. [ABSTRACT FROM AUTHOR]

Published
2012
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29. HIV-1 envelope-dependent restriction of CXCR4-using viruses in child but not adult untransformed CD4+T-lymphocyte lines

Author

Mariani, Samanta A., Brigida, Immacolata, Kajaste-Rudnitski, Anna, Ghezzi, Silvia, Rocchi, Alessia, Plebani, Anna, Vicenzi, Elisa, Aiuti, Alessandro, and Poli, Guido

Abstract

Phytohemagglutin-stimulated child and adult leukocytes equally supported CCR5-dependent (R5) and CXCR4-dependent (X4) HIV-1 replication. In contrast, when phytohemagglutin-stimulated leukocytes from either healthy or congenitally immunodeficient children were cultured on feeder cells, they well supported R5, but not X4 HIV-1 replication, whereas both viruses equally spread in adult cells maintained in similar conditions. Both child and adult cells showed similar levels of proliferation and surface expression of CD4, CCR5, CXCR4, CD25, CD69, and HLA-DR. Lack of X4 HIV-1 replication in child versus adult cells was not caused by a differential expression of several known HIV-1 restriction factors. Similar levels of HIV DNA synthesis occurred in child cells infected with R5 and X4 viruses up to 48 hours after infection when R5 HIV-1 showed a significantly superior capacity to spread in culture than X4 virus. Cultured child cells well supported single round vescicular stomatitis virus-G pseudotyped virus replication, whereas superinfection of R5-infected cells with X4 HIV-1 (or vice versa) rescued the replication of this latter virus. Thus, child cells exposed to feeder cell culture represent a novel model system in which the superior capacity of R5 versus X4 viruses to spread can be investigated in primary, untransformed CD4+cells.

Published
2012
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30. Follicular helper T cell signature of replicative exhaustion, apoptosis, and senescence in common variable immunodeficiency

Author

Giulia Milardi, Biagio Di Lorenzo, Jolanda Gerosa, Federica Barzaghi, Gigliola Di Matteo, Maryam Omrani, Tatiana Jofra, Ivan Merelli, Matteo Barcella, Matteo Filippini, Anastasia Conti, Francesca Ferrua, Francesco Pozzo Giuffrida, Francesca Dionisio, Patrizia Rovere‐Querini, Sarah Marktel, Andrea Assanelli, Simona Piemontese, Immacolata Brigida, Matteo Zoccolillo, Emilia Cirillo, Giuliana Giardino, Maria Giovanna Danieli, Fernando Specchia, Lucia Pacillo, Silvia Di Cesare, Carmela Giancotta, Francesca Romano, Alessandro Matarese, Alfredo Antonio Chetta, Matteo Trimarchi, Andrea Laurenzi, Maurizio De Pellegrin, Silvia Darin, Davide Montin, Maddalena Marinoni, Rosa Maria Dellepiane, Valeria Sordi, Vassilios Lougaris, Angelo Vacca, Raffaella Melzi, Rita Nano, Chiara Azzari, Lucia Bongiovanni, Claudio Pignata, Caterina Cancrini, Alessandro Plebani, Lorenzo Piemonti, Constantinos Petrovas, Raffaella Di Micco, Maurilio Ponzoni, Alessandro Aiuti, Maria Pia Cicalese, Georgia Fousteri, Milardi, Giulia, Di Lorenzo, Biagio, Gerosa, Jolanda, Barzaghi, Federica, Di Matteo, Gigliola, Omrani, Maryam, Jofra, Tatiana, Merelli, Ivan, Barcella, Matteo, Filippini, Matteo, Conti, Anastasia, Ferrua, Francesca, Pozzo Giuffrida, Francesco, Dionisio, Francesca, Rovere-Querini, Patrizia, Marktel, Sarah, Assanelli, Andrea, Piemontese, Simona, Brigida, Immacolata, Zoccolillo, Matteo, Cirillo, Emilia, Giardino, Giuliana, Danieli, Maria Giovanna, Specchia, Fernando, Pacillo, Lucia, Di Cesare, Silvia, Giancotta, Carmela, Romano, Francesca, Matarese, Alessandro, Chetta, Alfredo Antonio, Trimarchi, Matteo, Laurenzi, Andrea, De Pellegrin, Maurizio, Darin, Silvia, Montin, Davide, Marinoni, Maddalena, Dellepiane, Rosa Maria, Sordi, Valeria, Lougaris, Vassilio, Vacca, Angelo, Melzi, Raffaella, Nano, Rita, Azzari, Chiara, Bongiovanni, Lucia, Pignata, Claudio, Cancrini, Caterina, Plebani, Alessandro, Piemonti, Lorenzo, Petrovas, Constantino, Di Micco, Raffaella, Ponzoni, Maurilio, Aiuti, Alessandro, Cicalese, Maria Pia, Fousteri, Georgia, and Giuffrida, Francesco Pozzo

Subjects
T cell exhaustion, B cells, B cell, T Follicular Helper Cells, Immunology, Programmed Cell Death 1 Receptor, Apoptosi, Apoptosis, T-Lymphocytes, Helper-Inducer, Common variable immunodeficiency, Common Variable Immunodeficiency, Settore MED/02, T-cell exhaustion, Immune aging, Humans, T follicular helper cells, Immunology and Allergy, T Follicular Helper Cell, immune aging, Human
Abstract

Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency whereby follicular helper T (Tfh) cells fail to establish productive responses with B cells in germinal centers. Here, we analyzed the frequency, phenotype, transcriptome and function of circulating Tfh (cTfh) cells in CVID patients displaying autoimmunity as an additional phenotype. A group of patients showed a high frequency of cTfh1 cells and a prominent expression of PD-1 and ICOS, as well as a cTfh mRNA signature consistent with highly activated, but exhausted, senescent and apoptotic cells. Plasmatic CXCL13 levels were elevated in this group and positively correlated with cTfh1 cell frequency and PD-1 levels. Monoallelic variants in RTEL1, a telomere length- and DNA repair-related gene, were identified in four patients belonging to this group. Their blood lymphocytes showed shortened telomeres, while their cTfh were more prone to apoptosis. These data point toward a novel pathogenetic mechanism in CVID, whereby alterations in DNA repair and telomere elongation might predispose to antibody deficiency. A Th1, highly activated but exhausted and apoptotic cTfh phenotype was associated with this form of CVID. This article is protected by copyright. All rights reserved.

Published
2022
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31. Corrigendum: Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

Author

Cristina Cifaldi, Immacolata Brigida, Federica Barzaghi, Matteo Zoccolillo, Valentina Ferradini, Davide Petricone, Maria Pia Cicalese, Dejan Lazarevic, Davide Cittaro, Maryam Omrani, Enrico Attardi, Francesca Conti, Alessia Scarselli, Maria Chiriaco, Silvia Di Cesare, Francesco Licciardi, Montin Davide, Francesca Ferrua, Clementina Canessa, Claudio Pignata, Silvia Giliani, Simona Ferrari, Georgia Fousteri, Graziano Barera, Pietro Merli, Paolo Palma, Simone Cesaro, Marco Gattorno, Antonio Trizzino, Viviana Moschese, Loredana Chini, Anna Villa, Chiara Azzari, Andrea Finocchi, Franco Locatelli, Paolo Rossi, Federica Sangiuolo, Alessandro Aiuti, Caterina Cancrini, Gigliola Di Matteo, Cifaldi, Cristina, Brigida, Immacolata, Barzaghi, Federica, Zoccolillo, Matteo, Ferradini, Valentina, Petricone, Davide, Cicalese, Maria Pia, Lazarevic, Dejan, Cittaro, Davide, Omrani, Maryam, Attardi, Enrico, Conti, Francesca, Scarselli, Alessia, Chiriaco, Maria, Di Cesare, Silvia, Licciardi, Francesco, Montin, Davide, Ferrua, Francesca, Canessa, Clementina, Pignata, Claudio, Giliani, Silvia, Ferrari, Simona, Fousteri, Georgia, Barera, Graziano, Merli, Pietro, Palma, Paolo, Cesaro, Simone, Gattorno, Marco, Trizzino, Antonio, Moschese, Viviana, Chini, Loredana, Villa, Anna, Azzari, Chiara, Finocchi, Andrea, Locatelli, Franco, Rossi, Paolo, Sangiuolo, Federica, Aiuti, Alessandro, Cancrini, Caterina, and Di Matteo, Gigliola

Subjects
lcsh:Immunologic diseases. Allergy, Primary (chemistry), Immunology, Next Generation Sequencing, Haloplex, Ion semiconductor sequencing, Computational biology, Biology, Ion Torrent, DNA sequencing, gene panel, gene panels, Targeted ngs, Gene panel, Immunology and Allergy, lcsh:RC581-607, Gene Discovery, primary immunodeficiencies
Abstract

[This corrects the article DOI: 10.3389/fimmu.2019.00316.].

Published
2019
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32. Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

Author

Cristina Cifaldi, Immacolata Brigida, Federica Barzaghi, Matteo Zoccolillo, Valentina Ferradini, Davide Petricone, Maria Pia Cicalese, Dejan Lazarevic, Davide Cittaro, Maryam Omrani, Enrico Attardi, Francesca Conti, Alessia Scarselli, Maria Chiriaco, Silvia Di Cesare, Francesco Licciardi, Montin Davide, Francesca Ferrua, Clementina Canessa, Claudio Pignata, Silvia Giliani, Simona Ferrari, Georgia Fousteri, Graziano Barera, Pietro Merli, Paolo Palma, Simone Cesaro, Marco Gattorno, Antonio Trizzino, Viviana Moschese, Loredana Chini, Anna Villa, Chiara Azzari, Andrea Finocchi, Franco Locatelli, Paolo Rossi, Federica Sangiuolo, Alessandro Aiuti, Caterina Cancrini, Gigliola Di Matteo, Cifaldi, Cristina, Brigida, Immacolata, Barzaghi, Federica, Zoccolillo, Matteo, Ferradini, Valentina, Petricone, Davide, Cicalese, MARIA PIA, Lazarevic, Dejan, Cittaro, Davide, Omrani, Maryam, Attardi, Enrico, Conti, Francesca, Scarselli, Alessia, Chiriaco, Maria, Di Cesare, Silvia, Licciardi, Francesco, Davide, Montin, Ferrua, Francesca, Canessa, Clementina, Pignata, Claudio, Giliani, Silvia, Ferrari, Simona, Fousteri, Georgia, Barera, Graziano, Merli, Pietro, Palma, Paolo, Cesaro, Simone, Gattorno, Marco, Trizzino, Antonio, Moschese, Viviana, Chini, Loredana, Villa, Anna, Azzari, Chiara, Finocchi, Andrea, Locatelli, Franco, Rossi, Paolo, Sangiuolo, Federica, Aiuti, Alessandro, Cancrini and Gigliola Di Matteo, Caterina, Cifaldi, C., Brigida, I., Barzaghi, F., Zoccolillo, M., Ferradini, V., Petricone, D., Cicalese, M. P., Lazarevic, D., Cittaro, D., Omrani, M., Attardi, E., Conti, F., Scarselli, A., Chiriaco, M., Di Cesare, S., Licciardi, F., Montin, D., Ferrua, F., Canessa, C., Pignata, C., Giliani, S., Ferrari, S., Fousteri, G., Barera, G., Merli, P., Palma, P., Cesaro, S., Gattorno, M., Trizzino, A., Moschese, V., Chini, L., Villa, A., Azzari, C., Finocchi, A., Locatelli, F., Rossi, P., Sangiuolo, F., Aiuti, A., Cancrini, C., and Di Matteo, G.

Subjects
Haloplex, Ion Torrent, Next Generation Sequencing, gene panels, primary immunodeficiencies, Adolescent, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Genetic Testing, High-Throughput Nucleotide Sequencing, Humans, Infant, Infant, Newborn, Italy, Male, Phenotype, Primary Immunodeficiency Diseases, 0301 basic medicine, Gene panel, Primary immunodeficiencies, Candidate gene, 0302 clinical medicine, Targeted ngs, NGS, primary immunodeficiencies, child, genetic, Medicine, Immunology and Allergy, Technology Report, Exome, primary immunodeficiencies, Next Generation Sequencing, gene panels, Ion Torrent, Haloplex, lcsh:Immunologic diseases. Allergy, Immunology, Computational biology, DNA sequencing, 03 medical and health sciences, Preschool, Gene, Settore MED/38 - Pediatria Generale e Specialistica, business.industry, Correction, Ion semiconductor sequencing, Newborn, 030104 developmental biology, lcsh:RC581-607, business, Gene Discovery, 030215 immunology
Abstract

Background: Primary Immunodeficiencies (PIDs) are a heterogeneous group of genetic immune disorders. While some PIDs can manifest with more than one phenotype, signs, and symptoms of various PIDs overlap considerably. Recently, novel defects in immune-related genes and additional variants in previously reported genes responsible for PIDs have been successfully identified by Next Generation Sequencing (NGS), allowing the recognition of a broad spectrum of disorders. Objective: To evaluate the strength and weakness of targeted NGS sequencing using custom-made Ion Torrent and Haloplex (Agilent) panels for diagnostics and research purposes. Methods: Five different panels including known and candidate genes were used to screen 105 patients with distinct PID features divided in three main PID categories: T cell defects, Humoral defects and Other PIDs. The Ion Torrent sequencing platform was used in 73 patients. Among these, 18 selected patients without a molecular diagnosis and 32 additional patients were analyzed by Haloplex enrichment technology. Results: The complementary use of the two custom-made targeted sequencing approaches allowed the identification of causative variants in 28.6% (n = 30) of patients. Twenty-two out of 73 (34.6%) patients were diagnosed by Ion Torrent. In this group 20 were included in the SCID/CID category. Eight out of 50 (16%) patients were diagnosed by Haloplex workflow. Ion Torrent method was highly successful for those cases with well-defined phenotypes for immunological and clinical presentation. The Haloplex approach was able to diagnose 4 SCID/CID patients and 4 additional patients with complex and extended phenotypes, embracing all three PID categories in which this approach was more efficient. Both technologies showed good gene coverage. Conclusions: NGS technology represents a powerful approach in the complex field of rare disorders but its different application should be weighted. A relatively small NGS target panel can be successfully applied for a robust diagnostic suspicion, while when the spectrum of clinical phenotypes overlaps more than one PID an in-depth NGS analysis is required, including also whole exome/genome sequencing to identify the causative gene.

Published
2019

33. ALPS-Like Phenotype Caused by ADA2 Deficiency Rescued by Allogeneic Hematopoietic Stem Cell Transplantation

Author

Federica Barzaghi, Federica Minniti, Margherita Mauro, Massimiliano De Bortoli, Rita Balter, Elisa Bonetti, Ada Zaccaron, Virginia Vitale, Maryam Omrani, Matteo Zoccolillo, Immacolata Brigida, Maria Pia Cicalese, Massimo Degano, Michael S. Hershfield, Alessandro Aiuti, Anastasiia V. Bondarenko, Matteo Chinello, Simone Cesaro, Barzaghi, Federica, Minniti, Federica, Mauro, Margherita, Bortoli, Massimiliano De, Balter, Rita, Bonetti, Elisa, Zaccaron, Ada, Vitale, Virginia, Omrani, Maryam, Zoccolillo, Matteo, Brigida, Immacolata, Cicalese, Maria Pia, Degano, Massimo, Hershfield, Michael S., Aiuti, Alessandro, Bondarenko, Anastasiia V., Chinello, Matteo, and Cesaro, Simone

Subjects
lcsh:Immunologic diseases. Allergy, 0301 basic medicine, Transplantation Conditioning, Adenosine Deaminase, medicine.medical_treatment, Immunology, ALPS, Apoptosis, Case Report, Hematopoietic stem cell transplantation, Disease, Neutropenia, medicine.disease_cause, ADA2, Autoimmunity, 03 medical and health sciences, 0302 clinical medicine, Granulocyte Colony-Stimulating Factor, ADA2 deficiency, medicine, Humans, Transplantation, Homologous, neutropenia, Immunology and Allergy, fas Receptor, Immunodeficiency, business.industry, Autoimmune Lymphoproliferative Syndrome, autoimmunity, Hematopoietic Stem Cell Transplantation, CECR1, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, HSCT, immunodeficiency, Child, Preschool, Autoimmune lymphoproliferative syndrome, Autoimmune neutropenia, Intercellular Signaling Peptides and Proteins, Female, Bone marrow, lcsh:RC581-607, Unrelated Donors, business, 030215 immunology
Abstract

Adenosine deaminase 2 (ADA2) deficiency is an auto-inflammatory disease due to mutations in cat eye syndrome chromosome region candidate 1 (CECR1) gene, currently named ADA2. The disease has a wide clinical spectrum encompassing early-onset vasculopathy (targeting skin, gut and central nervous system), recurrent fever, immunodeficiency and bone marrow dysfunction. Different therapeutic options have been proposed in literature, but only steroids and anti-cytokine monoclonal antibodies (such as tumor necrosis factor inhibitor) proved to be effective. If a suitable donor is available, hematopoietic stem cell transplantation (HSCT) could be curative. Here we describe a case of ADA2 deficiency in a 4-year-old Caucasian girl. The patient was initially classified as autoimmune neutropenia and then she evolved toward an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype. The diagnosis of ALPS became uncertain due to atypical clinical features and normal FAS-induced apoptosis test. She was treated with G-CSF first and subsequently with immunosuppressive drugs without improvement. Only HSCT from a 9/10 HLA-matched unrelated donor, following myeloablative conditioning, completely solved the clinical signs related to ADA2 deficiency. Early diagnosis in cases presenting with hematological manifestations, rather than classical vasculopathy, allows the patients to promptly undergo HSCT and avoid more severe evolution. Finally, in similar cases highly suspicious for genetic disease, it is desirable to obtain molecular diagnosis before performing HSCT, since it can influence the transplant procedure. However, if HSCT has to be performed without delay for clinical indication, related donors should be excluded to avoid the risk of relapse or partial benefit due to a hereditary genetic defect.

Published
2019

34. Next-Generation Sequencing Reveals A JAGN1 Mutation in a Syndromic Child with Intermittent Neutropenia

Author

Giuseppe Palumbo, Gigliola Di Matteo, Caterina Cancrini, Rita De Vito, Immacolata Brigida, Cristina Cifaldi, Jessica Serafinelli, Paolo Rossi, Alessandro Aiuti, Paolo Palma, Silvia Di Cesare, Andrea Finocchi, Davide Petricone, Maria Chiriaco, Cifaldi, Cristina, Serafinelli, Jessica, Petricone, Davide, Brigida, Immacolata, Di Cesare, Silvia, Di Matteo, Gigliola, Chiriaco, Maria, De Vito, Rita, Palumbo, Giuseppe, Rossi, Paolo, Palma, Paolo, Cancrini, Caterina, Aiuti, Alessandro, and Finocchi, Andrea

Subjects
Male, Neutropenia, medicine.disease_cause, DNA sequencing, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Neutrophil differentiation, medicine, Humans, neutropenia, Congenital Neutropenia, Gene, Mutation, business.industry, Endoplasmic reticulum, Homozygote, High-Throughput Nucleotide Sequencing, Membrane Proteins, Hematology, Golgi apparatus, medicine.disease, Settore MED/38, Oncology, 030220 oncology & carcinogenesis, Child, Preschool, JAGN1, Immunology, Pediatrics, Perinatology and Child Health, symbols, next-generation sequencing, business, 030215 immunology
Abstract

Background Jagunal homolog 1 (JAGN1) gene was identified as a novel responsible for severe congenital neutropenia. The protein encoded by this gene is required for neutrophil differentiation, survival and function in microbial activity. JAGN1-deficient human neutrophils are characterized by alterations in trafficking within the endoplasmic reticulum and golgi compartments because of ultrastructural defects in endoplasmic reticulum and susceptibility to apoptosis. Observations We report a patient exhibiting an intermittent neutropenia, for which a next-generation sequencing revealed a homozygous mutation in the JAGN1 gene. Conclusions The patient extends the clinical variability associated to JAGN1 mutations, and this case highlights the importance of genetic investigations in patients with suspected neutropenia.

Published
2018

35. First Occurrence of Plasmablastic Lymphoma in Adenosine Deaminase-Deficient Severe Combined Immunodeficiency Disease Patient and Review of the Literature

Author

Maddalena Migliavacca, Andrea Assanelli, Maurilio Ponzoni, Roberta Pajno, Federica Barzaghi, Fabio Giglio, Francesca Ferrua, Marta Frittoli, Immacolata Brigida, Francesca Dionisio, Roberto Nicoletti, Miriam Casiraghi, Maria Grazia Roncarolo, Claudio Doglioni, Jacopo Peccatori, Fabio Ciceri, Maria Pia Cicalese, Alessandro Aiuti, Migliavacca, Maddalena, Assanelli, Andrea, Ponzoni, Maurilio, Pajno, Roberta, Barzaghi, Federica, Giglio, Fabio, Ferrua, Francesca, Frittoli, Marta, Brigida, Immacolata, Dionisio, Francesca, Nicoletti, Roberto, Casiraghi, Miriam, Roncarolo, Maria Grazia, Doglioni, Claudio, Peccatori, Jacopo, Ciceri, Fabio, Cicalese, Maria Pia, and Aiuti, Alessandro

Subjects
0301 basic medicine, Oncology, lcsh:Immunologic diseases. Allergy, medicine.medical_specialty, Epstein-Barr Virus Infections, Lymphoma, Adolescent, Adenosine Deaminase, medicine.medical_treatment, Genetic enhancement, Immunology, Lymphoproliferative disorders, Case Report, lymphoma, Hematopoietic stem cell transplantation, plasmablastic lymphoma, primary immunodeficiency, 03 medical and health sciences, Gene therapy, Fatal Outcome, Review of literature, immune system diseases, Agammaglobulinemia, Internal medicine, medicine, adenosine deaminase-deficient severe combined immunodeficiency disease, Immunology and Allergy, Humans, Enzyme Replacement Therapy, gene therapy for rare diseases, Primary immunodeficiency, Adenosine deaminase-deficient severe combined immunodeficiency disease, business.industry, Gene therapy for rare disease, Enzyme replacement therapy, medicine.disease, gene therapy, 030104 developmental biology, review of literature, Female, Severe Combined Immunodeficiency, business, Complication, lcsh:RC581-607, Plasmablastic lymphoma
Abstract

Adenosine deaminase-deficient severe combined immunodeficiency disease (ADA-SCID) is a primary immune deficiency characterized by mutations in the ADA gene resulting in accumulation of toxic compounds affecting multiple districts. Hematopoietic stem cell transplantation (HSCT) from a matched donor and hematopoietic stem cell gene therapy are the preferred options for definitive treatment. Enzyme replacement therapy (ERT) is used to manage the disease in the short term, while a decreased efficacy is reported in the medium-long term. To date, eight cases of lymphomas have been described in ADA-SCID patients. Here we report the first case of plasmablastic lymphoma occurring in a young adult with ADA-SCID on long-term ERT, which turned out to be Epstein-Barr virus associated. The patient previously received infusions of genetically modified T cells. A cumulative analysis of the eight published cases of lymphoma from 1992 to date, and the case here described, reveals a high mortality (89%). The most common form is diffuse large B-cell lymphoma, which predominantly occurs in extra nodal sites. Seven cases occurred in patients on ERT and two after haploidentical HSCT. The significant incidence of immunodeficiency-associated lymphoproliferative disorders and poor survival of patients developing this complication highlight the priority in finding a prompt curative treatment for ADA-SCID.

Published
2017

36. Role of reduced intensity conditioning in T-cell and B-cell immune reconstitution after HLA-identical bone marrow transplantation in ADA-SCID.

Author

Cancrini C, Ferrua F, Scarselli A, Brigida I, Romiti ML, Barera G, Finocchi A, Roncarolo MG, Caniglia M, and Aiuti A

Subjects
Adenosine Deaminase deficiency, Agammaglobulinemia therapy, B-Lymphocytes cytology, Bone Marrow Transplantation immunology, Graft Survival, Humans, Infant, Siblings, T-Lymphocytes cytology, Transplantation, Isogeneic, Bone Marrow Transplantation methods, Severe Combined Immunodeficiency therapy, Transplantation Conditioning methods
Abstract

The treatment of choice for severe combined immunodeficiency is bone marrow transplantation from an HLA-identical donor sibling without conditioning. However, this may result in low donor stem cell chimerism, leading to reduced long-term immune reconstitution. We compared engraftment, metabolic, and T-cell and B-cell immune reconstitution of HLA-identical sibling bone marrow transplantation performed in 2 severe combined immunodeficiency infants with adenosine deaminase deficiency from the same family treated with or without a reduced intensity conditioning regimen (busulfan/fludarabine). Only the patient who received conditioning showed a stable mixed chimerism in all lineages, including bone marrow myeloid and B cells. The use of conditioning resulted in higher thymus-derived naïve T cells and T-cell receptor excision circles, normalization of the T-cell repertoire, and faster and complete B-cell and metabolic reconstitution. These results suggest the utility of exploring the use of reduced intensity conditioning in bone marrow transplantation from HLA-identical donor in severe combined immunodeficiency to improve long-term immune reconstitution.

Published
2010
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