372 results on '"Carsetti, R."'
Search Results
102. A Prospective Study on Children with Initial Diagnosis of Transient Hypogammaglobulinemia of Infancy: Results from the Italian Primary Immunodeficiency Network.
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Moschese, V., Graziani, S., Avanzini, M.A., Carsetti, R., Marconi, M., La Rocca, M., Chini, L., Pignata, C., Soresina, A.R., Consolini, R., Bossi, G., Trizzino, A., Martino, S., Cardinale, F., Bertolini, P., Marseglia, G.L., Zecca, M., Di Cesare, S., Quinti, I., and Rondelli, R. more...
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- 2008
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103. Role of c-myc and CD45 in spontaneous and anti-receptor-induced apoptosis in adult murine B cells.
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Scott, D W, Lamers, M, Köhler, G, Sidman, C L, Maddox, B, and Carsetti, R
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Although adult murine B cells can be stimulated to proliferate by Igm receptor cross-linking, we and others have shown that these cells will undergo apoptosis in vitro in a dose-, time- and temperature-dependent manner with polyclonal but not monoclonal anti-IgM, To test the role of c-myc and cell cycle progression in B cell apoptosis, we examined normal, Sp6 anti-TNP lg and E micro-myc transgenic splenocytes for receptor-mediated apoptosis in vitro. In normal mice, both spontaneous and anti-IgM-induced programmed cell death were specifically blocked by antisense oligodeoxynucleotides for the c-myc proto-oncogene, whereas nonsense myc oligonucleotides and irrelevant oligonucleotides had only a minor effect. Similarly, TNP-dextran-induced apoptosis in Sp6 anti-TNF transgenics was inhibited by antisense c-myc. This effect was not due to the mitogenic effects of unmethylated CpG-containing sequences because ones lacking this motif, as well as methylated oligonucleotides containing this motif, prevented apoptosis, and mitogenic doses of lipopolysaccharide failed to inhibit anti-IgM-driven cell death. Importantly, antisense c-myc also prevented the anti-IgM-induced increase in myc protein species. Moreover, spontaneous apoptosis in vitro was exaggerated in E micro-myc transgenic B cells. To examine the role of CD45 in anti-IgM-induced apoptosis, we treated spleen cells from CD45 knockout mice, which do not proliferate with anti-IgM, and found that B cells from these underwent apoptosis normally despite the lack of entry into S. These data suggest that anti-IgM driven apoptosis does not require CD45. Rather, apoptosis may be due to an overexpression of myc protein in the absence of signals which can drive B cells productively into S, but the failure to proliferate normally is insufficient for apoptosis to occur. more...
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- 1996
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104. A novel mouse thymocyte antigen (F3Ag): down-regulation during the CD4+CD8+ double-positive stage indicates positive selection.
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Barthlott, T, Potocnik, A J, Kohler, H, Carsetti, R, Pircher, H, Fowlkes, B J, and Eichmann, K
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We describe a novel mAb (F3) which reacts with a 65 kDa thymocyte surface protein, expressed on approximately 80% of thymocytes, referred to as F3Ag. In ontogeny, F3Ag expression begins in the CD4(-)CD8(-) double-negative (DN) CD25(+) population and is maintained through approximately 85% of the CD4(+)CD8(+) double-positive (DP) stage. DP cells with high TCR expression and CD4(+) single-positive (SP) cells are predominantly negative for F3Ag, whereas many CD8(+) SP thymocytes express F3Ag. F3Ag-DP thymocytes show a reduced expression of RAG-1 and RAG-2 compared with F3Ag+ DP cells. The shutdown of F3Ag expression during the DP stage is related to positive selection: mice deficient for MHC class I and class II molecules maintain F3Ag expression in almost all DP cells. Transgenic (tg) mice carrying TCR restricted for MHC class II show a more pronounced down-regulation of F3Ag in the DP compartment than normal mice, depending on the presence of a positively selecting MHC. The size of the F3Ag- DP subset is positively correlated with the efficacy of positive selection into the CD4(+) SP compartment. Because some CD8(+) SP cells express F3Ag, the relationship between F3Ag down-regulation and positive selection is less obvious in DP cells of mice carrying MHC class I-restricted tg TCR. However, in reaggregate thymic organ cultures, sorted F3Ag- DP cells differentiate into CD8(+) SP cells more rapidly than do F3Ag+ DP cells. Thus, after down-regulation in the DP stage, a proportion of CD8(+) SP cells appears to re-express F3Ag. In addition, the proportion of F3Ag-CD8(+) SP cells depends on the efficacy of positive selection into the CD8 lineage. Taken together, the regulation of the expression of the F3Ag appears to be associated with signals that control thymic repertoire selection. more...
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- 1996
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105. Splenic hypofunction and the spectrum of autoimmune and malignant complications in celiac disease
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Di Sabatino, A., Rosado, M.M., Cazzola, P., Morera, R., Riboni, R., Biagi, F., Carsetti, R., and Corazza, G.R.
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- 2006
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106. Immunological characterization of children with transient hypogammaglobulinemia of infancy (THI): In vitro immunoglobulin production is a candidate predictive marker
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Moschese, V., Graziani, S., Avanzini, Ma, Carsetti, R., Quinti, I., Plebani, A., Soresino, A., Di Cesare, S., Chini, L., Marconi, M., PAOLO ROSSI, and Ugazio, Ag
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Settore MED/38 - Pediatria Generale e Specialistica
107. A Primitive Extra-Follicular Pathway of IgM Memory B-Cell Development in Severe Combined Immune Deficiency
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Aranburu, A., Mortari, E. Piano, Capolunghi, F., Giorda, E., Marcellini, V., Cascioli, S., Monzo, F. R., Danielli, E., Capponi, C., Ceccarelli, S., Putignani, L., Federica Del Chierico, Nicolosi, L., Lanfranchi, A., Porta, F., Cancrini, C., Scarselli, A., Di Matteo, G., Finocchi, A., Rossi, P., Bertaina, A., Locatelli, F., and Carsetti, R. more...
108. Evaluation of humoral and cellular response to four vaccines against COVID-19 in different age groups: A longitudinal study
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Giorgio Fedele, Filippo Trentini, Ilaria Schiavoni, Sergio Abrignani, Guido Antonelli, Vincenzo Baldo, Tatjana Baldovin, Alessandra Bandera, Filippa Bonura, Pierangelo Clerici, Massimo De Paschale, Francesca Fortunato, Andrea Gori, Renata Grifantini, Giancarlo Icardi, Tiziana Lazzarotto, Vittorio Lodi, Claudio Maria Mastroianni, Andrea Orsi, Rosa Prato, Vincenzo Restivo, Rita Carsetti, Eva Piano Mortari, Pasqualina Leone, Eleonora Olivetta, Stefano Fiore, Angela Di Martino, Silvio Brusaferro, Stefano Merler, Anna Teresa Palamara, Paola Stefanelli, Fedele G, Trentini F, Schiavoni I, Abrignani S, Antonelli G, Baldo V, Baldovin T, Bandera A, Bonura F, Clerici P, De Paschale M, Fortunato F, Gori A, Grifantini R, Icardi G, Lazzarotto T, Lodi V, Mastroianni CM, Orsi A, Prato R, Restivo V, Carsetti R, Piano Mortari E, Leone P, Olivetta E, Fiore S, Di Martino A, Brusaferro S, Merler S, Palamara AT, Stefanelli P., Fedele, Giorgio, Trentini, Filippo, Schiavoni, Ilaria, Abrignani, Sergio, Antonelli, Guido, Baldo, Vincenzo, Baldovin, Tatjana, Bandera, Alessandra, Bonura, Filippa, Clerici, Pierangelo, De Paschale, Massimo, Fortunato, Francesca, Gori, Andrea, Grifantini, Renata, Icardi, Giancarlo, Lazzarotto, Tiziana, Lodi, Vittorio, Mastroianni, Claudio Maria, Orsi, Andrea, Prato, Rosa, Restivo, Vincenzo, Carsetti, Rita, Piano Mortari, Eva, Leone, Pasqualina, Olivetta, Eleonora, Fiore, Stefano, Di Martino, Angela, Brusaferro, Silvio, Merler, Stefano, Palamara, Anna Teresa, and Stefanelli, Paola more...
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COVID-19 Vaccines ,Ad26COVS1 ,vaccines ,SARS-CoV-2 ,Immunology ,COVID-19 ,serology ,Viral Vaccines ,Humans ,B-cell memory ,cell-mediated immunity ,Immunology and Allergy ,B-CELL MEMORY, COVID-19, CELL-MEDIATED IMMUNITY, SEROLOGY, VACCINES ,Longitudinal Studies ,Aged - Abstract
To date there has been limited head-to-head evaluation of immune responses to different types of COVID-19 vaccines. A real-world population-based longitudinal study was designed with the aim to define the magnitude and duration of immunity induced by each of four different COVID-19 vaccines available in Italy at the time of this study. Overall, 2497 individuals were enrolled at time of their first vaccination (T0). Vaccine-specific antibody responses induced over time by Comirnaty, Spikevax, Vaxzevria, Janssen Ad26.COV2.S and heterologous vaccination were compared up to six months after immunization. On a subset of Comirnaty vaccinees, serology data were correlated with the ability to neutralize a reference SARS-CoV-2 B strain, as well as Delta AY.4 and Omicron BA.1. The frequency of SARS-CoV-2-specific CD4+ T cells, CD8+ T cells, and memory B cells induced by the four different vaccines was assessed six months after the immunization. We found that mRNA vaccines are stronger inducer of anti-Spike IgG and B-memory cell responses. Humoral immune responses are lower in frail elderly subjects. Neutralization of the Delta AY.4 and Omicron BA.1 variants is severely impaired, especially in older individuals. Most vaccinees display a vaccine-specific T-cell memory six months after the vaccination. By describing the immunological response during the first phase of COVID-19 vaccination campaign in different cohorts and considering several aspects of the immunological response, this study allowed to collect key information that could facilitate the implementation of effective prevention and control measures against SARS-CoV-2. more...
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- 2022
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109. The immune system of children: the key to understanding SARS-CoV-2 susceptibility?
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Alimuddin Zumla, Isabella Quinti, Giuseppe Ippolito, Eva Piano Mortari, Concetta Quintarelli, Franco Locatelli, Rita Carsetti, Carsetti, R., Quintarelli, C., Quinti, I., Piano Mortari, E., Zumla, A., Ippolito, G., and Locatelli, F. more...
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Cellular immunity ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pneumonia, Viral ,Article ,Child health ,Immune system ,Disease severity ,Developmental and Educational Psychology ,Humans ,Medicine ,Pediatrics, Perinatology, and Child Health ,Child ,Pandemics ,B-Lymphocytes ,Innate immune system ,biology ,business.industry ,SARS-CoV-2 ,COVID-19 ,Severe acute respiratory syndrome-related coronavirus ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Immune System ,Pediatrics, Perinatology and Child Health ,Immunology ,biology.protein ,Disease Susceptibility ,Antibody ,Coronavirus Infections ,business ,Immunologic Memory ,Immunologic memory ,CD27 Ligand - Published
- 2020
110. A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function
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Immacolata Brigida, Lamberto Torralba-Raga, Radovan Dvorsky, Silvia Di Cesare, Andrea Finocchi, AnnaCarin Horne, Ivan K. Chinn, Serena Scala, Simone Martinelli, Antonia Pascarella, Asbjørg Stray-Pedersen, Erika Zara, Marco Tartaglia, Emily M. Mace, Franco Locatelli, Luca Pannone, Stefano Levi Mortera, Claudia Bracaglia, Giusi Prencipe, Mohammad Akbarzadeh, Paolo Palma, Petra Janning, Anna Pastore, Rita Carsetti, Mohammad Reza Ahmadian, Fabrizio De Benedetti, Michael R. Diehl, Petra Netter, Shalini N. Jhangiani, Richard A. Gibbs, Caterina Cancrini, Tram N. Cao, James R. Lupski, Alexandre F. Carisey, Vittorio Rosti, Pietro Merli, Alessandro Aiuti, Zeynep H. Coban-Akdemir, Donna M. Muzny, Yenan T. Bryceson, Francesca Pantaleoni, Martina Di Rocco, Serena Camerini, Marcello Niceta, Virginia Messia, Cristina Cifaldi, Marcel Buchholzer, Andrea Ciolfi, Michael T. Lam, Hans Christian Erichsen, Antonella Insalaco, Kim Ramme, Oliver H.F. Krumbach, Francesca Conti, Luca Basso-Ricci, Simona Coppola, Jordan S. Orange, Maria Chiriaco, Lorenza Putignani, Luciapia Farina, Lam, M. T., Coppola, S., Krumbach, O. H. F., Prencipe, G., Insalaco, A., Cifaldi, C., Brigida, I., Zara, E., Scala, S., Di Cesare, S., Martinelli, S., Di Rocco, M., Pascarella, A., Niceta, M., Pantaleoni, F., Ciolfi, A., Netter, P., Carisey, A. F., Diehl, M., Akbarzadeh, M., Conti, F., Merli, P., Pastore, A., Levi Mortera, S., Camerini, S., Farina, L., Buchholzer, M., Pannone, L., Cao, T. N., Coban-Akdemir, Z. H., Jhangiani, S. N., Muzny, D. M., Gibbs, R. A., Basso-Ricci, L., Chiriaco, M., Dvorsky, R., Putignani, L., Carsetti, R., Janning, P., Stray-Pedersen, A., Erichsen, H. C., Horne, A., Bryceson, Y. T., Torralba-Raga, L., Ramme, K., Rosti, V., Bracaglia, C., Messia, V., Palma, P., Finocchi, A., Locatelli, F., Chinn, I. K., Lupski, J. R., Mace, E. M., Cancrini, C., Aiuti, A., Ahmadian, M. R., Orange, J. S., De Benedetti, F., and Tartaglia, M. more...
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Male ,Models, Molecular ,0301 basic medicine ,Molecular Conformation ,medicine.disease_cause ,Mice ,0302 clinical medicine ,Immunology and Allergy ,Child ,cdc42 GTP-Binding Protein ,Research Articles ,Mutation ,Rash ,Phenotype ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Cdc42 GTP-Binding Protein ,030220 oncology & carcinogenesis ,Female ,Disease Susceptibility ,biological phenomena, cell phenomena, and immunity ,medicine.symptom ,Protein Binding ,HLH ,Genotype ,Immunology ,Inflammation ,macromolecular substances ,Lymphohistiocytosis, Hemophagocytic ,Article ,03 medical and health sciences ,Immune system ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Alleles ,Genetic Association Studies ,Cytopenia ,Hemophagocytic lymphohistiocytosis ,Binding Sites ,business.industry ,Infant ,Immune dysregulation ,CDC42 ,dyshematopoiesis ,inflammation ,RHO-GTPase ,medicine.disease ,030104 developmental biology ,Amino Acid Substitution ,business - Abstract
Lam et al. characterize a novel hematological/autoinflammatory disorder due to a de novo recurrent missense mutation of CDC42. The authors use in silico, in vitro, and in vivo analyses to correlate the molecular mechanisms altering CDC42 function to the observed phenotype., Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo CDC42 mutation (Chr1:22417990C>T, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation. CDC42 mutations had been associated with syndromic neurodevelopmental disorders. In vitro and in vivo assays documented unique effects of p.R186C on CDC42 localization and function, correlating with the distinctiveness of the trait. Emapalumab was critical to the survival of one patient, who underwent successful bone marrow transplantation. Early recognition of the disorder and establishment of treatment followed by bone marrow transplant are important to survival., Graphical Abstract more...
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- 2019
111. Inhibition of B-cell proliferation and antibody production by mesenchymal stromal cells is mediated by T cells
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Francesco Emma, Antonella Conforti, Maria Manuela Rosado, Francesca Rossi, Isabella Guzzo, Simona Cascioli, Marina Vivarelli, Marco Scarsella, Maria Ester Bernardo, Rita Carsetti, Franco Locatelli, Simone Biagini, Luca Dello Strologo, Ezio Giorda, Rosado, Mm1, Bernardo, Me, Scarsella, M, Conforti, A, Giorda, E, Biagini, S, Cascioli, S, Rossi, Francesca, Guzzo, I, Vivarelli, M, Dello Strologo, L, Emma, F, Locatelli, F, Carsetti, R., Rosado, M. M., Bernardo, M. E., Scarsella, M., Conforti, A., Giorda, E., Biagini, S., Cascioli, S., Rossi, F., Guzzo, I., Vivarelli, M., Dello Strologo, L., Emma, F., and Locatelli, F. more...
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Adult ,CD4-Positive T-Lymphocytes ,Graft Rejection ,Male ,Adolescent ,Cell Communication ,Biology ,CD8-Positive T-Lymphocytes ,in-vitro ,Cell therapy ,stem-cells ,Original Research Reports ,systemic-lupus-erythematosus ,interferon-gamma ,therapy ,differentiation ,activation ,disease ,immune ,msc ,medicine ,Humans ,Lupus Erythematosus, Systemic ,Child ,Cell Proliferation ,B-Lymphocytes ,Lupus erythematosus ,Cell growth ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Hematology ,medicine.disease ,Kidney Transplantation ,In vitro ,Coculture Techniques ,medicine.anatomical_structure ,CpG site ,Child, Preschool ,Immunology ,Antibody Formation ,Cancer research ,Female ,Bone marrow ,CD8 ,Developmental Biology - Abstract
Bone marrow (BM)-derived mesenchymal stromal cells (MSCs), endowed with immunosuppressive and anti-inflammatory properties, represent a promising tool in immunoregulatory and regenerative cell therapy. Clarifying the interactions between MSCs and B-lymphocytes may be crucial for designing innovative MSC-based strategies in conditions in which B cells play a role, including systemic lupus erythematosus (SLE) and rejection of kidney transplantation. In this study, we show that, both in healthy subjects and in patients, in vitro B-cell proliferation, plasma-cell differentiation, and antibody production are inhibited by BM-derived MSCs when peripheral blood lymphocytes are stimulated with CpG, but not when sorted B cells are cultured with MSCs+CpG. Inhibition is restored in CpG+MSC cocultures when sorted T cells are added to sorted B cells, suggesting that this effect is mediated by T cells, with both CD4(+) and CD8(+) cells playing a role. Moreover, cell-cell contact between MSCs and T cells, but not between MSCs and B cells, is necessary to inhibit B-cell proliferation. Thus, the presence of functional T cells, as well as cell-cell contact between MSCs and T cells, are crucial for B-cell inhibition. This information can be relevant for implementing MSC-based therapeutic immune modulation in patients in whom T-cell function is impaired. more...
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- 2015
112. Longitudinal Evaluation of Immune Reconstitution and B-cell Function After Hematopoietic Cell Transplantation for Primary Immunodeficiency
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Paolo Palma, Barbarella Lucarelli, Maria Luisa Romiti, Giuseppe Palumbo, Rita Carsetti, Caterina Cancrini, Maurizio Caniglia, Alessia Scarselli, Silvia Di Cesare, Andrea Finocchi, Simona Cascioli, Gigliola Di Matteo, Rita Maria Pinto, Ippolita Rana, Paolo Rossi, Alessandro Aiuti, Claudia Capponi, Alessandra Simonetti, Scarselli, A., Di Cesare, S., Capponi, C., Cascioli, S, Romiti, M. L., Di Matteo, G., Simonetti, A., Palma, P., Finocchi, A., Lucarelli, B., Pinto, R. M., Rana, I., Palumbo, G., Caniglia, M., Rossi, P., Carsetti, R., Cancrini, C., and Aiuti, Alessandro more...
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Male ,Adolescent ,medicine.medical_treatment ,T-Lymphocytes ,Immunology ,B-Lymphocyte Subsets ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Lymphocyte Activation ,Immunoglobulin D ,CD19 ,Immunophenotyping ,Immune system ,In vivo ,medicine ,Immunology and Allergy ,Humans ,Transplantation, Homologous ,Lymphocyte Count ,Child ,B cell ,Settore MED/38 - Pediatria Generale e Specialistica ,B-Lymphocytes ,Transplantation Chimera ,biology ,business.industry ,Graft Survival ,Hematopoietic Stem Cell Transplantation ,Immunity ,Immunologic Deficiency Syndromes ,Infant ,medicine.disease ,Transplantation ,Immunoglobulin Isotypes ,medicine.anatomical_structure ,Treatment Outcome ,Child, Preschool ,Antibody Formation ,Primary immunodeficiency . hematopoietic stem cell transplantation . immune reconstitution . B-Lymphocytes . conditioning . follow up studies . child ,biology.protein ,Primary immunodeficiency ,Female ,business ,Follow-Up Studies - Abstract
Hematopoietic cell transplantation (HCT) provides a curative therapy for severe forms of primary immunodeficiencies (PID). While the timing and extent of T-cell reconstitution following transplant for PID has been studied in depth, less is known about the kinetics of B-cell development and long-term restoration of humoral functions, which been often reported to be suboptimal after HCT. We studied longitudinally B-cell development and function in a cohort of 13 PID patients transplanted between 1997 and 2010, with a follow-up ranging from 0.7 to 15 years. Flow cytometric analysis of naive and antigen-experienced B-cell subsets and in vitro functional responses to CpG were compared with data from healthy children and correlated with the degree of B-cell chimerism and in vivo antibody production. We found that total memory B-cells count remained below normal levels for the first 2 years of follow up and progressively normalized. Switched memory B-cells (CD19+CD27+IgD-IgM-) were restored early and better than IgM memory B-cells (CD19+CD27+IgD+IgM+), which remained significantly reduced long-term. The recovery of memory B-cells correlated with good in vivo humoral function and normalization of CpG-response. A complete B-cell reconstitution was usually associated with donor B-cells chimerism and pre-transplant conditioning. Donor source and the underlying genetic defect represented also important variables. Monitoring of phenotypic and functional changes on B-cells following HCT may prove clinically relevant to tailor patients’ care. In particular the analysis of IgM memory and switched memory B-cells in addition to in vitro B-cells stimulation are recommended before Ig replacement therapy (IgRT) discontinuation. more...
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- 2014
113. Plasma cells in the mucosa of patients with inflammatory bowel disease produce granzyme B and possess cytotoxic activities
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Alfredo Colantoni, Massimiliano Sarra, Ivan Monteleone, Pierpaolo Sileri, Giuseppe S. Sica, Angela Ortenzi, Rita Carsetti, Giovanni Monteleone, Maria Laura Cupi, Eleonora Franzè, Francesco Pallone, Maria Manuela Rosado, Thomas T. MacDonald, Irene Marafini, Cupi, M, Sarra, M, Marafini, I, Monteleone, Ivan, Franzè, E, Ortenzi, Angela, Colantoni, Alfredo, Sica, Giuseppe, Sileri, Pierpaolo, Rosado, M, Carsetti, R, Macdonald, T, Pallone, Francesco, and Monteleone, Giovanni more...
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Enzymologic ,Male ,medicine.medical_treatment ,Immunology ,Antigens, CD19 ,Plasma Cells ,Biology ,CD38 ,Gene Expression Regulation, Enzymologic ,Granzymes ,Interleukin 21 ,Intestinal mucosa ,Antigen ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,Antigens ,Intestinal Mucosa ,CD20 ,Settore MED/12 - Gastroenterologia ,CD19 ,hemic and immune systems ,Female ,Immunoglobulin A ,Inflammatory Bowel Diseases ,digestive system diseases ,Granzyme B ,Settore MED/18 - Chirurgia Generale ,Cytokine ,Gene Expression Regulation ,Cancer research ,biology.protein ,hormones, hormone substitutes, and hormone antagonists - Abstract
In both Crohn’s disease (CD) and ulcerative colitis (UC), the gut is massively infiltrated with B cells and plasma cells, but the role of these cell types in the pathogenesis of gut tissue damage remains largely unknown. Human B cells express granzyme B (GrB) when cultured with IL-21, a cytokine overproduced in CD and UC mucosa. We therefore examined whether mucosal B cells express GrB and have cytotoxic activity in inflammatory bowel disease (IBD). GrB-expressing CD19+ and IgA+ cells were seen in the normal intestinal mucosa, but they were significantly more frequent in both CD and UC. In contrast, only a minority of CD19+ and IgA+ cells expressed perforin with no difference between IBD and controls. GrB-producing CD19+ cells expressed CD27 and were CD38high and CD20 negative. CD19+ B cells from IBD patients induced HCT-116 cell death. IL-21 enhanced GrB expression in control CD19+ B cells and increased their cytotoxic activity. These data indicate that IBD-related inflammation is marked by mucosal accumulation of cytotoxic, GrB-expressing CD19+ and IgA+ cells, suggesting a role for these cells in IBD-associated epithelial damage. more...
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- 2014
114. HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders
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Maria Ester Bernardo, Daniela Pende, Alessandro Moretta, Francesca Moretta, Alice Bertaina, Manuela Testi, Riccardo Masetti, Franco Locatelli, Letizia Pomponia Brescia, Andrea Finocchi, Daria Pagliara, Pietro Merli, Michela Falco, Rupert Handgretinger, Sergio Rutella, Lorenzo Moretta, Rita Carsetti, Caterina Cancrini, Barbarella Lucarelli, Giuseppina Li Pira, Nabil Kabbara, Bertaina A, Merli P, Rutella S, Pagliara D, Bernardo ME, Masetti R, Pende D, Falco M, Handgretinger R, Moretta F, Lucarelli B, Brescia LP, Li Pira G, Testi M, Cancrini C, Kabbara N, Carsetti R, Finocchi A, Moretta A, Moretta L, Locatelli F, Bertaina, Alice, Merli, Pietro, Rutella, Sergio, Pagliara, Daria, Bernardo, MARIA ESTER, Masetti, Riccardo, Pende, Daniela, Falco, Michela, Handgretinger, Rupert, Moretta, Francesca, Lucarelli, Barbarella, Brescia, Letizia P., Pira, Giuseppina Li, Testi, Manuela, Cancrini, Caterina, Kabbara, Nabil, Carsetti, Rita, Finocchi, Andrea, Moretta, Alessandro, Moretta, Lorenzo, and Locatelli, Franco more...
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Male ,Receptors, Antigen, T-Cell, alpha-beta ,T-Lymphocytes ,medicine.medical_treatment ,CD34 ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Biochemistry ,Inside BLOOD Commentary ,Receptors ,Humans ,Retrospective Studies ,Child ,B-Lymphocytes ,Child, Preschool ,Infant ,Antigens, CD ,Lymphocyte Depletion ,Allografts ,Hematopoietic Stem Cell Transplantation ,Follow-Up Studies ,Female ,alpha-beta ,biology ,Hematology ,CD ,GRAFT VERSUS HOST DISEASE ,surgical procedures, operative ,medicine.anatomical_structure ,N/A ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Antigen ,Stem cell ,T cell ,Immunology ,Human leukocyte antigen ,CD19 ,medicine ,Antigens ,Preschool ,business.industry ,Cell Biology ,T-Cell ,MARROW TRANSPLANTATION, APLASTIC-ANEMIA, INNATE IMMUNITY, FANCONI-ANEMIA, GRAFT, DONORS, BLOOD, LYMPHOCYTES, THALASSEMIA ,Transplantation ,biology.protein ,business - Abstract
Twenty-three children with nonmalignant disorders received HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) after ex vivo elimination of αβ(+) T cells and CD19(+) B cells. The median number of CD34(+), αβ(+)CD3(+), and B cells infused was 16.8 × 10(6), 40 × 10(3), and 40 × 10(3) cells/kg, respectively. No patient received any posttransplantation pharmacologic prophylaxis for graft-versus-host disease (GVHD). All but 4 patients engrafted, these latter being rescued by a second allograft. Three patients experienced skin-only grade 1 to 2 acute GVHD. No patient developed visceral acute or chronic GVHD. Cumulative incidence of transplantation-related mortality was 9.3%. With a median follow-up of 18 months, 21 of 23 children are alive and disease-free, the 2-year probability of disease-free survival being 91.1%. Recovery of γδ(+) T cells was prompt, but αβ(+) T cells progressively ensued over time. Our data suggest that this novel graft manipulation strategy is safe and effective for haplo-HSCT. This trial was registered at www.clinicaltrials.gov as #NCT01810120. more...
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- 2014
115. Preserved antibody levels and loss of memory B cells against pneumococcus and tetanus after splenectomy: Tailoring better vaccination strategies
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Rosado, M Manuela, Gesualdo, Francesco, Marcellini, Valentina, Di Sabatino, Antonio, Corazza, Gino Roberto, Smacchia, Maria Paola, Nobili, Bruno, Baronci, Carlo, Russo, Lidia, Rossi, Francesca, Vito, Rita De, Nicolosi, Luciana, Inserra, Alessandro, Locatelli, Franco, Tozzi, Alberto E, Carsetti, Rita, Rosado, Mm, Gesualdo, F, Marcellini, V, Di Sabatino, A, Corazza, Gr, Smacchia, Mp, Nobili, Bruno, Baronci, C, Russo, L, Rossi, Francesca, Vito, Rd, Nicolosi, L, Inserra, A, Locatelli, F, Tozzi, Ae, and Carsetti, R. more...
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Adult ,Male ,Adolescent ,B-Lymphocyte Subsets ,asplenia ,serum anti-pnps ,Pneumococcal Infections ,splenectomy ,Pneumococcal Vaccines ,Young Adult ,Humans ,Child ,Aged ,Aged, 80 and over ,streptococcus pneumoniae ,Antigens, Bacterial ,Tetanus ,Polysaccharides, Bacterial ,Vaccination ,Infant ,Middle Aged ,Antibodies, Bacterial ,memory b cells ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Child, Preschool ,Immunoglobulin G ,Settore MED/20 ,Female ,Immunologic Memory ,Spleen - Abstract
Splenectomized patients are exposed to an increased risk of septicemia caused by encapsulated bacteria. Defense against infection is ensured by preformed serum antibodies produced by long-lived plasma cells and by memory B cells that secrete immunoglobulin in response to specific antigenic stimuli. Studying a group of asplenic individuals (57 adults and 21 children) without additional immunologic defects, we found that spleen removal does not alter serum anti-pneumococcal polysaccharide (PnPS) IgG concentration, but reduces the number of PnPS-specific memory B cells, of both IgM and IgG isotypes. The number of specific memory B cells was low in splenectomized adults and children that had received the PnPS vaccine either before or after splenectomy. Seven children were given the 13-valent pneumococcal conjugated vaccine after splenectomy. In this group, the number of PnPS-specific IgG memory B cells was similar to that of eusplenic children, suggesting that pneumococcal conjugated vaccine administered after splenectomy is able to restore the pool of anti-PnPS IgG memory B cells. Our data further elucidate the crucial role of the spleen in the immunological response to infections caused by encapsulated bacteria and suggest that glycoconjugated vaccines may be the most suitable choice to generate IgG-mediated protection in these patients. more...
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- 2013
116. Early-life gut microbiota under physiological and pathological conditions : the central role of combined meta-omics-based approaches
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Gian Luigi Marseglia, Maria Elisabetta Guerzoni, Andrea Urbani, Lorenza Putignani, Federica Del Chierico, Rita Carsetti, Paola Roncada, Bruno Dallapiccola, Pamela Vernocchi, Luigi Bonizzi, Guglielmo Salvatori, Fabrizio Signore, Maurizio Muraca, Melania Manco, Anna Maria Castellazzi, Willem M. de Vos, Del Chierico F(1), P.VERNOCCHI, Bonizzi L, Carsetti R, Castellazzi AM, Dallapiccola B, de Vos W, Guerzoni ME, Manco M, Marseglia GL, Muraca M, Roncada P, Salvatori G, Signore F, Urbani A, and Putignani L. more...
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Proteomics ,intestinal microbiota ,Aging ,newborns ,Proteome ,Systems biology ,Biophysics ,Computational biology ,Biology ,Gut flora ,Animals ,Intestines ,Humans ,Intestinal Diseases ,Biochemistry ,digestive system ,Microbiology ,03 medical and health sciences ,Microbiologie ,metabonomics ,Intestinal Mucosa ,Pathological ,030304 developmental biology ,VLAG ,0303 health sciences ,fecal microbiota ,inflammatory-bowel-disease ,030306 microbiology ,business.industry ,Settore BIO/12 ,pathogenesis ,systems biology ,Omics ,biology.organism_classification ,Early life ,communities ,Gut microbiota, Early-life gut onset and development, Meta-omics gut charts, Personalized medicine ,host ,Immunology ,identification ,Identification (biology) ,Personalized medicine ,business - Abstract
The establishment of gut microbiota immediately after birth is modulated by different mechanisms that can be considered specific determinants of temporal and spatial variability. Over the last few years, molecular methods have been offering a complementary support to the classical microbiology, often underpowered by its inability to provide unbiased representation of gut microbiota. The advent of high-throughput-omics-based methods has opened new avenues in the knowledge of the gut ecosystem by shedding light on its shape and modulation. Such methods may unveil taxa distribution, role and density of microbial habitants, hence highlighting individual phenotyping (physiological traits) and their relationship with gut dysbiosis, inflammation processes, metabolic disorders (pathological conditions). Synergic meta-omics or "systems biology"-based approaches may concur in providing advanced information on microbiota establishment and pathogen control. During early-life stages this massive amount of data may provide gut microbiota descriptive and functional charts which can be exploited to perform a good practice in childcare and pediatrics, thus providing nutraceutical benefits and endorsing healthy development and aging. This article is part of a Special Issue entitled: Translational Proteomics. more...
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- 2012
117. 17-beta-estradiol elicits genomic and non-genomic responses in mouse male germ cells
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Elena, Vicini, Maria, Loiarro, Silvia, Di Agostino, Serena, Corallini, Federica, Capolunghi, Rita, Carsetti, Paolo, Chieffi, Raffaele, Geremia, Mario, Stefanini, Claudio, Sette, Vicini, E., Loiarro, M., DI AGOSTINO, S., Corallini, S., Capolunghi, F., Carsetti, R., Chieffi, Paolo, Geremia, R., Stefanini, M., and Sette, C. more...
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Transcriptional Activation ,Male ,Settore BIO/16 ,Cultured ,Estradiol ,MAP Kinase Signaling System ,Cells ,Estrogen Receptor alpha ,Apoptosis ,Animals ,Enzyme Activation ,Humans ,Mice ,Extracellular Signal-Regulated MAP Kinases ,Spermatocytes ,Germ Cells ,Cells, Cultured ,Genes, Reporter ,Cell Line ,Estrogen Receptor beta ,Genes ,Reporter - Abstract
Estrogens have been postulated to exert a detrimental effect on spermatogenesis in vivo. Since mouse male germ cells express estrogen receptors, we have investigated whether molecular pathways are activated by estrogen stimulation of these cells. Our results demonstrate that estrogen receptor beta is expressed in mitotic and meiotic male germ cells as well as in the spermatogonia derived GC-1 cell line. By using this cell line, we show that 17-beta-estradiol triggers activation of a transcriptional response that requires a functional estrogen receptor. Moreover, GC-1 cells respond to estrogens by transiently activating a signal transduction pathway that impinges on the mitogen-activated protein kinases (MAPK) ERK1 and -2. A similar dose-dependent transient activation of ERKs was also observed in primary mouse spermatocytes in culture. Activation by the estrogen was specific because other steroids such as progesterone and dihydrotestosterone were ineffective and because it could be blocked by the selective inhibitor of the ERK pathway and by competitive inhibitors of the estrogen receptor. Finally, we observed that 17-beta-estradiol does not affect spontaneous or induced apoptosis in cultured mouse spermatocytes, indicating that the apoptotic effects observed in vivo require additional testicular components. more...
- Published
- 2006
118. A prospective study on children with initial diagnosis of transient hypogammaglobulinemia of infancy: Results from the Italian Primary Immunodeficiency Network
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Fabio Cardinale, M. Marconi, A Soresina, Marco Zecca, Viviana Moschese, Plinio Rossi, P Bertolini, M.A. Avanzini, Rita Carsetti, Isabella Quinti, Rita Consolini, S Di Cesare, Simona Graziani, Maria Cristina Pietrogrande, A Trizzino, Claudio Pignata, Gian Luigi Marseglia, Alessandro Plebani, M La Rocca, Roberto Rondelli, Loredana Chini, Grazia Bossi, Silvana Martino, Moschese, V., Graziani, S., Avanzini, M. A., Carsetti, R., Marconi, M., LA ROCCA, M., Chini, L., Pignata, Claudio, Soresina, A. R., Consolini, R., Bossi, G., Trizzino, A., Martino, S., Cardinale, F., Bertolini, P., Marseglia, G. L., Zecca, M., DI CESARE, S., Quinti, I., Rondelli, R., Pietrogrande, M. C., Rossi, P., and Plebani, A. more...
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Male ,Aging ,Pediatrics ,medicine.medical_specialty ,Allergy ,Immunology ,Immunoglobulins ,primary immunodeficiency ,transient hypogammaglobulinemia of infancy ,Memory B cell subsets ,in vitro immunoglobulin production ,Hypogammaglobulinemia ,Agammaglobulinemia ,medicine ,Humans ,Immunology and Allergy ,Prospective Studies ,Transient hypogammaglobulinemia of infancy ,Prospective cohort study ,Memory B cell ,Pharmacology ,Autoimmune disease ,Settore MED/38 - Pediatria Generale e Specialistica ,B-Lymphocytes ,biology ,business.industry ,Immunologic Deficiency Syndromes ,Infant ,medicine.disease ,Immunoglobulin A ,Treatment Outcome ,Immunoglobulin M ,Italy ,Child, Preschool ,Immunoglobulin G ,Disease Progression ,Primary immunodeficiency ,biology.protein ,Female ,memory b cell subsets ,Antibody ,business ,Immunologic Memory - Abstract
Transient hypogammaglobulinemia of infancy (THI) is a heterogeneous disorder characterized by reduced serum IgG levels in early infancy. A putative diagnosis is initially made after exclusion of other causes of hypogammaglobulinemia while a definitive diagnosis of THI can only be made a posteriori in patients with normalization of IgG levels. The aim of this study is to characterize clinical and immunological features of children with an initial diagnosis of THI in correlation to natural outcome, and to assess predictive laboratory parameters of clinical evolution for this disorder. We prospectively analysed clinical and immunological characteristics of 77 THI children at initial diagnosis and of 57 patients at follow-up. Memory B cell subsets and in vitro immunoglobulin production were evaluated. Seventy patients (91 percent) showed clinical symptoms. Patients suffered from infections (91 percent), allergies (47 percent) and autoimmune disease (4 percent). During follow-up 41/57 children (72 percent) normalized IgG values, mostly within 24 months of age (p less than 0.001), allowing the diagnosis of THI. The 16 children who did not normalize their IgG levels showed a higher frequency of severe infections and autoimmune disease (p less than 0.01). Moreover, they expressed a reduced frequency of IgM and switched memory B cells (p less than 0.01) and an inability to produce IgG in vitro (p less than 0.02). We conclude that most patients with an initial diagnosis of THI spontaneously recover within 24 months of age and have a benign clinical course, while a subgroup of children with undefined hypogammaglobulinemia share a clinical and immunological profile with other primary immunodeficiencies. Early recognition of children with hypogammaglobulinemia during infancy who are likely to suffer from permanent immunodeficiencies later in life would allow prompt and appropriate laboratory and clinical interventions. more...
119. Pediatric brain tumor patients display altered immune activation and reduced lymphopoiesis at the onset of disease.
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Rosichini M, Del Baldo G, De Luca CD, Benini F, Genah S, Vinci M, Cerimele A, Coccetti M, Flamini S, Carsetti R, Cacchione A, Carai A, Mastronuzzi A, Locatelli F, and Velardi E
- Abstract
Optimal immune function is crucial in preventing cancer development and growth and for the success of anti-cancer therapies. Here, we characterized the peripheral immunological status of 83 steroids-naïve pediatric patients with central nervous system neoplasia at the disease onset. Tumors were classified into low-grade gliomas (LGG), high-grade gliomas (HGG), medulloblastoma, and other tumors. We revealed that glioma patients showed an altered lymphocyte pool. T-cells of HGG patients shifted from naïve to effector memory phenotype. LGG patients exhibited T-cell central memory expansion and higher T-cell activation. Interestingly, HGG patients displayed reduced thymic function. Furthermore, LGG and HGG patients showed reduced activated B-cells and suboptimal B-cell formation. Our data demonstrate that glioma patients have reduced lymphopoiesis at the disease onset, which could contribute to the systemic lymphopenia characterizing these patients. This study offers novel insights into the immunological status of brain tumor patients which may help in designing more effective treatments., Competing Interests: Competing interests: The authors have no conflict of interest related to this work. Prof. Locatelli reports personal fees from Amgen, personal fees from Novartis, other from Bellicum Pharmaceutical, other from Neovii, personal fees from Miltenyi, personal fees from Medac, personal fees from Jazz Pharmaceutical, personal fees from Takeda, outside the submitted work., (© 2024. The Author(s).) more...
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- 2024
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120. Antibodies in breast milk: Pro-bodies designed for healthy newborn development.
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Verhasselt V, Tellier J, Carsetti R, and Tepekule B
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This manuscript sheds light on the impact of maternal breast milk antibodies on infant health. Milk antibodies prepare and protect the newborn against environmental exposure, guide and regulate the offspring's immune system, and promote transgenerational adaptation of the immune system to its environment. While the transfer of IgG across the placenta ceases at birth, milk antibodies are continuously replenished by the maternal immune system. They reflect the mother's real-time adaptation to the environment to which the infant is exposed. They cover the infant's upper respiratory and digestive mucosa and are perfectly positioned to control responses to environmental antigens and might also reach their circulation. Maternal antibodies in breast milk play a key role in the immune defense of the developing child, with a major impact on infectious disease susceptibility in both HIC and LMIC. They also influence the development of another major health burden in children-allergies. Finally, emerging evidence shows that milk antibodies also actively shape immune development. Much of this is likely to be mediated by their effect on the seeding, composition and function of the microbiota, but not only. Further understanding of the bridge that maternal antibodies provide between the child and its environment should enable the best interventions to promote healthy development., (© 2024 The Author(s). Immunological Reviews published by John Wiley & Sons Ltd.) more...
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- 2024
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121. B Cells Isolated from Individuals Who Do Not Respond to the HBV Vaccine Are Characterized by Higher DNA Methylation-Estimated Aging Compared to Responders.
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Kwiatkowska KM, Anticoli S, Salvioli S, Calzari L, Gentilini D, Albano C, Di Prinzio RR, Zaffina S, Carsetti R, Ruggieri A, and Garagnani P
- Abstract
Healthcare workers (HCWs) are a high-risk group for hepatitis B virus (HBV) infection. Notably, about 5-10% of the general population does not respond to the HBV vaccination. In this study, we aimed to investigate DNA methylation (DNAm) in order to estimate the biological age of B cells from HCW of both sexes, either responder (R) or non-responder (NR), to HBV vaccination. We used genome-wide DNA methylation data to calculate a set of biomarkers in B cells collected from 41 Rs and 30 NRs between 22 and 62 years old. Unresponsiveness to HBV vaccination was associated with accelerated epigenetic aging (DNAmAge, AltumAge, DunedinPoAm) and was accompanied by epigenetic drift. Female non-responders had higher estimates of telomere length and lower CRP inflammation risk score when compared to responders. Overall, epigenetic differences between responders and non-responders were more evident in females than males. In this study we demonstrated that several methylation DNAm-based clocks and biomarkers are associated with an increased risk of non-response to HBV vaccination, particularly in females. Based on these results, we propose that accelerated epigenetic age could contribute to vaccine unresponsiveness. These insights may help improve the evaluation of the effectiveness of vaccination strategies, especially among HCWs and vulnerable patients. more...
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- 2024
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122. TLR2/4 are novel activating receptors for SARS-CoV-2 spike protein on NK cells.
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Landolina N, Ricci B, Veneziani I, Alicata C, Mariotti FR, Pelosi A, Quatrini L, Mortari EP, Carsetti R, Vacca P, Tumino N, Azzarone B, Moretta L, and Maggi E
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- Humans, Angiotensin-Converting Enzyme 2 genetics, Angiotensin-Converting Enzyme 2 immunology, Cytokines immunology, Lymphocyte Activation immunology, COVID-19 immunology, COVID-19 virology, Killer Cells, Natural immunology, SARS-CoV-2 immunology, Spike Glycoprotein, Coronavirus immunology, Toll-Like Receptor 2 immunology, Toll-Like Receptor 4 immunology
- Abstract
Background: In early infected or severe coronavirus disease 2019 (COVID-19) patients, circulating NK cells are consistently reduced, despite being highly activated or exhausted. The aim of this paper was to establish whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (SP) may directly trigger NK cells and through which receptor(s)., Methods: SP-stimulated human NK cells have been evaluated for the expression of activation markers, cytokine release, and cytotoxic activity, as well as for gene expression profiles and NF-kB phosphorylation, and they have been silenced with specific small interfering RNAs., Results: SPs from the Wuhan strain and other variants of concern (VOCs) directly bind and stimulate purified NK cells by increasing activation marker expression, cytokine release, and cytolytic activity, prevalently in the CD56
bright NK cell subset. VOC-SPs differ in their ability to activate NK cells, G614, and Delta-Plus strains providing the strongest activity in the majority of donors. While VOC-SPs do not trigger ACE2, which is not expressed on NK cells, or other activating receptors, they directly and variably bind to both Toll-like receptor 2 (TLR2) and TLR4. Moreover, SP-driven NK cell functions are inhibited upon masking such receptors or silencing the relative genes. Lastly, VOC-SPs upregulate CD56dim NK cell functions in COVID-19 recovered, but not in non-infected, individuals., Conclusions: TLR2 and TLR4 are novel activating receptors for SP in NK cells, suggesting a new role of these cells in orchestrating the pathophysiology of SARS-CoV-2 infection. The pathogenic relevance of this finding is highlighted by the fact that free SP providing NK cell activation is frequently detected in a SARS-CoV-2 inflamed environment and in plasma of infected and long-COVID-19 subjects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Landolina, Ricci, Veneziani, Alicata, Mariotti, Pelosi, Quatrini, Mortari, Carsetti, Vacca, Tumino, Azzarone, Moretta and Maggi.) more...- Published
- 2024
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123. Editorial: IgA and mucosal immunity in vaccinology and in protection from infection.
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Carsetti R and Quinti I
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- Humans, Vaccinology methods, Vaccines immunology, Animals, Vaccination, Immunity, Mucosal, Immunoglobulin A immunology
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Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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- 2024
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124. SARS-CoV-2-specific mucosal immune response in vaccinated versus infected children.
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Conti MG, Piano Mortari E, Nenna R, Pierangeli A, Sorrentino L, Frasca F, Petrarca L, Mancino E, Di Mattia G, Matera L, Fracella M, Albano C, Scagnolari C, Capponi M, Cinicola B, Carsetti R, and Midulla F more...
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- Adult, Child, Humans, SARS-CoV-2, Immunoglobulin A, Mucous Membrane, Vaccination, Antibodies, Viral, Immunity, Mucosal, COVID-19
- Abstract
The anti-COVID-19 intramuscular vaccination induces a strong systemic but a weak mucosal immune response in adults. Little is known about the mucosal immune response in children infected or vaccinated against SARS-CoV-2. We found that 28% of children had detectable salivary IgA against SARS-CoV-2 even before vaccination, suggesting that, in children, SARS-CoV-2 infection may be undiagnosed. After vaccination, only receptor-binding domain (RBD)-specific IgA1 significantly increased in the saliva. Conversely, infected children had significantly higher salivary RBD-IgA2 compared to IgA1, indicating that infection more than vaccination induces a specific mucosal immune response in children. Future efforts should focus on development of vaccine technologies that also activate mucosal immunity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Conti, Piano Mortari, Nenna, Pierangeli, Sorrentino, Frasca, Petrarca, Mancino, Di Mattia, Matera, Fracella, Albano, Scagnolari, Capponi, Cinicola, Carsetti and Midulla.) more...
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- 2024
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125. Hyperactivation and altered selection of B cells in patients with paediatric Sjogren's syndrome.
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Boni A, Nicolai R, Caiello I, Marinaro F, Farina L, Pires Marafon D, Carsetti R, De Benedetti F, Bracaglia C, and Marasco E
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- Adult, Humans, Child, B-Lymphocytes, T-Lymphocyte Subsets, Sjogren's Syndrome, Autoimmune Diseases
- Abstract
Objectives: Paediatric Sjögren's syndrome (pSS) is a rare chronic autoimmune disorder, characterised by inflammation of exocrine glands. B cell hyperactivation plays a central role in adult-onset Sjogren. This study was designed to analyse B cell and T cell phenotype, levels of BAFF, and selection of autoreactive B cells in patients with pSS., Methods: A total of 17 patients diagnosed with pSS and 13 healthy donors (controls) comparable for age were enrolled in the study. B cell and T cell subsets and frequency of autoreactive B cells in peripheral blood were analysed by flow cytometry. Levels of BAFF were analysed by ELISA., Results: The relative frequency of total B cells, transitional, naïve and switched memory B cells was similar between pSS patients and controls. In patients with pSS, we observed a reduction in the frequency of unswitched memory B cells, an increased frequency of atypical memory B cells and an expansion of PD1
hi CXCR5- T peripheral helper cells. Levels of BAFF were higher in patients with pSS compared with controls and correlated with serum levels of total IgG and titres of anti-Ro antibodies. The frequency of autoreactive B cells in the transitional, unswitched memory and plasmablast compartment was significantly higher in pSS patients than in controls., Conclusions: Our results point to a hyperactivation of B cells in pSS. Current therapies do not seem to affect B cell abnormalities, suggesting that novel therapies targeting specifically B cell hyperactivation need to be implemented for paediatric patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) more...- Published
- 2024
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126. Non-apoptotic FAS signaling controls mTOR activation and extrafollicular maturation in human B cells.
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Staniek J, Kalina T, Andrieux G, Boerries M, Janowska I, Fuentes M, Díez P, Bakardjieva M, Stancikova J, Raabe J, Neumann J, Schwenk S, Arpesella L, Stuchly J, Benes V, García Valiente R, Fernández García J, Carsetti R, Piano Mortari E, Catala A, de la Calle O, Sogkas G, Neven B, Rieux-Laucat F, Magerus A, Neth O, Olbrich P, Voll RE, Alsina L, Allende LM, Gonzalez-Granado LI, Böhler C, Thiel J, Venhoff N, Lorenzetti R, Warnatz K, Unger S, Seidl M, Mielenz D, Schneider P, Ehl S, Rensing-Ehl A, Smulski CR, and Rizzi M more...
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- Humans, Apoptosis genetics, Germinal Center, TOR Serine-Threonine Kinases, Hypergammaglobulinemia, Lymphoproliferative Disorders genetics
- Abstract
Defective FAS (CD95/Apo-1/TNFRSF6) signaling causes autoimmune lymphoproliferative syndrome (ALPS). Hypergammaglobulinemia is a common feature in ALPS with FAS mutations (ALPS-FAS), but paradoxically, fewer conventional memory cells differentiate from FAS-expressing germinal center (GC) B cells. Resistance to FAS-induced apoptosis does not explain this phenotype. We tested the hypothesis that defective non-apoptotic FAS signaling may contribute to impaired B cell differentiation in ALPS. We analyzed secondary lymphoid organs of patients with ALPS-FAS and found low numbers of memory B cells, fewer GC B cells, and an expanded extrafollicular (EF) B cell response. Enhanced mTOR activity has been shown to favor EF versus GC fate decision, and we found enhanced PI3K/mTOR and BCR signaling in ALPS-FAS splenic B cells. Modeling initial T-dependent B cell activation with CD40L in vitro, we showed that FAS competent cells with transient FAS ligation showed specifically decreased mTOR axis activation without apoptosis. Mechanistically, transient FAS engagement with involvement of caspase-8 induced nuclear exclusion of PTEN, leading to mTOR inhibition. In addition, FASL-dependent PTEN nuclear exclusion and mTOR modulation were defective in patients with ALPS-FAS. In the early phase of activation, FAS stimulation promoted expression of genes related to GC initiation at the expense of processes related to the EF response. Hence, our data suggest that non-apoptotic FAS signaling acts as molecular switch between EF versus GC fate decisions via regulation of the mTOR axis and transcription. The defect of this modulatory circuit may explain the observed hypergammaglobulinemia and low memory B cell numbers in ALPS. more...
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- 2024
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127. Immunological characterization of an Italian PANDAS cohort.
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Leonardi L, Lorenzetti G, Carsetti R, Piano Mortari E, Guido CA, Zicari AM, Förster-Waldl E, Loffredo L, Duse M, and Spalice A
- Abstract
This cross-sectional study aimed to contribute to the definition of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) pathophysiology. An extensive immunological assessment has been conducted to investigate both immune defects, potentially leading to recurrent Group A β-hemolytic Streptococcus (GABHS) infections, and immune dysregulation responsible for a systemic inflammatory state. Twenty-six PANDAS patients with relapsing-remitting course of disease and 11 controls with recurrent pharyngotonsillitis were enrolled. Each subject underwent a detailed phenotypic and immunological assessment including cytokine profile. A possible correlation of immunological parameters with clinical-anamnestic data was analyzed. No inborn errors of immunity were detected in either group, using first level immunological assessments. However, a trend toward higher TNF-alpha and IL-17 levels, and lower C3 levels, was detected in the PANDAS patients compared to the control group. Maternal autoimmune diseases were described in 53.3% of PANDAS patients and neuropsychiatric symptoms other than OCD and tics were detected in 76.9% patients. ASO titer did not differ significantly between the two groups. A possible correlation between enduring inflammation (elevated serum TNF-α and IL-17) and the persistence of neuropsychiatric symptoms in PANDAS patients beyond infectious episodes needs to be addressed. Further studies with larger cohorts would be pivotal to better define the role of TNF-α and IL-17 in PANDAS pathophysiology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Leonardi, Lorenzetti, Carsetti, Piano Mortari, Guido, Zicari, Förster-Waldl, Loffredo, Duse and Spalice.) more...
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- 2024
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128. SARS-CoV-2 pre-exposure prophylaxis with tixagevimab/cilgavimab (AZD7442) provides protection in inborn errors of immunity with antibody defects: a real-world experience.
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Pulvirenti F, Garzi G, Milito C, Sculco E, Sciannamea M, Napoli A, Cinti L, Roberto P, Punziano A, Carrabba M, Piano Mortari E, Carsetti R, Antonelli G, and Quinti I
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- Humans, SARS-CoV-2, Prospective Studies, Antibodies, Monoclonal, Antibodies, Viral, Immunoglobulin G, Pre-Exposure Prophylaxis, COVID-19
- Abstract
Background: Preventive strategies against severe COVID-19 in Inborn Errors of Immunity (IEI) include bivalent vaccines, treatment with SARS-CoV-2 monoclonal antibodies (mAbs), early antiviral therapies, and pre-exposure prophylaxis (PrEP)., Objective: To assess the effectiveness of the PrEP with tixagevimab/cilgavimab (AZD7442) in IEI with primary antibody defects during the COVID-19 Omicron wave., Methods: A six-month prospective study evaluated the SARS-CoV-2 infection rate and the COVID-19 severity in the AZD7442 group, in the no-AZD7442 group, and in a group of patients with a recent SARS-CoV-2 infection (< three months). Spike-specific IgG levels were measured at regular intervals., Results: Six out of thirty-three patients (18%) and 54/170 patients (32%) became infected in the AZD7442 group and in the no-AZD7442 group, respectively. Within 90 days post-administration, the AZD7442 group was 85% less likely to be infected and 82% less likely to have a symptomatic disease than the no-AZD7442 group. This effect was lost thereafter. In the entire cohort, no mortality/hospitalisation was observed. The control group of 35 recently infected patients was 88% and 92% less likely to be infected than the AZD7442 and no-AZD7442 groups. Serum anti-Spike IgG reached the highest peak seven days post-AZD7442 PrEP then decreased, remaining over 1000 BAU/mL 180 days thereafter., Conclusion: In patients with IEI and antibody defects, AZD7442 prophylaxis had a transient protective effect, possibly lost possibly because of the appearance of new variants. However, PrEP with newer mAbs might still represent a feasible preventive strategy in the future in this population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pulvirenti, Garzi, Milito, Sculco, Sciannamea, Napoli, Cinti, Roberto, Punziano, Carrabba, Piano Mortari, Carsetti, Antonelli and Quinti.) more...
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- 2023
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129. Lower magnitude and faster waning of antibody responses to SARS-CoV-2 vaccination in anti-TNF-α-treated IBD patients are linked to lack of activation and expansion of cTfh1 cells and impaired B memory cell formation.
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Garner-Spitzer E, Wagner A, Gudipati V, Schoetta AM, Orola-Taus M, Kundi M, Kunert R, Mayrhofer P, Huppa JB, Stockinger H, Carsetti R, Gattinger P, Valenta R, Kratzer B, Sehgal ANA, Pickl WF, Reinisch W, Novacek G, and Wiedermann U more...
- Abstract
Background: Patients with inflammatory bowel disease (IBD) and healthy controls received primary SARS-CoV-2-mRNA vaccination and a booster after six months. Anti-TNF-α-treated patients showed significantly lower antibody (Ab) levels and faster waning than α4β7-integrin-antagonist recipients and controls. This prospective cohort study aimed to elucidate the underlying mechanisms on the basis of circulating T-follicular helper cells (cTfh) and B memory cells., Methods: We measured SARS-CoV-2- Wuhan and Omicron specific Abs, B- and T-cell subsets at baseline and kinetics of Spike (S)-specific B memory cells along with distributions of activated cTfh subsets before and after primary and booster vaccination., Findings: Lower and faster waning of Ab levels in anti-TNF-α treated IBD patients was associated with low numbers of total and naïve B cells vs. expanded plasmablasts prior to vaccination. Along with their low Ab levels against Wuhan and Omicron VOCs, reduced S-specific B memory cells were identified after the 2nd dose which declined to non-detectable after 6 months. In contrast, IBD patients with α4β7-integrin-antagonists and controls mounted and retained high Ab levels after the 2nd dose, which was associated with a pronounced increase in S-specific B memory cells that were maintained or expanded up to 6 months. Booster vaccination led to a strong increase of Abs with neutralizing capacity and S-specific B memory cells in these groups, which was not the case in anti-TNF-α treated IBD patients. Of note, Ab levels and S-specific B memory cells in particular post-booster correlated with the activation of cTfh1 cells after primary vaccination., Interpretations: The reduced magnitude, persistence and neutralization capacity of SARS-CoV-2 specific Abs after vaccination in anti-TNF-α-treated IBD patients were associated with impaired formation and maintenance of S-specific B memory cells, likely due to absent cTfh1 activation leading to extra-follicular immune responses and diminished B memory cell diversification. These observations have implications for patient-tailored vaccination schedules/vaccines in anti-TNF-α-treated patients, irrespective of their underlying disease., Funding: The study was funded by third party funding of the Institute of Specific Prophylaxis and Tropical Medicine at the Medical University Vienna. The funders had no role in study design, data collection, data analyses, interpretation, or writing of report., Competing Interests: Declaration of interests EGS: none; AW: received fees from AbbVie and Astra Zeneca; VG: none; AS: none; MOT: none; MK: received an investigator initiated research contract from Pfizer outside the present work; RK: none; PM: none; JBH: Boehringer Ingelheim; HS: none; GN has received fees from AbbVie, MSD, Takeda, Janssen, Sandoz, Pfizer, Astro Pharma, Falk Pharma, Ferring Galapagos, Bristol-Myers Squibb, and Vifor; PG: none; RV: has received research grants from Worg Pharmaceuticals, Hangzhou, China, HVD Biotech, Vienna, Austria and Viravaxx, Vienna, Austria. He serves as consultant for Viravaxx and Worg; BK: none; ANAS: none; WFP: has received fees from Novartis, Astra Zeneca, Medical Dialogue, BMS; WR has served as speaker for AbbVie, Celltrion, Falk Pharma GmbH, Ferring, Janssen, Galapagos Medice, MSD, Roche, Pfizer, Pharmacosmos, Shire, Takeda, Therakos, as consultant for AbbVie, Amgen, AOP Orphan, Arena Pharmaceuticals, Astellas, Astra Zeneca, Bioclinica, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celgene, Celltrion, Eli Lilly, Falk Pharma GmbH, Ferring, Galapagos, Gatehouse Bio Inc., Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Landos Biopharma, Medahead, MedImmune, Microbiotica, Mitsubishi Tanabe Pharma Corporation, MSD, Novartis, OMass, Otsuka, Parexel, Periconsulting, Pharmacosmos, Pfizer, Protagonist, Provention, Quell Therapeutics, Sandoz, Seres Therapeutics, Setpointmedical, Sigmoid, Sublimity, Takeda, Teva Pharma, Therakos, Theravance, Zealand, as advisory board member for AbbVie, Amgen, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Galapagos, Janssen, Mitsubishi Tanabe Pharma Corporation, MSD, Pharmacosmos, Pfizer, Sandoz, Takeda, and has received research funding from AbbVie, Janssen, MSD, Sandoz, Sanofi, Takeda; RC: none; UW is PI of clinical studies sponsored by GSK, Novartis and Pfizer. No conflict of interest regarding the presented clinical study., (Copyright © 2023. Published by Elsevier B.V.) more...
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- 2023
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130. Age and memory B cells at baseline are associated with risk of relapse and memory B-cell reappearance following anti-CD20 treatment in pediatric frequently-relapsing/steroid-dependent nephrotic syndrome.
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Colucci M, Angeletti A, Zotta F, Carsetti R, Lugani F, Ravà L, Ravani P, Emma F, Ghiggeri GM, and Vivarelli M
- Subjects
- Child, Humans, Young Adult, Antibodies, Monoclonal therapeutic use, Immunosuppressive Agents, Memory B Cells, Recurrence, Rituximab therapeutic use, Steroids therapeutic use, Treatment Outcome, Antineoplastic Agents therapeutic use, Nephrotic Syndrome drug therapy
- Abstract
B-cell depleting anti-CD20 monoclonal antibodies, such as rituximab, have proven efficacy in children with frequently-relapsing/steroid-dependent nephrotic syndrome (FR/SDNS). However, drug-free remission is variable and specific baseline markers predictive of relapse after anti-CD20 treatment are still being defined. To clarify these, we performed a bicentric observational study in a large cohort of 102 children and young adults with FR/SDNS treated with anti-CD20 monoclonal antibodies (rituximab and ofatumumab). Sixty-two patients (60.8%) relapsed during a 24-month period (median [interquartile range] relapse-free survival, 14.4 months [7.9-24.0]). A lower risk of relapse was significantly associated with an older age (over 9.8 years, hazard ratio, 0.44; 95% confidence interval, 0.26-0.74) and a higher risk of relapse was significantly associated with higher circulating levels of memory B cells (1.14; 1.09-1.32) at time of anti-CD20 infusion, independent of time elapsed from onset, previous anti-CD20 treatment, type of administered anti-CD20 monoclonal antibodies, and previous or maintenance oral immunosuppression. Patients younger than 9.8 years at anti-CD20 infusion had a subsequent higher recovery of total, transitional, mature-naïve and memory B-cell subsets independent of previous anti-CD20 treatment and maintenance immunosuppression. Significantly, younger age and higher circulating levels of memory B cells at time of anti-CD20 infusion were also independently associated with the recovery of memory B cells by linear mixed-effects modelling. Thus, both younger age and higher circulating levels of memory B cells at time of infusion are independently associated with a higher risk of relapse and an earlier recovery of memory B cells following anti-CD20 treatment in children with FR/SDNS., (Copyright © 2023 International Society of Nephrology. All rights reserved.) more...
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- 2023
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131. Persistently active interferon-γ pathway and expansion of T-bet + B cells in a subset of patients with childhood-onset systemic lupus erythematosus.
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Moneta GM, Bracaglia C, Caiello I, Farroni C, Pires Marafon D, Carlomagno R, Hiraki L, Vivarelli M, Gianviti A, Carbogno S, Ferlin W, de Min C, Silverman E, Carsetti R, De Benedetti F, and Marasco E
- Subjects
- Humans, Interferon-gamma metabolism, Transcription Factors, Lupus Nephritis, Lupus Erythematosus, Systemic, Interferon Type I
- Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease causing significant morbidity and mortality, despite important improvements in its management in the last decades. The objective of this work is to investigate the role of IFN-γ in the pathogenesis of childhood-onset systemic lupus erythematosus (cSLE), evaluating the crosstalk between IFN-α and IFN-γ and the expression of T-bet, a transcription factor induced by IFN-γ, in B cells of patients with cSLE. Expression levels of both IFN-α and IFN-γ-induced genes were upregulated in patients with cSLE. We found increased serum levels of CXCL9 and CXCL10 in patients with cSLE. Type I IFN score decreased with initiation of immunosuppressive treatment; conversely, type II IFN score and levels of CXCL9 were not significantly affected by immunosuppressive treatment. Type II IFN score and CXCL9 were significantly higher in patients with lupus nephritis. We observed the expansion of a population of naïve B cells expressing T-bet in a cluster of patients with cSLE. IFN-γ, but not IFN-α, induced the expression of T-bet in B cells. Our data suggest that IFN-γ is hyperactive in cSLE, especially in patients with lupus nephritis, and it is not modulated by therapy. Our data reinforce the potential of IFN-γ as a therapeutic target in SLE., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.) more...
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- 2023
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132. GRAd-COV2 vaccine provides potent and durable humoral and cellular immunity to SARS-CoV-2 in randomized placebo-controlled phase 2 trial.
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Capone S, Fusco FM, Milleri S, Borrè S, Carbonara S, Lo Caputo S, Leone S, Gori G, Maggi P, Cascio A, Lichtner M, Cauda R, Dal Zoppo S, Cossu MV, Gori A, Roda S, Confalonieri P, Bonora S, Missale G, Codeluppi M, Mezzaroma I, Capici S, Pontali E, Libanore M, Diani A, Lanini S, Battella S, Contino AM, Piano Mortari E, Genova F, Parente G, Dragonetti R, Colloca S, Visani L, Iannacone C, Carsetti R, Folgori A, and Camerini R more...
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- Humans, SARS-CoV-2, COVID-19 Vaccines, Immunity, Cellular, COVID-19 prevention & control, Vaccines
- Abstract
The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and heterologous immunization approaches implemented worldwide for booster doses call for diversified vaccine portfolios. GRAd-COV2 is a gorilla adenovirus-based COVID-19 vaccine candidate encoding prefusion-stabilized spike. The safety and immunogenicity of GRAd-COV2 is evaluated in a dose- and regimen-finding phase 2 trial (COVITAR study, ClinicalTrials.gov: NCT04791423) whereby 917 eligible participants are randomized to receive a single intramuscular GRAd-COV2 administration followed by placebo, or two vaccine injections, or two doses of placebo, spaced over 3 weeks. Here, we report that GRAd-COV2 is well tolerated and induces robust immune responses after a single immunization; a second administration increases binding and neutralizing antibody titers. Potent, variant of concern (VOC) cross-reactive spike-specific T cell response peaks after the first dose and is characterized by high frequencies of CD8s. T cells maintain immediate effector functions and high proliferative potential over time. Thus, GRAd vector is a valuable platform for genetic vaccine development, especially when robust CD8 response is needed., Competing Interests: Declaration of interests S. Capone, R. Camerini, R.D., F.G., S. Battella, A.M.C., G.P., S. Colloca, and A.F. are full employees of ReiThera Srl. S. Colloca and A.F. are founders and shareholders of Keires AG. S. Colloca is named inventor of the patent application no. 20183515.4 titled “GORILLA ADENOVIRUS NUCLEIC ACID- AND AMINO ACID-SEQUENCES, VECTORS CONTAINING SAME, AND USES THEREOF.” L.V. is full employee of Exom, the CRO in charge of the COVITAR study management. S.L.C. received honoraria from Gilead, ViiV, GSK, Janssen, and MSD, has participated on the advisory boards of Gilead, ViiV, GSK, Janssen, and MSD, and has received support for attending meetings from Gilead. M. Lichtner received honoraria and support for attending meetings from Gilead, MSD, and ViiV, participated on the advisory boards of ViiV, Abbvie, and MSD, and received grants through the institution from Gilead and Abbvie. R. Carsetti was a member of the COVITAR study steering committee. C.I. received financial support from Exom for statistical analysis of the COVITAR study., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.) more...
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- 2023
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133. Inflammatory and senescence-associated mediators affect the persistence of humoral response to COVID-19 mRNA vaccination in transfusion-dependent beta-thalassemic patients.
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Bordoni V, Casale M, Pinto VM, Carsetti R, Gianesin B, Gamberini MR, Mazdai L, Barella S, Denotti AR, Colavita F, Perrotta S, Maggio A, Pitrolo L, Quintino S, Caminati M, Mazzi F, Ceolan J, De Franceschi L, Forni GL, Locatelli F, and Agrati C more...
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- Humans, Blood Transfusion, RNA, Messenger, Vaccination, Antibodies, Viral, Immunity, Humoral, COVID-19 prevention & control, beta-Thalassemia genetics, beta-Thalassemia therapy
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- 2023
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134. Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestations.
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Friman V, Quinti I, Davydov AN, Shugay M, Farroni C, Engström E, Pour Akaber S, Barresi S, Mohamed A, Pulvirenti F, Milito C, Granata G, Giorda E, Ahlström S, Karlsson J, Marasco E, Marcellini V, Bocci C, Cascioli S, Scarsella M, Phad G, Tilevik A, Tartaglia M, Bemark M, Chudakov DM, Carsetti R, and Grimsholm O more...
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- Humans, B-Lymphocytes, Germinal Center, Precursor Cells, B-Lymphoid, Autoimmunity, Common Variable Immunodeficiency genetics
- Abstract
Common variable immune deficiency (CVID) is a heterogeneous disorder characterized by recurrent infections, low levels of serum immunoglobulins, and impaired vaccine responses. Autoimmune manifestations are common, but B cell central and peripheral selection mechanisms in CVID are incompletely understood. Here, we find that receptor editing, a measure of central tolerance, is increased in transitional B cells from CVID patients and that these cells have a higher immunoglobulin κ:λ ratio in CVID patients with autoimmune manifestations than in those with infection only. Contrariwise, the selection pressure in the germinal center on CD27
bright memory B cells is decreased in CVID patients with autoimmune manifestations. Finally, functionally, T cell-dependent activation showed that naive B cells in CVID patients are badly equipped for activation and induction of mismatch repair genes. We conclude that central tolerance is functional whereas peripheral selection is defective in CVID patients with autoimmune manifestations, which could underpin the development of autoimmunity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.) more...- Published
- 2023
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135. Natural killer cells and innate lymphoid cells 1 tune anxiety-like behavior and memory in mice via interferon-γ and acetylcholine.
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Garofalo S, Cocozza G, Mormino A, Bernardini G, Russo E, Ielpo D, Andolina D, Ventura R, Martinello K, Renzi M, Fucile S, Laffranchi M, Mortari EP, Carsetti R, Sciumè G, Sozzani S, Santoni A, Tremblay ME, Ransohoff RM, and Limatola C more...
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- Animals, Mice, Lymphocytes, Immunity, Innate, Killer Cells, Natural, Anxiety, Interferon-gamma, Acetylcholine
- Abstract
The mechanisms of communication between the brain and the immune cells are still largely unclear. Here, we characterize the populations of resident natural killer (NK) cells and innate lymphoid cells (ILC) 1 in the meningeal dura layer of adult mice. We describe that ILC1/NK cell-derived interferon-γ and acetylcholine can contribute to the modulation of brain homeostatic functions, shaping synaptic neuronal transmission and neurotransmitter levels with effects on mice behavior. In detail, the interferon-γ plays a role in the formation of non-spatial memory, tuning the frequency of GABAergic neurotransmission on cortical pyramidal neurons, while the acetylcholine is a mediator involved in the modulation of brain circuitries that regulate anxiety-like behavior. These findings disclose mechanisms of immune-to-brain communication that modulate brain functions under physiological conditions., (© 2023. The Author(s).) more...
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- 2023
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136. Functional CVIDs phenotype clusters identified by the integration of immune parameters after BNT162b2 boosters.
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Piano Mortari E, Pulvirenti F, Marcellini V, Terreri S, Salinas AF, Ferrari S, Di Napoli G, Guadagnolo D, Sculco E, Albano C, Guercio M, Di Cecca S, Milito C, Garzi G, Pesce AM, Bonanni L, Sinibaldi M, Bordoni V, Di Cecilia S, Accordini S, Castilletti C, Agrati C, Quintarelli C, Zaffina S, Locatelli F, Carsetti R, and Quinti I more...
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- Humans, BNT162 Vaccine, Longitudinal Studies, SARS-CoV-2, Antibodies, Neutralizing, Phenotype, COVID-19, Common Variable Immunodeficiency
- Abstract
Introduction: Assessing the response to vaccinations is one of the diagnostic criteria for Common Variable Immune Deficiencies (CVIDs). Vaccination against SARS-CoV-2 offered the unique opportunity to analyze the immune response to a novel antigen. We identify four CVIDs phenotype clusters by the integration of immune parameters after BTN162b2 boosters., Methods: We performed a longitudinal study on 47 CVIDs patients who received the 3rd and 4th vaccine dose of the BNT162b2 vaccine measuring the generation of immunological memory. We analyzed specific and neutralizing antibodies, spike-specific memory B cells, and functional T cells., Results: We found that, depending on the readout of vaccine efficacy, the frequency of responders changes. Although 63.8% of the patients have specific antibodies in the serum, only 30% have high-affinity specific memory B cells and generate recall responses., Discussion: Thanks to the integration of our data, we identified four functional groups of CVIDs patients with different B cell phenotypes, T cell functions, and clinical diseases. The presence of antibodies alone is not sufficient to demonstrate the establishment of immune memory and the measurement of the in-vivo response to vaccination distinguishes patients with different immunological defects and clinical diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Piano Mortari, Pulvirenti, Marcellini, Terreri, Salinas, Ferrari, Di Napoli, Guadagnolo, Sculco, Albano, Guercio, Di Cecca, Milito, Garzi, Pesce, Bonanni, Sinibaldi, Bordoni, Di Cecilia, Accordini, Castilletti, Agrati, Quintarelli, Zaffina, Locatelli, Carsetti and Quinti.) more...
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- 2023
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137. Influence of Defatting and Pasteurization on Nutrients and Oxidative Stress Markers in Human Milk.
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D'Alessandro A, Pastore A, Amadio P, D'Agostini M, Terreri S, Carsetti R, Argentieri M, Bernaschi P, Onetti Muda A, Porzio O, Dotta A, and Salvatori G
- Subjects
- Infant, Female, Humans, Pasteurization methods, Cross-Sectional Studies, Prospective Studies, Breast Feeding, Nutrients analysis, Triglycerides, Oxidative Stress, Milk, Human, Milk Banks
- Abstract
Background: It is well known that the best nutritional option for infants is human milk, and that when breastfeeding is not possible, human milk banks are a possible alternative. However, in the case of infants with fat transport disorder like chylothorax, defatting of human milk is mandatory., Research Aim: The aim of the study was to reduce milk fat content without reducing other nutrients, increasing oxidative stress, or introducing harmful microorganisms., Methods: In this prospective, cross-sectional, observational study, we examined the influence of defatting and pasteurization of 50 donor samples on fat, macro- and micronutrients, as well as on oxidative stress markers., Results: Low-temperature centrifugation proved to be very efficient in defatting, reducing the concentration of triglycerides by 85% and cholesterol by 50%. The macronutrients (proteins, albumin, and Immunoglobulin A) did not undergo significant changes due to defatting and pasteurization procedures, while iron decreased by 36%. However, as the majority of iron is retained, this result does not remarkably change the milk composition. Furthermore, oxidative stress markers and antioxidant levels were unchanged, and the milk result was microbiologically safe., Conclusions: Cold milk centrifugation proved to be an effective technique that allows the reduction of human milk lipids. The determination of triglycerides and cholesterol can be used as an indicator of skimming. This procedure is not accompanied by substantial modifications of other components present in the milk. more...
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- 2023
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138. Dual stimulation by autoantigen and CpG fosters the proliferation of exhausted rheumatoid factor-specific CD21 low B cells in hepatitis C virus-cured mixed cryoglobulinemia.
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Del Padre M, Marrapodi R, Minafò YA, Piano Mortari E, Radicchio G, Bocci C, Gragnani L, Camponeschi A, Colantuono S, Stefanini L, Basili S, Carsetti R, Fiorilli M, Casato M, and Visentini M
- Subjects
- Humans, Autoantigens, Cell Proliferation, Hepacivirus, Myeloid Differentiation Factor 88 metabolism, NF-kappa B metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Rheumatoid Factor, Toll-Like Receptor 9 metabolism, CpG Islands, Receptors, Complement 3d immunology, B-Lymphocytes immunology, Cryoglobulinemia etiology, Hepatitis C
- Abstract
Introduction: Hepatitis C virus (HCV) causes mixed cryoglobulinemia (MC) by driving clonal expansion of B cells expressing B cell receptors (BCRs), often encoded by the VH1-69 variable gene, endowed with both rheumatoid factor (RF) and anti-HCV specificity. These cells display an atypical CD21low phenotype and functional exhaustion evidenced by unresponsiveness to BCR and Toll-like receptor 9 (TLR9) stimuli. Although antiviral therapy is effective on MC vasculitis, pathogenic B cell clones persist long thereafter and can cause virus-independent disease relapses., Methods: Clonal B cells from patients with HCV-associated type 2 MC or healthy donors were stimulated with CpG or heath-aggregated IgG (as surrogate immune complexes) alone or in combination; proliferation and differentiation were then evaluated by flow cytometry. Phosphorylation of AKT and of the p65 NF-kB subunit were measured by flow cytometry. TLR9 was quantified by qPCR and by intracellular flow cytometry, and MyD88 isoforms were analyzed using RT-PCR., Discussion: We found that dual triggering with autoantigen and CpG restored the capacity of exhausted VH1-69pos B cells to proliferate. The signaling mechanism for this BCR/TLR9 crosstalk remains elusive, since TLR9 mRNA and protein as well as MyD88 mRNA were normally expressed and CpG-induced phosphorylation of p65 NF-kB was intact in MC clonal B cells, whereas BCR-induced p65 NF-kB phosphorylation was impaired and PI3K/Akt signaling was intact. Our findings indicate that autoantigen and CpG of microbial or cellular origin may unite to foster persistence of pathogenic RF B cells in HCV-cured MC patients. BCR/TLR9 crosstalk might represent a more general mechanism enhancing systemic autoimmunity by the rescue of exhausted autoreactive CD21low B cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Del Padre, Marrapodi, Minafò, Piano Mortari, Radicchio, Bocci, Gragnani, Camponeschi, Colantuono, Stefanini, Basili, Carsetti, Fiorilli, Casato and Visentini.) more...
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- 2023
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139. COVID-19 Severity, Cardiological Outcome, and Immunogenicity of mRNA Vaccine on Adult Patients With 22q11.2 DS.
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Pulvirenti F, Mortari EP, Putotto C, Terreri S, Fernandez Salinas A, Cinicola BL, Cimini E, Di Napoli G, Sculco E, Milito C, Versacci P, Agrati C, Marino B, Carsetti R, and Quinti I
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- Humans, Adult, BNT162 Vaccine, COVID-19 Vaccines, SARS-CoV-2, Vaccination, mRNA Vaccines, COVID-19 epidemiology, COVID-19 prevention & control, DiGeorge Syndrome, Lymphopenia
- Abstract
Background: The contemporaneous presence of immune defects and heart diseases in patients with 22q11.2 deletion syndrome (22q11.3DS) might represent risk factors for severe coronavirus 2019 disease (COVID-19)., Objective: To analyze severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outcome in 22q11.2DS patients and immunogenicity of different doses of mRNA SARS-CoV-2 vaccine., Methods: Longitudinal observational study on SARS-CoV-2 outcome in 60 adults with 22q11.2DS (March 2020-June 2022). Anti-Spike, and anti-receptor binding domain (RBD) antibody responses, generation of Spike-specific memory B cells (MBCs) and Spike-specific T cells at different time points before and after the mRNA BNT162b2 vaccination were evaluated in 16 22q11.2DS patients., Results: We recorded a 95% rate of vaccination, with almost all patients being immunized with the booster dose. Twenty-one patients had SARS-CoV-2 infection. Three patients were infected before vaccine availability, 6 after receiving 2 doses of vaccine, and 12 after one booster dose. The SARS-CoV-2- infection had a mild course, except in one unvaccinated patient with several comorbidities who died from acute respiratory distress syndrome (fatality rate 5%). Infected patients had more frequently moderate/severe intellectual disability, lymphopenia, and lower CD4+ count. Despite major congenital heart diseases, COVID-19 did not impact cardiological conditions. The BNT162b2 vaccine induced S1-immunoglobulin G (IgG) responses, low serum S1-IgA, and slightly impaired specific MBCs response. Specific T-cell responses observed were related to lymphocytes and CD4+ T cell counts., Conclusions: The SARS-CoV-2 infection had a mild course in most patients with 22q11.2DS, even in patients with major cardiovascular diseases. Immunization induced Spike-specific IgG responses and generated specific MBCs and memory T cells. The weaker memory responses in patients with lymphopenia suggested the need for additional doses., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.) more...
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- 2023
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140. The BNT162b2 vaccine induces humoral and cellular immune memory to SARS-CoV-2 Wuhan strain and the Omicron variant in children 5 to 11 years of age.
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Cinicola BL, Piano Mortari E, Zicari AM, Agrati C, Bordoni V, Albano C, Fedele G, Schiavoni I, Leone P, Fiore S, Capponi M, Conti MG, Petrarca L, Stefanelli P, Spalice A, Midulla F, Palamara AT, Quinti I, Locatelli F, and Carsetti R more...
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- Humans, Child, Child, Preschool, BNT162 Vaccine, SARS-CoV-2, Immunologic Memory, mRNA Vaccines, Antibodies, COVID-19 prevention & control, Vaccines
- Abstract
SARS-CoV-2 mRNA vaccines prevent severe COVID-19 by generating immune memory, comprising specific antibodies and memory B and T cells. Although children are at low risk of severe COVID-19, the spreading of highly transmissible variants has led to increasing in COVID-19 cases and hospitalizations also in the youngest, but vaccine coverage remains low. Immunogenicity to mRNA vaccines has not been extensively studied in children 5 to 11 years old. In particular, cellular immunity to the wild-type strain (Wuhan) and the cross-reactive response to the Omicron variant of concern has not been investigated. We assessed the humoral and cellular immune response to the SARS-CoV-2 BNT162b2 vaccine in 27 healthy children. We demonstrated that vaccination induced a potent humoral and cellular immune response in all vaccinees. By using spike-specific memory B cells as a measurable imprint of a previous infection, we found that 50% of the children had signs of a past, undiagnosed infection before vaccination. Children with pre-existent immune memory generated significantly increased levels of specific antibodies, and memory T and B cells, directed against not only the wild type virus but also the omicron variant., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cinicola, Piano Mortari, Zicari, Agrati, Bordoni, Albano, Fedele, Schiavoni, Leone, Fiore, Capponi, Conti, Petrarca, Stefanelli, Spalice, Midulla, Palamara, Quinti, Locatelli and Carsetti.) more...
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- 2022
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141. Asplenia and spleen hypofunction.
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Lenti MV, Luu S, Carsetti R, Osier F, Ogwang R, Nnodu OE, Wiedermann U, Spencer J, Locatelli F, Corazza GR, and Di Sabatino A
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- Humans, Splenectomy adverse effects, Antibiotic Prophylaxis, Bacterial Infections etiology, Splenic Diseases complications, Splenic Diseases diagnosis
- Abstract
Asplenia (the congenital or acquired absence of the spleen) and hyposplenism (defective spleen function) are common causes of morbidity and mortality. The spleen is a secondary lymphoid organ that is responsible for the regulation of immune responses and blood filtration. Hence, asplenia or hyposplenism increases susceptibility to severe and invasive infections, especially those sustained by encapsulated bacteria (namely, Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae type b). Asplenia is predominantly due to splenectomy for either traumatic events or oncohaematological conditions. Hyposplenism can be caused by several conditions, including haematological, infectious, autoimmune and gastrointestinal disorders. Anatomical disruption of the spleen and depletion of immune cells, especially IgM memory B cells, seem to be predominantly responsible for the clinical manifestations. Early recognition of hyposplenism and proper management of asplenia are warranted to prevent overwhelming post-splenectomy infections through vaccination and antibiotic prophylaxis. Although recommendations are available, the implementation of vaccination strategies, including more effective and immunogenic vaccines, is needed. Additionally, screening programmes for early detection of hyposplenism in high-risk patients and improvement of patient education are warranted., (© 2022. Springer Nature Limited.) more...
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- 2022
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142. The immune response as a double-edged sword: The lesson learnt during the COVID-19 pandemic.
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Agrati C, Carsetti R, Bordoni V, Sacchi A, Quintarelli C, Locatelli F, Ippolito G, and Capobianchi MR
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- Humans, Immunity, Inflammation, Pandemics, SARS-CoV-2, COVID-19
- Abstract
The COVID-19 pandemic has represented an unprecedented challenge for the humanity, and scientists around the world provided a huge effort to elucidate critical aspects in the fight against the pathogen, useful in designing public health strategies, vaccines and therapeutic approaches. One of the first pieces of evidence characterizing the SARS-CoV-2 infection has been its breadth of clinical presentation, ranging from asymptomatic to severe/deadly disease, and the indication of the key role played by the immune response in influencing disease severity. This review is aimed at summarizing what the SARS-CoV-2 infection taught us about the immune response, highlighting its features of a double-edged sword mediating both protective and pathogenic processes. We will discuss the protective role of soluble and cellular innate immunity and the detrimental power of a hyper-inflammation-shaped immune response, resulting in tissue injury and immunothrombotic events. We will review the importance of B- and T-cell immunity in reducing the clinical severity and their ability to cross-recognize viral variants., (© 2022 The Authors. Immunology published by John Wiley & Sons Ltd.) more...
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- 2022
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143. Evaluation of humoral and cellular response to four vaccines against COVID-19 in different age groups: A longitudinal study.
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Fedele G, Trentini F, Schiavoni I, Abrignani S, Antonelli G, Baldo V, Baldovin T, Bandera A, Bonura F, Clerici P, De Paschale M, Fortunato F, Gori A, Grifantini R, Icardi G, Lazzarotto T, Lodi V, Mastroianni CM, Orsi A, Prato R, Restivo V, Carsetti R, Piano Mortari E, Leone P, Olivetta E, Fiore S, Di Martino A, Brusaferro S, Merler S, Palamara AT, and Stefanelli P more...
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- Humans, Aged, COVID-19 Vaccines, Longitudinal Studies, Ad26COVS1, SARS-CoV-2, COVID-19 prevention & control, Viral Vaccines
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To date there has been limited head-to-head evaluation of immune responses to different types of COVID-19 vaccines. A real-world population-based longitudinal study was designed with the aim to define the magnitude and duration of immunity induced by each of four different COVID-19 vaccines available in Italy at the time of this study. Overall, 2497 individuals were enrolled at time of their first vaccination (T0). Vaccine-specific antibody responses induced over time by Comirnaty, Spikevax, Vaxzevria, Janssen Ad26.COV2.S and heterologous vaccination were compared up to six months after immunization. On a subset of Comirnaty vaccinees, serology data were correlated with the ability to neutralize a reference SARS-CoV-2 B strain, as well as Delta AY.4 and Omicron BA.1. The frequency of SARS-CoV-2-specific CD4+ T cells, CD8+ T cells, and memory B cells induced by the four different vaccines was assessed six months after the immunization. We found that mRNA vaccines are stronger inducer of anti-Spike IgG and B-memory cell responses. Humoral immune responses are lower in frail elderly subjects. Neutralization of the Delta AY.4 and Omicron BA.1 variants is severely impaired, especially in older individuals. Most vaccinees display a vaccine-specific T-cell memory six months after the vaccination. By describing the immunological response during the first phase of COVID-19 vaccination campaign in different cohorts and considering several aspects of the immunological response, this study allowed to collect key information that could facilitate the implementation of effective prevention and control measures against SARS-CoV-2., Competing Interests: The authors declare that in this study the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fedele, Trentini, Schiavoni, Abrignani, Antonelli, Baldo, Baldovin, Bandera, Bonura, Clerici, De Paschale, Fortunato, Gori, Grifantini, Icardi, Lazzarotto, Lodi, Mastroianni, Orsi, Prato, Restivo, Carsetti, Piano Mortari, Leone, Olivetta, Fiore, Di Martino, Brusaferro, Merler, Palamara and Stefanelli.) more...
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- 2022
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144. Premature aging of the immune system affects the response to SARS-CoV-2 mRNA vaccine in β-thalassemia: role of an additional dose.
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Carsetti R, Agrati C, Pinto VM, Gianesin B, Gamberini R, Fortini M, Barella S, Denotti R, Perrotta S, Casale M, Maggio A, Pitrolo L, Tartaglia E, Mortari EP, Colavita F, Puro V, Francalancia M, Marini V, Caminati M, Mazzi F, De Franceschi L, Forni GL, and Locatelli F more...
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- Antibodies, Viral, COVID-19 Vaccines, Humans, Immune System, SARS-CoV-2, Vaccines, Synthetic, mRNA Vaccines, Aging, Premature, COVID-19 prevention & control, beta-Thalassemia genetics, beta-Thalassemia therapy
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- 2022
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145. COVID-19-Associated Multisystem Inflammatory Syndrome in a Neonate with Atypical Coronary Artery Involvement.
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Costa S, Delogu AB, Bottoni A, Purcaro V, D'Andrea V, Paladini A, Muto S, Marano R, Savino G, Secinaro A, De Benedetti F, Carsetti R, Mortari EP, Spanu T, and Vento G
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- Child, Coronary Vessels diagnostic imaging, Hospitalization, Humans, Immunoglobulin G, Infant, Newborn, SARS-CoV-2, Systemic Inflammatory Response Syndrome, COVID-19 complications
- Abstract
Objective: The study aimed to report a novel coronavirus disease 2019 (COVID-19)-associated multisystem inflammatory syndrome in children (MIS-C) in a neonate found to have an atypical diffuse thickening in coronary artery walls whose diagnosis required a multi-imaging approach., Study Design: A neonate presented at birth with multiple organ involvement and coronary artery anomalies. A diagnosis of MIS-C associated with COVID-19 was supported by maternal severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection during pregnancy, and by the presence of both immunoglobulin (Ig)-G against SARS-CoV-2 and spike-specific memory B-cells response in the neonatal blood. Other plausible causes of the multiple organ involvement were excluded., Result: At admission, a severe coronary artery dilatation was identified on echocardiography, supporting the diagnosis of the MIS-C Kawasaki-like disease; however, coronary artery internal diameters were found to be normal using cardiac computed tomography angiography. At discharge, comparing the two imaging techniques each other, the correct diagnosis resulted to be an abnormal thickening in coronary arterial walls. These findings suggest that the inflammatory process affecting the coronary arterial wall in MIS-C could result not only in typical coronary artery lesions such as dilatation of the lumen or aneurysms development but also in abnormal thickening of the coronary artery wall., Conclusion: Our case provides an alert for pediatric cardiologists about the complexity to assess coronary artery involvement in MIS-C and raises the question that whether an abnormal vascular remodeling, with normal inner diameters, is to be considered like coronary artery dilatation for risk stratification., Key Points: · COVID-19 associated MIS-C can present in neonates with multiple organ involvement.. · Coronary artery assessment in neonatal MIS-C could be complex, and a multi-imaging approach could be required.. · Beside the typical coronary artery lesions, such as dilatation of the lumen or aneurysms, also abnormal thickening of the coronary artery wall can occur.., Competing Interests: None declared., (Thieme. All rights reserved.) more...
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- 2022
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146. Severe Acute Respiratory Syndrome Coronavirus 2 Infection Versus Vaccination in Pregnancy: Implications for Maternal and Infant Immunity.
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Conti MG, Terreri S, Terrin G, Natale F, Pietrasanta C, Salvatori G, Brunelli R, Midulla F, Papaevangelou V, Carsetti R, and Angelidou A
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- Antibodies, Viral, BNT162 Vaccine, COVID-19 Vaccines, Female, Humans, Immunoglobulin A, Immunoglobulin G, Infant, Infant, Newborn, Lactation, Placenta, Pregnancy, Prospective Studies, SARS-CoV-2, Vaccination, COVID-19 prevention & control, Viral Vaccines
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Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with adverse maternal and neonatal outcomes, yet uptake of SARS-CoV-2 vaccines during pregnancy and lactation has been slow. As a result, millions of pregnant and lactating women and their infants remain susceptible to the virus., Methods: We measured spike-specific immunoglobulin G (anti-S IgG) and immunoglobulin A (anti-S IgA) in serum and breastmilk (BM) samples from 3 prospective mother-infant cohorts recruited in 2 academic medical centers. The primary aim was to determine the impact of maternal SARS-CoV-2 immunization vs infection and their timing on systemic and mucosal immunity., Results: The study included 28 mothers infected with SARS-CoV-2 in late pregnancy (INF), 11 uninfected mothers who received 2 doses of the BNT162b2 vaccine in the latter half of pregnancy (VAX-P), and 12 uninfected mothers who received 2 doses of BNT162b2 during lactation. VAX dyads had significantly higher serum anti-S IgG compared to INF dyads (P < .0001), whereas INF mothers had higher BM:serum anti-S IgA ratios compared to VAX mothers (P = .0001). Median IgG placental transfer ratios were significantly higher in VAX-P compared to INF mothers (P < .0001). There was a significant positive correlation between maternal and neonatal serum anti-S IgG after vaccination (r = 0.68, P = .013), but not infection., Conclusions: BNT161b2 vaccination in late pregnancy or lactation enhances systemic immunity through serum anti-S immunoglobulin, while SARS-CoV-2 infection induces mucosal over systemic immunity more efficiently through BM immunoglobulin production. Next-generation vaccines boosting mucosal immunity could provide additional protection to the mother-infant dyad. Future studies should focus on identifying the optimal timing of primary and/or booster maternal vaccination for maximal benefit., Competing Interests: Potential conflicts of interest . V. P. participated in a lecture on coronavirus disease 2019 vaccination in children (with honorarium made to their university), and also participated in the National Greek Advisory Committee for Immunization Practices. C. P. was a steering committee member for clinical trials MN42988 and MN42989 by La Roche Ltd. A. A. received an National Institute of Allergy and Infectious Diseases (NIAID) Development of Sample Sparing Assays (DSSA) for Monitoring Immune Responses Infrastructure & Opportunity Fund (IOF) Award grant for Comprehensive Analysis of the Neonatal Immune System via High-Throughout Proteomics; and honorarium for an invited review article on neonatal vaccination. All other authors report no potential conflicts., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) more...
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- 2022
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147. Hydroxytyrosol Recovers SARS-CoV-2-PLpro-Dependent Impairment of Interferon Related Genes in Polarized Human Airway, Intestinal and Liver Epithelial Cells.
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Crudele A, Smeriglio A, Ingegneri M, Panera N, Bianchi M, Braghini MR, Pastore A, Tocco V, Carsetti R, Zaffina S, Alisi A, and Trombetta D
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The SARS-CoV-2 pandemic has caused approximately 6.3 million deaths, mainly due to the acute respiratory distress syndrome or multi-organ failure that characterizes COVID-19 acute disease. Post-acute COVID-19 syndrome, also known as long-COVID, is a condition characterized by a complex of symptoms that affects 10-20% of the individuals who have recovered from the infection. Scientific and clinical evidence demonstrates that long-COVID can develop in both adults and children. It has been hypothesized that multi-organ effects of long-COVID could be associated with the persistence of virus RNA/proteins in host cells, but the real mechanism remains to be elucidated. Therefore, we sought to determine the effects of the exogenous expression of the papain-like protease (PLpro) domain of the non-structural protein (NSP3) of SARS-CoV-2 in polarized human airway (Calu-3), intestinal (Caco-2), and liver (HepG2) epithelial cells, and to evaluate the ability of the natural antioxidant hydroxytyrosol (HXT) in neutralizing these effects. Our results demonstrated that PLpro was able to induce a cascade of inflammatory genes and proteins (mainly associated with the interferon pathway) and increase the apoptotic rate and expression of several oxidative stress markers in all evaluated epithelial cells. Noteably, the treatment with 10 μM HXT reverted PL-pro-dependent effects almost completely. This study provides the first evidence that SARS-CoV-2 PLpro remaining in host cells after viral clearance may contribute to the pathogenetic mechanisms of long-COVID. These effects may be counteracted by natural antioxidants. Further clinical and experimental studies are necessary to confirm this hypothesis. more...
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- 2022
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148. T-Cell Defects Associated to Lack of Spike-Specific Antibodies after BNT162b2 Full Immunization Followed by a Booster Dose in Patients with Common Variable Immune Deficiencies.
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Pulvirenti F, Di Cecca S, Sinibaldi M, Piano Mortari E, Terreri S, Albano C, Guercio M, Sculco E, Milito C, Ferrari S, Locatelli F, Quintarelli C, Carsetti R, and Quinti I
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- Antibodies, Viral, CD40 Ligand, Humans, Immunization, Immunoglobulin A, Immunoglobulin G, SARS-CoV-2, Tumor Necrosis Factor-alpha, Vaccines, Synthetic, mRNA Vaccines, BNT162 Vaccine, COVID-19 prevention & control
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Following the third booster dose of the mRNA vaccine, Common Variable Immune Deficiencies (CVID) patients may not produce specific antibodies against the virus spike protein. The T-cell abnormalities associated with the absence of antibodies are still a matter of investigation. Spike-specific IgG and IgA, peripheral T cell subsets, CD40L and cytokine expression, and Spike-specific specific T-cells responses were evaluated in 47 CVID and 26 healthy donors after three doses of BNT162b2 vaccine. Testing was performed two weeks after the third vaccine dose. Thirty-six percent of the patients did not produce anti-SARS-CoV-2 IgG or IgA antibodies. Non responder patients had lower peripheral blood lymphocyte counts, circulating naïve and central memory T-cells, low CD40L expression on the CD4+CD45+RO+ and CD8+CD45+RO+ T-cells, high frequencies of TNFα and IFNγ expressing CD8+ T-cells, and defective release of IFNγ and TNFα following stimulation with Spike peptides. Non responders had a more complex disease phenotype, with higher frequencies of structural lung damage and autoimmunity, especially autoimmune cytopenia. Thirty-five percent of them developed a SARS-CoV-2 infection after immunization in comparison to twenty percent of CVID who responded to immunization with antibodies production. CVID-associated T cell abnormalities contributed to the absence of SARS-CoV-2 specific antibodies after full immunization. more...
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- 2022
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149. CD21 - CD27 - Atypical B Cells in a Pediatric Cohort Study: An Extensive Single Center Flow Cytometric Analysis.
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Corrente F, Terreri S, Palomba P, Capponi C, Mirabella M, Perno CF, and Carsetti R
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Atypical B cells (atBCs) are a distinct B-cell population and represent approximately 5% of B cells in peripheral blood (PB) of healthy adult individuals. However, in adults these cells are expanded in conditions of chronic infections, inflammation, primary immunodeficiencies, autoimmune diseases, and aging. Their immunophenotype is characterized by the lack of CD21 expression and the hallmark human memory B-cell marker CD27. In this study, we investigated the immunophenotype of atBCs in different pediatric pathological conditions and correlated their expansion with the children's clinical diagnosis. We were able to retrospectively evaluate 1,571 consecutive PB samples, corresponding to 1,180 pediatric patients, by using a 9-color flow-cytometric panel. The results, compared with a pediatric healthy cohort, confirmed an expansion of atBCs in patient samples with percentages greater than 5% of total B cells. Four subpopulations with different expressions of IgM and IgD were discriminated: IgM
+ IgD+ , IgM+ -only, IgD+ -only, and IgM- IgD- . IgG+ atBCs were predominant in the IgM- IgD- subpopulation. Moreover, the study highlighted some features of atBCs, such as a low CD38 expression, a heterogeneity of CD24, a high expression of CD19 and a large cell size. We also demonstrated that an increase of atBCs in a pediatric cohort is correlated with immunodeficiencies, autoimmune, inflammatory, and hematological disorders, consistent with previous studies mainly performed in adults. Furthermore, our flow cytometric clustering analysis corroborated the recent hypothesis of an alternative B origin for atBCs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Corrente, Terreri, Palomba, Capponi, Mirabella, Perno and Carsetti.) more...- Published
- 2022
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150. Mortality in Severe Antibody Deficiencies Patients during the First Two Years of the COVID-19 Pandemic: Vaccination and Monoclonal Antibodies Efficacy.
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Milito C, Cinetto F, Palladino A, Garzi G, Punziano A, Lagnese G, Scarpa R, Rattazzi M, Pesce AM, Pulvirenti F, Di Napoli G, Spadaro G, Carsetti R, and Quinti I
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Patients with severely impaired antibody responses represent a group at-risk in the SARS-CoV-2 pandemic due to the lack of Spike-specific neutralizing antibodies. The main objective of this paper was to assess, by a longitudinal prospective study, COVID-19 infection and mortality rates, and disease severity in the first two years of the pandemic in a cohort of 471 Primary Antibody Defects adult patients. As secondary endpoints, we compared SARS-CoV-2 annual mortality rate to that observed over a 10-year follow-up in the same cohort, and we assessed the impact of interventions done in the second year, vaccination and anti-SARS-CoV-2 monoclonal antibodies administration on the disease outcome. Forty-one and 84 patients were infected during the first and the second year, respectively. Despite a higher infection and reinfection rate, and a higher COVID-19-related mortality rate compared to the Italian population, the pandemic did not modify the annual mortality rate for any cause in our cohort compared to that registered over the last ten years in the same cohort. PADs patients who died from COVID-19 had an underlying end-stage lung disease. We showed a beneficial effect of MoAbs administration on the likelihood of hospitalization and development of severe disease. In conclusion, COVID-19 did not cause excess mortality in Severe Antibody Deficiencies. more...
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- 2022
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