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1. Deuxième analyse intermédiaire d’une étude en ouvert du Leniolisib dans le syndrome PI3Kδ activée : efficacité et tolérance long terme

Author

Rao, V.K., primary, Sediva, A., additional, Dalm, V., additional, Alessandro, P., additional, Catharina, S., additional, Shcherbina, A., additional, Trizzino, A., additional, Kulm, E., additional, Zharankova, Y., additional, Körholz, J., additional, Lougaris, V., additional, Rodina, J., additional, Bradt, J., additional, Webster, S., additional, Alanvin, O., additional, Vandier, D., additional, Amores, X., additional, Relan, A., additional, and Gulbu, U., additional

Published
2024
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3. Modeling, optimization, and comparable efficacy of T cell and hematopoietic stem cell gene editing for treating hyper-IgM syndrome

Author

Vavassori, V, Mercuri, E, Marcovecchio, G, Castiello, M, Schiroli, G, Albano, L, Margulies, C, Buquicchio, F, Fontana, E, Beretta, S, Merelli, I, Cappelleri, A, Rancoita, P, Lougaris, V, Plebani, A, Kanariou, M, Lankester, A, Ferrua, F, Scanziani, E, Cotta-Ramusino, C, Villa, A, Naldini, L, Genovese, P, Vavassori V., Mercuri E., Marcovecchio G. E., Castiello M. C., Schiroli G., Albano L., Margulies C., Buquicchio F., Fontana E., Beretta S., Merelli I., Cappelleri A., Rancoita P. M. V., Lougaris V., Plebani A., Kanariou M., Lankester A., Ferrua F., Scanziani E., Cotta-Ramusino C., Villa A., Naldini L., Genovese P., Vavassori, V, Mercuri, E, Marcovecchio, G, Castiello, M, Schiroli, G, Albano, L, Margulies, C, Buquicchio, F, Fontana, E, Beretta, S, Merelli, I, Cappelleri, A, Rancoita, P, Lougaris, V, Plebani, A, Kanariou, M, Lankester, A, Ferrua, F, Scanziani, E, Cotta-Ramusino, C, Villa, A, Naldini, L, Genovese, P, Vavassori V., Mercuri E., Marcovecchio G. E., Castiello M. C., Schiroli G., Albano L., Margulies C., Buquicchio F., Fontana E., Beretta S., Merelli I., Cappelleri A., Rancoita P. M. V., Lougaris V., Plebani A., Kanariou M., Lankester A., Ferrua F., Scanziani E., Cotta-Ramusino C., Villa A., Naldini L., and Genovese P.

Abstract

Precise correction of the CD40LG gene in T cells and hematopoietic stem/progenitor cells (HSPC) holds promise for treating X-linked hyper-IgM Syndrome (HIGM1), but its actual therapeutic potential remains elusive. Here, we developed a one-size-fits-all editing strategy for effective T-cell correction, selection, and depletion and investigated the therapeutic potential of T-cell and HSPC therapies in the HIGM1 mouse model. Edited patients’ derived CD4 T cells restored physiologically regulated CD40L expression and contact-dependent B-cell helper function. Adoptive transfer of wild-type T cells into conditioned HIGM1 mice rescued antigen-specific IgG responses and protected mice from a disease-relevant pathogen. We then obtained ~ 25% CD40LG editing in long-term repopulating human HSPC. Transplanting such proportion of wild-type HSPC in HIGM1 mice rescued immune functions similarly to T-cell therapy. Overall, our findings suggest that autologous edited T cells can provide immediate and substantial benefits to HIGM1 patients and position T-cell ahead of HSPC gene therapy because of easier translation, lower safety concerns and potentially comparable clinical benefits.

Published
2021

4. The Italian Registry for Primary Immunodeficiencies (Italian Primary Immunodeficiency Network; IPINet): Twenty Years of Experience (1999–2019)

Author

Lougaris, V, Pession, A, Baronio, M, Soresina, A, Rondelli, R, Gazzurelli, L, Benvenuto, A, Martino, S, Gattorno, M, Biondi, A, Zecca, M, Marinoni, M, Fabio, G, Aiuti, A, Marseglia, G, Putti, M, Agostini, C, Lunardi, C, Tommasini, A, Bertolini, P, Gambineri, E, Consolini, R, Matucci, A, Azzari, C, Danieli, M, Paganelli, R, Duse, M, Cancrini, C, Moschese, V, Chessa, L, Spadaro, G, Civino, A, Vacca, A, Cardinale, F, Martire, B, Carpino, L, Trizzino, A, Russo, G, Cossu, F, Badolato, R, Pietrogrande, M, Quinti, I, Rossi, P, Ugazio, A, Pignata, C, Plebani, A, Lougaris V., Pession A., Baronio M., Soresina A., Rondelli R., Gazzurelli L., Benvenuto A., Martino S., Gattorno M., Biondi A., Zecca M., Marinoni M., Fabio G., Aiuti A., Marseglia G., Putti M. C., Agostini C., Lunardi C., Tommasini A., Bertolini P., Gambineri E., Consolini R., Matucci A., Azzari C., Danieli M. G., Paganelli R., Duse M., Cancrini C., Moschese V., Chessa L., Spadaro G., Civino A., Vacca A., Cardinale F., Martire B., Carpino L., Trizzino A., Russo G., Cossu F., Badolato R., Pietrogrande M. C., Quinti I., Rossi P., Ugazio A., Pignata C., Plebani A., Lougaris, V, Pession, A, Baronio, M, Soresina, A, Rondelli, R, Gazzurelli, L, Benvenuto, A, Martino, S, Gattorno, M, Biondi, A, Zecca, M, Marinoni, M, Fabio, G, Aiuti, A, Marseglia, G, Putti, M, Agostini, C, Lunardi, C, Tommasini, A, Bertolini, P, Gambineri, E, Consolini, R, Matucci, A, Azzari, C, Danieli, M, Paganelli, R, Duse, M, Cancrini, C, Moschese, V, Chessa, L, Spadaro, G, Civino, A, Vacca, A, Cardinale, F, Martire, B, Carpino, L, Trizzino, A, Russo, G, Cossu, F, Badolato, R, Pietrogrande, M, Quinti, I, Rossi, P, Ugazio, A, Pignata, C, Plebani, A, Lougaris V., Pession A., Baronio M., Soresina A., Rondelli R., Gazzurelli L., Benvenuto A., Martino S., Gattorno M., Biondi A., Zecca M., Marinoni M., Fabio G., Aiuti A., Marseglia G., Putti M. C., Agostini C., Lunardi C., Tommasini A., Bertolini P., Gambineri E., Consolini R., Matucci A., Azzari C., Danieli M. G., Paganelli R., Duse M., Cancrini C., Moschese V., Chessa L., Spadaro G., Civino A., Vacca A., Cardinale F., Martire B., Carpino L., Trizzino A., Russo G., Cossu F., Badolato R., Pietrogrande M. C., Quinti I., Rossi P., Ugazio A., Pignata C., and Plebani A.

Abstract

Primary immunodeficiencies (PIDs) are heterogeneous disorders, characterized by variable clinical and immunological features. National PID registries offer useful insights on the epidemiology, diagnosis, and natural history of these disorders. In 1999, the Italian network for primary immunodeficiencies (IPINet) was established. We report on data collected from the IPINet registry after 20 years of activity. A total of 3352 pediatric and adult patients affected with PIDs are registered in the database. In Italy, a regional distribution trend of PID diagnosis was observed. Based on the updated IUIS classification of 2019, PID distribution in Italy showed that predominantly antibody deficiencies account for the majority of cases (63%), followed by combined immunodeficiencies with associated or syndromic features (22.5%). The overall age at diagnosis was younger for male patients. The minimal prevalence of PIDs in Italy resulted in 5.1 per 100.000 habitants. Mortality was similar to other European registries (4.2%). Immunoglobulin replacement treatment was prescribed to less than one third of the patient cohort. Collectively, this is the first comprehensive description of the PID epidemiology in Italy.

Published
2020

5. Prevalence of Immunological Defects in a Cohort of 97 Rubinstein–Taybi Syndrome Patients

Author

Saettini, F, Herriot, R, Prada, E, Nizon, M, Zama, D, Marzollo, A, Romaniouk, I, Lougaris, V, Cortesi, M, Morreale, A, Kosaki, R, Cardinale, F, Ricci, S, Dominguez-Garrido, E, Montin, D, Vincent, M, Milani, D, Biondi, A, Gervasini, C, Badolato, R, Saettini F., Herriot R., Prada E., Nizon M., Zama D., Marzollo A., Romaniouk I., Lougaris V., Cortesi M., Morreale A., Kosaki R., Cardinale F., Ricci S., Dominguez-Garrido E., Montin D., Vincent M., Milani D., Biondi A., Gervasini C., Badolato R., Saettini, F, Herriot, R, Prada, E, Nizon, M, Zama, D, Marzollo, A, Romaniouk, I, Lougaris, V, Cortesi, M, Morreale, A, Kosaki, R, Cardinale, F, Ricci, S, Dominguez-Garrido, E, Montin, D, Vincent, M, Milani, D, Biondi, A, Gervasini, C, Badolato, R, Saettini F., Herriot R., Prada E., Nizon M., Zama D., Marzollo A., Romaniouk I., Lougaris V., Cortesi M., Morreale A., Kosaki R., Cardinale F., Ricci S., Dominguez-Garrido E., Montin D., Vincent M., Milani D., Biondi A., Gervasini C., and Badolato R.

Abstract

Although recurrent infections in Rubinstein–Taybi syndrome (RSTS) are common, and probably multifactorial, immunological abnormalities have not been extensively described with only isolated cases or small case series of immune deficiency and dysregulation having been reported. The objective of this study was to investigate primary immunodeficiency (PID) and immune dysregulation in an international cohort of patients with RSTS. All published cases of RSTS were identified. The corresponding authors and researchers involved in the diagnosis of inborn errors of immunity or genetic syndromes were contacted to obtain up-to-date clinical and immunological information. Ninety-seven RSTS patients were identified. For 45 patients, we retrieved data from the published reports while for 52 patients, a clinical update was provided. Recurrent or severe infections, autoimmune/autoinflammatory complications, and lymphoproliferation were observed in 72.1%, 12.3%, and 8.2% of patients. Syndromic immunodeficiency was diagnosed in 46.4% of individuals. Despite the broad heterogeneity of immunodeficiency disorders, antibody defects were observed in 11.3% of subjects. In particular, these patients presented hypogammaglobulinemia associated with low B cell counts and reduction of switched memory B cell numbers. Immunoglobulin replacement therapy, antibiotic prophylaxis, and immunosuppressive treatment were employed in 16.4%, 8.2%, and 9.8% of patients, respectively. Manifestations of immune dysfunctions, affecting mostly B cells, are more common than previously recognized in patients with RSTS. Full immunological assessment is warranted in these patients, who may require detailed investigation and specific supportive treatment. [Figure not available: see fulltext.]

Published
2020

6. Two siblings presenting with novel ADA2 variants, lymphoproliferation, persistence of large granular lymphocytes, and T-cell perturbations

Author

Saettini, F, Fazio, G, Corti, P, Quadri, M, Bugarin, C, Gaipa, G, Penco, F, Moratto, D, Chiarini, M, Baronio, M, Gazzurelli, L, Imberti, L, Paghera, S, Giliani, S, Cazzaniga, G, Plebani, A, Badolato, R, Lougaris, V, Gattorno, M, Biondi, A, Saettini F., Fazio G., Corti P., Quadri M., Bugarin C., Gaipa G., Penco F., Moratto D., Chiarini M., Baronio M., Gazzurelli L., Imberti L., Paghera S., Giliani S., Cazzaniga G., Plebani A., Badolato R., Lougaris V., Gattorno M., Biondi A., Saettini, F, Fazio, G, Corti, P, Quadri, M, Bugarin, C, Gaipa, G, Penco, F, Moratto, D, Chiarini, M, Baronio, M, Gazzurelli, L, Imberti, L, Paghera, S, Giliani, S, Cazzaniga, G, Plebani, A, Badolato, R, Lougaris, V, Gattorno, M, Biondi, A, Saettini F., Fazio G., Corti P., Quadri M., Bugarin C., Gaipa G., Penco F., Moratto D., Chiarini M., Baronio M., Gazzurelli L., Imberti L., Paghera S., Giliani S., Cazzaniga G., Plebani A., Badolato R., Lougaris V., Gattorno M., and Biondi A.

Abstract

The presence of large granular lymphocytes has been reported in patients with ADA2 deficiency and T-LGL leukemia. Here we describe two siblings with novel ADA2 variants, expanding the mutational spectrum of ADA2 deficiency. We show that lymphoproliferation, persistence of large granular lymphocytes, T-cell perturbations, and activation of PI3K pathway, measured by means of phosphorylation levels of S6, are detectable in DADA2 patients without T-LGL leukemia.

Published
2020

7. Inherited defects in the complement system

Author

Leonardi, L, La Torre, F, Soresina, A, Federici, S, Cancrini, C, Castagnoli, R, Cinicola, B, Corrente, S, Giardino, G, Lougaris, V, Volpi, S, Marseglia, G, Cardinale, F, and Immunology Task Force of the Italian Society of Pediatric Allergy and Immunology (SIAIP)

Subjects
Immunology, pathways, alternative, classical, complement, deficiency, inherited, lectin, system, Complement System Proteins, Settore MED/02, Pediatrics, Perinatology and Child Health, Humans, Immunology and Allergy
Abstract

The complement system plays an essential role in both innate and adaptive immune responses. Any dysregulation in this system can disturb normal host defense and alter inflammatory response leading to both infections and autoimmune diseases. The complement system can be activated through three different pathways. Inherited complement deficiencies have been described for all complement components and their regulators. Despite being rare diseases, complement deficiencies are often severe, with a frequent onset during childhood. We provide an overview of clinical disorders related to these disorders and describe current diagnostic strategies required for their comprehensive characterization and management.

Published
2022

8. Immunological basis of virus-host interaction in COVID-19

Author

La Torre, F, Leonardi, L, Giardino, G, Volpi, S, Federici, S, Soresina, A, Cancrini, C, Lougaris, V, Castagnoli, R, Corrente, S, Cardinale, F, Immunology Commission of the Italian Society of Pediatric Allergy, I, La Torre, F., Leonardi, L., Giardino, G., Volpi, S., Federici, S., Soresina, A., Cancrini, C., Lougaris, V., Castagnoli, R., Corrente, S., and Cardinale, F.

Subjects
Coronavirus disease 2019 (COVID-19), Immunology, Inflammation, Virus-host interaction, Covid‐19 in Children and Adolescents, 03 medical and health sciences, 2020 Update from The Italian Society of Pediatric Allergy and Immunology, 0302 clinical medicine, Immune system, Host Microbial Interaction, children, COVID‐19, Medicine, Immunology and Allergy, Humans, 030212 general & internal medicine, Pediatrics, Perinatology, and Child Health, Host Microbial Interactions, Kawasaki disease, business.industry, SARS-CoV-2, COVID-19, cytokine storm, immunopathogenesis, Cytokine Release Syndrome, Pneumonia, medicine.disease, Cytokine release syndrome, Settore MED/02, 030228 respiratory system, immunopathogenesi, Pediatrics, Perinatology and Child Health, Etiology, Supplement Article, Viral disease, medicine.symptom, business, Cytokine storm, Human
Abstract

COVID‐19 is a complex new viral disease, in which a strict balance between anti‐viral immune response and the ensuing organ inflammation has a critical role in determining the clinical course. In adults, compelling evidence exists indicating that an uncontrolled inflammatory response ("cytokine storm") is pivotal in determining disease progression and mortality. Children may rarely present with severe disease. Modulating factors related to the host's genetic factors, age‐related susceptibility, and the capability to mount appropriate immune responses might play a role in control virus load at an early stage and regulating the inflammatory reaction. Elucidating these mechanisms seems crucial in developing target therapies according to patient's age, immunologic status, and disease evolution in COVID‐19.

Published
2020

9. Primary atopic disorders and chronic skin disease

Author

Cinicola, B, Corrente, S, Castagnoli, R, Lougaris, V, Giardino, G, Leonardi, L, Volpi, S, La Torre, F, Federici, S, Soresina, A, Cancrini, C, Marseglia, G, Cardinale, F, and Immunology Task Force of the Italian Society of Pediatric Allergy, I

Subjects
IgE, allergy, inborn errors of immunity, primary atopic disorders, skin, Hypersensitivity, Immediate, Immediate, Urticaria, Immunology, Eczema, Skin Diseases, Settore MED/02, Humans, Job Syndrome, Pediatrics, Perinatology and Child Health, Hypersensitivity, Immunology and Allergy
Abstract

Primary atopic disorders (PADs) are monogenic diseases characterized by allergy or atopy-related symptoms as fundamental features. In patients with PADs, primary immune deficiency and immune dysregulation symptoms are usually coexist. Chronic skin disease, manifesting with erythroderma, severe atopic dermatitis or eczema, and urticaria, is one of the main features observed in PADs, such as hyper-IgE syndromes, Omenn syndrome, Wiskott-Aldrich syndrome, IPEX-linked syndrome, skin barrier disorders, as well as some autoinflammatory diseases. The recognition of PADs in the context of an allergic phenotype is crucial to ensure prompt diagnosis and appropriate treatment. This article provides an overview of the main PADs with skin involvement.

Published
2021

13. Therapeutic agents affecting the immune system and drug-induced inflammatory bowel disease (IBD): A review on etiological and pathogenetic aspects

Author

Del Sordo, R, Lougaris, V, Bassotti, G, Armuzzi, A, and Villanacci, V

Subjects
Tumor Necrosis Factor-alpha, Interleukins, Immunology, Drugs, Protein-Tyrosine Kinases, Inflammatory Bowel Diseases, Inflammatory bowel disease, Crohn's disease, Ulcerative colitis, Immune System, Humans, Immunologic Factors, Immunology and Allergy, Interferons, Isotretinoin, Rituximab, Immune Checkpoint Inhibitors
Abstract

In recent years, therapeutic agents affecting the immune system have been largely implemented in the treatment of various hematological, rheumatological and dermatological disorders. Their clinical use has offered important benefits for affected patients and has also ameliorated clinical outcome and prognosis in many cases. Nonetheless, as any treatment, the use of these drugs may be associated with side effects. One of the target organs in such cases is the gastrointestinal tract. In particular, the exacerbation or the onset of inflammatory bowel disease (IBD) in treated patients is not infrequent, although the mechanism of action of these agents may be different. In this review we will focus on the use of therapeutic agents affecting the immune system and the development or exacerbation of IBD, with a mention on the possible underlying pathogenetic mechanisms.

Published
2022

14. Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations

Author

Lorenzini, T., Fliegauf, M., Klammer, N., Frede, N., Proietti, M., Bulashevska, A., Camacho-Ordonez, N., Varjosalo, M., Kinnunen, M., Vries, E de, Meer, J.W.M. van der, Ameratunga, R., Roifman, C.M., Schejter, Y.D., Kobbe, R., Hautala, T., Atschekzei, F., Schmidt, R.E., Schröder, C., Stepensky, P., Shadur, B., Pedroza, L.A., Flier, M. van der, Martínez-Gallo, M., Gonzalez-Granado, L.I., Allende, L.M., Shcherbina, A., Kuzmenko, N., Zakharova, V., Neves, J.F., Svec, P., Fischer, U., Ip, W., Bartsch, O., Barış, S., Klein, C., Geha, R., Chou, J., Alosaimi, M., Weintraub, L., Boztug, K., Hirschmugl, T., Vilela, M.M. Dos Santos, Holzinger, D., Seidl, M., Lougaris, V., Plebani, A., Alsina, L., Piquer-Gibert, M., Deyà-Martínez, A., Slade, C.A., Aghamohammadi, A., Abolhassani, H., Hammarström, L., Kuismin, O., Helminen, M., Allen, H.L., Thaventhiran, J.E., Freeman, A.F., Cook, M., Bakhtiar, S., Christiansen, M., Cunningham-Rundles, C., Patel, N.C., Rae, W., Niehues, T., Brauer, N., Syrjänen, J., Seppänen, M.R.J., Burns, S.O., Tuijnenburg, P., Kuijpers, T.W., Warnatz, K., Grimbacher, B., Lorenzini, T., Fliegauf, M., Klammer, N., Frede, N., Proietti, M., Bulashevska, A., Camacho-Ordonez, N., Varjosalo, M., Kinnunen, M., Vries, E de, Meer, J.W.M. van der, Ameratunga, R., Roifman, C.M., Schejter, Y.D., Kobbe, R., Hautala, T., Atschekzei, F., Schmidt, R.E., Schröder, C., Stepensky, P., Shadur, B., Pedroza, L.A., Flier, M. van der, Martínez-Gallo, M., Gonzalez-Granado, L.I., Allende, L.M., Shcherbina, A., Kuzmenko, N., Zakharova, V., Neves, J.F., Svec, P., Fischer, U., Ip, W., Bartsch, O., Barış, S., Klein, C., Geha, R., Chou, J., Alosaimi, M., Weintraub, L., Boztug, K., Hirschmugl, T., Vilela, M.M. Dos Santos, Holzinger, D., Seidl, M., Lougaris, V., Plebani, A., Alsina, L., Piquer-Gibert, M., Deyà-Martínez, A., Slade, C.A., Aghamohammadi, A., Abolhassani, H., Hammarström, L., Kuismin, O., Helminen, M., Allen, H.L., Thaventhiran, J.E., Freeman, A.F., Cook, M., Bakhtiar, S., Christiansen, M., Cunningham-Rundles, C., Patel, N.C., Rae, W., Niehues, T., Brauer, N., Syrjänen, J., Seppänen, M.R.J., Burns, S.O., Tuijnenburg, P., Kuijpers, T.W., Warnatz, K., and Grimbacher, B.

Abstract

Item does not contain fulltext, BACKGROUND: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. OBJECTIVE: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. METHODS: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. RESULTS: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. CONCLUSIONS: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.

Published
2020

15. The Interplay between CD27dull and CD27bright B Cells Ensures the Flexibility, Stability, and Resilience of Human B Cell Memory

Author

Grimsholm, O., Piano Mortari, E., Davydov, A. N., Shugay, M., Obraztsova, A. S., Bocci, C., Marasco, E., Marcellini, V., Aranburu, A., Farroni, C., Silvestris, D. A., Cristofoletti, C., Giorda, E., Scarsella, M., Cascioli, S., Barresi, S., Lougaris, V., Plebani, A., Cancrini, C., Finocchi, A., Moschese, V., Valentini, D., Vallone, C., Signore, F., de Vincentiis, G., Zaffina, S., Russo, G., Gallo, A., Locatelli, Franco, Tozzi, A. E., Tartaglia, M., Chudakov, D. M., Carsetti, R., Locatelli F. (ORCID:0000-0002-7976-3654), Grimsholm, O., Piano Mortari, E., Davydov, A. N., Shugay, M., Obraztsova, A. S., Bocci, C., Marasco, E., Marcellini, V., Aranburu, A., Farroni, C., Silvestris, D. A., Cristofoletti, C., Giorda, E., Scarsella, M., Cascioli, S., Barresi, S., Lougaris, V., Plebani, A., Cancrini, C., Finocchi, A., Moschese, V., Valentini, D., Vallone, C., Signore, F., de Vincentiis, G., Zaffina, S., Russo, G., Gallo, A., Locatelli, Franco, Tozzi, A. E., Tartaglia, M., Chudakov, D. M., Carsetti, R., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Grimsholm et al. show that CD27dull and CD27bright represent sequential MBC developmental stages. T cell- and germinal center (GC)-independent CD27dull MBCs are the plastic source of strongly selected and GC-dependent CD27bright MBCs. CD27dull MBCs, able to expand and differentiate in response to change, ensure stability and flexibility of human B cell memory.

Published
2020

16. Consensus of the Italian Primary Immunodeficiency Network on transition management from pediatric to adult care in patients affected with childhood-onset inborn errors of immunity

Author

Cirillo, E., Giardino, G., Ricci, S., Moschese, V., Lougaris, V., Conti, F., Azzari, C., Barzaghi, F., Canessa, C., Martire, B., Badolato, R., Dotta, L., Soresina, A., Cancrini, C., Finocchi, A., Montin, D., Romano, R., Amodio, D., Ferrua, F., Tommasini, A., Baselli, L. A., Dellepiane, R. M., Polizzi, A., Chessa, L., Marzollo, A., Cicalese, M. P., Putti, M. C., Pession, A., Aiuti, A., Locatelli, Franco, Plebani, A., Pignata, C., Locatelli F. (ORCID:0000-0002-7976-3654), Cirillo, E., Giardino, G., Ricci, S., Moschese, V., Lougaris, V., Conti, F., Azzari, C., Barzaghi, F., Canessa, C., Martire, B., Badolato, R., Dotta, L., Soresina, A., Cancrini, C., Finocchi, A., Montin, D., Romano, R., Amodio, D., Ferrua, F., Tommasini, A., Baselli, L. A., Dellepiane, R. M., Polizzi, A., Chessa, L., Marzollo, A., Cicalese, M. P., Putti, M. C., Pession, A., Aiuti, A., Locatelli, Franco, Plebani, A., Pignata, C., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Medical advances have dramatically improved the long-term prognosis of children and adolescents with inborn errors of immunity (IEIs). Transfer of the medical care of individuals with pediatric IEIs to adult facilities is also a complex task because of the large number of distinct disorders, which requires involvement of patients and both pediatric and adult care providers. To date, there is no consensus on the optimal pathway of the transitional care process and no specific data are available in the literature regarding patients with IEIs. We aimed to develop a consensus statement on the transition process to adult health care services for patients with IEIs. Physicians from major Italian Primary Immunodeficiency Network centers formulated and answered questions after examining the currently published literature on the transition from childhood to adulthood. The authors voted on each recommendation. The most frequent IEIs sharing common main clinical problems requiring full attention during the transitional phase were categorized into different groups of clinically related disorders. For each group of clinically related disorders, physicians from major Italian Primary Immunodeficiency Network institutions focused on selected clinical issues representing the clinical hallmark during early adulthood.

Published
2020

17. Consensus statement of the Italian society of pediatric allergy and immunology for the pragmatic management of children and adolescents with allergic or immunological diseases during the COVID-19 pandemic

Author

Cardinale, F, Ciprandi, G, Barberi, S, Bernardini, R, Caffarelli, C, Calvani, M, Cavagni, G, Galli, E, Minasi, D, Del Giudice, M, Moschese, V, Novembre, E, Paravati, F, Peroni, D, Tosca, M, Traina, G, Tripodi, S, Marseglia, G, Amato, D, Anania, C, Anastasio, E, Antignani, R, Arasi, S, Baldassarre, M, Baldo, E, Barbalace, A, Barni, S, Betti, F, Bianchi, A, Bolzacchini, E, Bonini, M, Bottau, P, Bozzetto, S, Brighetti, M, Caimmi, D, Caimmi, S, Calzone, L, Cancrini, C, Caminiti, L, Capata, G, Capra, L, Capristo, C, Carboni, E, Carella, F, Castagnoli, R, Chiappini, E, Chiera, F, Chinellato, I, Chini, L, Cipriani, F, Civitelli, F, Comberiati, P, Contini, D, Corrente, S, Cravidi, C, Crisafulli, G, Cuomo, B, D'Auria, E, D'Elios, S, Decimo, F, Giustina, A, Piane, R, De Filippo, M, De Vittori, V, Diaferio, L, Di Mauro, M, Duse, M, Federici, S, Felice, G, Fenu, G, Ferrante, G, Foti, T, Franceschini, F, Ghiglioni, D, Giardino, G, Giovannini, M, Indirli, G, Indolfi, C, Landi, M, La Torre, F, Leone, L, Licari, A, Liotti, L, Lougaris, V, Maiello, N, Mantecca, P, Manti, S, Mariani, M, Martelli, A, Mastrorilli, C, Mastrorilli, V, Montin, D, Mori, F, Olcese, R, Ottaviano, G, Paglialunga, C, Pajno, G, Parisi, G, Pattini, S, Pecoraro, L, Pelosi, U, Pignata, C, Ricci, G, Ricci, S, Rizzi, S, Rizzo, C, Rosati, S, Rosso, P, Sangerardi, M, Santoro, A, Saretta, F, Sarti, L, Sartorio, M, Sgruletti, M, Soresina, A, Sfika, I, Sgrulletti, M, Tesse, N, Tranchino, V, Travaglini, A, Velia, M, Verduci, E, Vernich, M, Veronelli, E, Volpi, S, Votto, M, Zicari, A, Cardinale, F, Ciprandi, G, Barberi, S, Bernardini, R, Caffarelli, C, Calvani, M, Cavagni, G, Galli, E, Minasi, D, Del Giudice, M, Moschese, V, Novembre, E, Paravati, F, Peroni, D, Tosca, M, Traina, G, Tripodi, S, Marseglia, G, Amato, D, Anania, C, Anastasio, E, Antignani, R, Arasi, S, Baldassarre, M, Baldo, E, Barbalace, A, Barni, S, Betti, F, Bianchi, A, Bolzacchini, E, Bonini, M, Bottau, P, Bozzetto, S, Brighetti, M, Caimmi, D, Caimmi, S, Calzone, L, Cancrini, C, Caminiti, L, Capata, G, Capra, L, Capristo, C, Carboni, E, Carella, F, Castagnoli, R, Chiappini, E, Chiera, F, Chinellato, I, Chini, L, Cipriani, F, Civitelli, F, Comberiati, P, Contini, D, Corrente, S, Cravidi, C, Crisafulli, G, Cuomo, B, D'Auria, E, D'Elios, S, Decimo, F, Giustina, A, Piane, R, De Filippo, M, De Vittori, V, Diaferio, L, Di Mauro, M, Duse, M, Federici, S, Felice, G, Fenu, G, Ferrante, G, Foti, T, Franceschini, F, Ghiglioni, D, Giardino, G, Giovannini, M, Indirli, G, Indolfi, C, Landi, M, La Torre, F, Leone, L, Licari, A, Liotti, L, Lougaris, V, Maiello, N, Mantecca, P, Manti, S, Mariani, M, Martelli, A, Mastrorilli, C, Mastrorilli, V, Montin, D, Mori, F, Olcese, R, Ottaviano, G, Paglialunga, C, Pajno, G, Parisi, G, Pattini, S, Pecoraro, L, Pelosi, U, Pignata, C, Ricci, G, Ricci, S, Rizzi, S, Rizzo, C, Rosati, S, Rosso, P, Sangerardi, M, Santoro, A, Saretta, F, Sarti, L, Sartorio, M, Sgruletti, M, Soresina, A, Sfika, I, Sgrulletti, M, Tesse, N, Tranchino, V, Travaglini, A, Velia, M, Verduci, E, Vernich, M, Veronelli, E, Volpi, S, Votto, M, and Zicari, A

Abstract

The COVID-19 pandemic has surprised the entire population. The world has had to face an unprecedented pandemic. Only, Spanish flu had similar disastrous consequences. As a result, drastic measures (lockdown) have been adopted worldwide. Healthcare service has been overwhelmed by the extraordinary influx of patients, often requiring high intensity of care. Mortality has been associated with severe comorbidities, including chronic diseases. Patients with frailty were, therefore, the victim of the SARS-COV-2 infection. Allergy and asthma are the most prevalent chronic disorders in children and adolescents, so they need careful attention and, if necessary, an adaptation of their regular treatment plans. Fortunately, at present, young people are less suffering from COVID-19, both as incidence and severity. However, any age, including infancy, could be affected by the pandemic. Based on this background, the Italian Society of Pediatric Allergy and Immunology has felt it necessary to provide a Consensus Statement. This expert panel consensus document offers a rationale to help guide decision-making in the management of children and adolescents with allergic or immunologic diseases.

Published
2020

19. B cell-helper neutrophils stimulate immunoglobulin diversification and production: 1.18

Author

Puga, I., Cols, M., Barra, C. M., He, B., Cassis, L., Gentile, M., Comerma, L., Chorny, A., Shan, M., Xu, W., Magri, G., Knowles, D. M., Tam, W., Chiu, A., Bussel, J. B., Serrano, S., Lorente, J. A., Bellosillo, B., Lloreta, J., Juanpere, N., Alameda, F., Baró, T., de Heredia, C. D., Torán, N., Català, A., Torrebadell, M., Fortuny, C., Cusí, V., Carreras, C., Diaz, G. A., Blander, Magarian J., Farber, C. F., Silvestri, G., Cunningham-Rundles, C., Calvillo, M., Dufour, C., Notarangelo, L. D., Lougaris, V., Plebani, A., Casanova, J. L., Ganal, S. C., Diefenbach, A., Aróstegui, J. I., Juan, M., Yagüe, J., Mahlaoui, N., Donadieu, J., Chen, K., and Cerutti, A.

Published
2013

20. Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients

Author

Wong, G. K., Goldacker, S., Winterhalter, C., Grimbacher, B., Chapel, H., Lucas, M., Alecsandru, D., McEwen, D., Quinti, I., Martini, H., Schmidt, R. E., Ernst, D., Espanol, T., Vidaller, A., Carbone, J., Fernandez-Cruz, E., Lougaris, V., Plebani, A., Kutukculer, N., Gonzalez-Granado, L. I., Contreras, R., Kiani-Alikhan, S., Ibrahim, M. A. A., Litzman, J., Jones, A., Gaspar, H. B., Hammarstrom, L., Baumann, U., Warnatz, K., and Huissoon, A. P.

Published
2013
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23. Correction to: Imaging of Bronchial Pathology in Antibody Deficiency: Data from the European Chest CT Group (Journal of Clinical Immunology, (2019), 39, 1, (45-54), 10.1007/s10875-018-0577-9)

Author

Schutz, K., Alecsandru, D., Grimbacher, B., Haddock, J., Bruining, A., Driessen, G., de Vries, E., van Hagen, P. M., Hartmann, I., Fraioli, F., Milito, C., Mitrevski, M., Quinti, I., Serra, G., Kelleher, P., Loebinger, M., Litzman, J., Postranecka, V., Thon, V., Babar, J., Condliffe, A. M., Exley, A., Kumararatne, D., Screaton, N., Jones, A., Bondioni, M. P., Lougaris, V., Plebani, A., Soresina, A., Sirignano, C., Spadaro, G., Galal, N., Gonzalez-Granado, L. I., Dettmer, S., Stirling, R., Chapel, H., Lucas, M., Patel, S., Farber, C. -M., Meyts, I., Banerjee, A. K., Hackett, S., Hurst, J. R., Warnatz, K., Gathmann, B., Weidemann, J., Berthold, D., and Baumann, U.

Subjects
correction
Published
2019

24. Clinical, immunological, and molecular features of typical and atypical severe combined immunodeficiency: Report of the italian primary immunodeficiency network

Author

Cirillo, E., Cancrini, C., Azzari, C., Martino, S., Martire, B., Pession, A., Tommasini, A., Naviglio, S., Finocchi, A., Consolini, R., Pierani, P., D'Alba, I., Putti, M. C., Marzollo, A., Giardino, G., Prencipe, R., Esposito, F., Grasso, F., Scarselli, A., Di Matteo, G., Attardi, E., Ricci, S., Montin, D., Specchia, F., Barzaghi, F., Cicalese, M. P., Quaremba, G., Lougaris, V., Giliani, S., Locatelli, Franco, Rossi, P., Aiuti, A., Badolato, R., Plebani, A., Pignata, C., Locatelli F. (ORCID:0000-0002-7976-3654), Cirillo, E., Cancrini, C., Azzari, C., Martino, S., Martire, B., Pession, A., Tommasini, A., Naviglio, S., Finocchi, A., Consolini, R., Pierani, P., D'Alba, I., Putti, M. C., Marzollo, A., Giardino, G., Prencipe, R., Esposito, F., Grasso, F., Scarselli, A., Di Matteo, G., Attardi, E., Ricci, S., Montin, D., Specchia, F., Barzaghi, F., Cicalese, M. P., Quaremba, G., Lougaris, V., Giliani, S., Locatelli, Franco, Rossi, P., Aiuti, A., Badolato, R., Plebani, A., Pignata, C., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Severe combined immunodeficiencies (SCIDs) are a group of inborn errors of the immune system, usually associated with severe or life-threatening infections. Due to the variability of clinical phenotypes, the diagnostic complexity and the heterogeneity of the genetic basis, they are often difficult to recognize, leading to a significant diagnostic delay (DD). Aim of this study is to define presenting signs and natural history of SCID in a large cohort of patients, prior to hematopoietic stem cell or gene therapies. To this purpose, we conducted a 30-year retro-prospective multicenter study within the Italian Primary Immunodeficiency Network. One hundred eleven patients, diagnosed as typical or atypical SCID according to the European Society for Immune Deficiencies criteria, were included. Patients were subsequently classified based on the genetic alteration, pathogenic mechanism and immunological classification. A positive relationship between the age at onset and the DD was found. SCID patients with later onset were identified only in the last decade of observation. Syndromic SCIDs represented 28% of the cohort. Eight percent of the subjects were diagnosed in Intensive Care Units. Fifty-three percent had an atypical phenotype and most of them exhibited a discordant genotype-immunophenotype. Pre-treatment mortality was higher in atypical and syndromic patients. Our study broadens the knowledge of clinical and laboratory manifestations and genotype/phenotype correlation in patients with SCID and may facilitate the diagnosis of both typical and atypical forms of the disease in countries where newborn screening programs have not yet been implemented.

Published
2019

25. Challenges in investigating patients with isolated decreased serum IgM: The SIMcal study

Author

Janssen, Lisanne M A, van Hout, Roeland W N M, de Vries, Esther, Pignata, C, Cirillo, E, Arkwright, P D, Lougaris, V, Buckland, M, Garcia-Prat, M, d'Hebron, V, Soler-Palacin, P, Ouederni, M, Kralickova, P, Abolhassani, H, Hammerstrom, L, Aghamohamamdi, A, Santos-Pérez, J L, Sobh A, van de Werff Ten Bosch, J, Henriet, S, Kilic, S S, Karali, Y, Gonzalez-Granado, L I, Sediva, A, Huisarts & Ziekenhuis, Tranzo, Scientific center for care and wellbeing, Janssen, Lisanne M A, van Hout, Roeland W N M, de Vries, Esther, Pignata, C, Cirillo, E, Arkwright, P D, Lougaris, V, Buckland, M, Garcia-Prat, M, D'Hebron, V, Soler-Palacin, P, Ouederni, M, Kralickova, P, Abolhassani, H, Hammerstrom, L, Aghamohamamdi, A, Santos-Pérez, J L, Sobh, A, van de Werff Ten, Bosch, J, Henriet, S, Kilic, S S, Karali, Y, Gonzalez-Granado, L I, and Sediva, A

Subjects
Male, 0301 basic medicine, Pediatrics, unclassified antibody deficiency, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Immunologic Deficiency Syndromes/blood, Human Immunology, 0302 clinical medicine, Decreased serum IgM, T-Lymphocyte Subsets, Young adult, Child, Respiratory Tract Infections, IgM deficiency, biology, primary selective IgM deficiency, General Medicine, Middle Aged, Child, Preschool, Cohort, Variation and Distance, Female, medicine.symptom, Antibody, B-Lymphocyte Subsets/cytology, Adult, medicine.medical_specialty, Adolescent, Asymptomatic Diseases/epidemiology, Immunology, B-Lymphocyte Subsets, Respiratory Tract Infections/epidemiology, primary immunodeficiency, Asymptomatic, Young Adult, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, medicine, Humans, In patient, Preschool, business.industry, Immunologic Deficiency Syndromes, Infant, Newborn, Infant, Newborn, Immunoglobulin M/blood, medicine.disease, Language & Communication, T-Lymphocyte Subsets/cytology, 030104 developmental biology, Immunoglobulin M, Asymptomatic Diseases, Primary immunodeficiency, biology.protein, business, 030215 immunology
Abstract

The clinical consequences of isolated decreased serum immunoglobulin (Ig)M are not sufficiently known. Therefore, it is difficult to determine the clinical policy following such a finding. Only few reported IgM‐deficient patients fulfil the European Society for Immunodeficiencies (ESID) diagnostic criteria for selective IgM deficiency (true sIgMdef), or their diagnosis is uncertain due to insufficient laboratory data (possible sIgMdef). Decreased serum IgM is often incidentally found in asymptomatic adults. The objective of our study was to further characterize true sIgMdef and to compare the European data collected through the ESID Registry community (tertiary centres) to our previously published Dutch cohort (secondary centre). Fifteen centres (12 countries) participated with 98 patients. Patients were excluded if serum IgM was only determined once (n = 14), had normalized (n = 8), or if they also had other immunological abnormalities (n = 15). Ten patients (5 adults) completely fulfilled the ESID criteria for true sIgMdef. Age‐matched cut‐off values varied widely between centres; when using the ESID diagnostic protocol reference values, only six patients (five adults) had true sIgMdef. Because of these small numbers, further analyses were performed in patients with true or possible sIgMdef (13 adults, 48 children). Respiratory infections were commonly reported at presentation (adults 54%, children 60%). Symptomatic adults had lower serum IgM levels (mean 0.27 g/L, 95% CI 0.22‐0.31) than those without symptoms (mean 0.33 g/L, 95% CI 0.30‐0.36; P = 0.02). To be able to explore the clinical consequences of true sIgMdef, we should fully analyse and accurately describe those patients in whom a decreased serum IgM is found.

Published
2019

26. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects

Author

Schwab, C., Gabrysch, A., Olbrich, P., Patino, V., Warnatz, K., Wolff, D., Hoshino, A., Kobayashi, M., Imai, K., Takagi, M., Dybedal, I., Haddock, J.A., Sansom, D.M., Lucena, J.M., Seidl, M., Schmitt-Graeff, A., Reiser, V., Emmerich, F., Frede, N., Bulashevska, A., Salzer, U., Schubert, Desiree, Hayakawa, S., Okada, S., Kanariou, M., Kucuk, Z.Y., Chapdelaine, H., Petruzelkova, L., Sumnik, Z., Sediva, A., Slatter, M., Arkwright, P.D., Cant, A., Lorenz, H.M., Giese, T., Lougaris, V., Plebani, A., Price, C., Sullivan, K.E., Moutschen, M., Litzman, J., Freiberger, T., Veerdonk, F.L. van de, Recher, M., Albert, M.H., Hauck, F., Seneviratne, S., Schmid, J., Kolios, A., Unglik, G., Klemann, C., Speckmann, C., Ehl, S., Leichtner, A., Blumberg, R., Franke, A., Snapper, S., Zeissig, S., Cunningham-Rundles, C., Giulino-Roth, L., Elemento, O., Duckers, G., Niehues, T., Fronkova, E., Kanderova, V., Platt, C.D., Chou, J., Chatila, T.A., Geha, R., McDermott, E., Bunn, S., Kurzai, M., Schulz, A., Alsina, L., Casals, F., Deya-Martinez, A., Hambleton, S., Kanegane, H., Tasken, K., Neth, O., Grimbacher, B., Schwab, C., Gabrysch, A., Olbrich, P., Patino, V., Warnatz, K., Wolff, D., Hoshino, A., Kobayashi, M., Imai, K., Takagi, M., Dybedal, I., Haddock, J.A., Sansom, D.M., Lucena, J.M., Seidl, M., Schmitt-Graeff, A., Reiser, V., Emmerich, F., Frede, N., Bulashevska, A., Salzer, U., Schubert, Desiree, Hayakawa, S., Okada, S., Kanariou, M., Kucuk, Z.Y., Chapdelaine, H., Petruzelkova, L., Sumnik, Z., Sediva, A., Slatter, M., Arkwright, P.D., Cant, A., Lorenz, H.M., Giese, T., Lougaris, V., Plebani, A., Price, C., Sullivan, K.E., Moutschen, M., Litzman, J., Freiberger, T., Veerdonk, F.L. van de, Recher, M., Albert, M.H., Hauck, F., Seneviratne, S., Schmid, J., Kolios, A., Unglik, G., Klemann, C., Speckmann, C., Ehl, S., Leichtner, A., Blumberg, R., Franke, A., Snapper, S., Zeissig, S., Cunningham-Rundles, C., Giulino-Roth, L., Elemento, O., Duckers, G., Niehues, T., Fronkova, E., Kanderova, V., Platt, C.D., Chou, J., Chatila, T.A., Geha, R., McDermott, E., Bunn, S., Kurzai, M., Schulz, A., Alsina, L., Casals, F., Deya-Martinez, A., Hambleton, S., Kanegane, H., Tasken, K., Neth, O., and Grimbacher, B.

Abstract

Item does not contain fulltext, BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

Published
2018

28. NFKB1 regulates human NK cell maturation and effector functions

Author

Lougaris, V., Patrizi, O., Baronio, M., Tabellini, G., Tampella, G., Damiati, E., Frede, N., Meer, J.W.M. van der, Fliegauf, M., Grimbacher, B., Parolini, S., Plebani, A., Lougaris, V., Patrizi, O., Baronio, M., Tabellini, G., Tampella, G., Damiati, E., Frede, N., Meer, J.W.M. van der, Fliegauf, M., Grimbacher, B., Parolini, S., and Plebani, A.

Abstract

Contains fulltext : 169759.pdf (publisher's version ) (Closed access), NFKB1, a component of the canonical NF-kappaB pathway, was recently reported to be mutated in a limited number of CVID patients. CVID-associated mutations in NFKB2 (non-canonical pathway) have previously been shown to impair NK cell cytotoxic activity. Although a biological function of NFKB1 in non-human NK cells has been reported, the role of NFKB1 mutations for human NK cell biology and disease has not been investigated yet. We decided therefore to evaluate the role of monoallelic NFKB1 mutations in human NK cell maturation and functions. We show that NFKB1 mutated NK cells present impaired maturation, defective cytotoxicity and reduced IFN-gamma production upon in vitro stimulation. Furthermore, human IL-2 activated NFKB1 mutated NK cells fail to up-regulate the expression of the activating marker NKp44 and show reduced proliferative capacity. These data suggest that NFKB1 plays an essential novel role for human NK cell maturation and effector functions.

Published
2017

29. Relevance of biallelic vs monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes

Author

Salzer, US, Bacchelli, C, Buckridge, S, Pan-Hammar-Strom, Q, Jennings, S, Lougaris, V, Bergbreiter, A, Hagena, T, Birmelin, J, Plebani, A, Webster, A, Peter, H, Suez, D, Chapel, H, Maclean-Tooke, A, Spickett, G, Anover-Sombke, S, Ochs, H, Urschel, S, Belohradsky, B, Ugrinovic, S, Kumararatne, D, Lawrence, T, Holm, A, and Franco, J

Published
2016

30. Mutations in LRBA are Associated with a Syndrome of Immune Deficiency and Autoimmunity

Author

Lopez-Herrera, G, Tampella, G, Baronio, M, Vitali, M, Lougaris, V, Plebani, A, Pan-Hammarstroem, Q, Hammarstroem, L, Du, L, Hultenby, K, Trujillo-Vargas, C, Phadwal, K, Simon, A, Moutschen, M, Etzioni, A, Srugo, A, Melamed, D, Liu, C, Philippet, P, Dideberg, V, Aghamohammadi, A, Rezai, N, Enright, V, Stauss, H, and Herholz, P

Published
2016

32. Clinical features and follow-up in patients with 22q11.2 deletion syndrome

Author

Cancrini, C, Puliafito, P, Digilio, M, Soresina, A, Martino, S, Rondelli, R, Consolini, R, Ruga, E, Cardinale, F, Finocchi, A, Romiti, Ml, Martire, B, Bacchetta, R, Albano, V, Carotti, A, Specchia, F, Montin, D, Cirillo, E, Cocchi, G, Trizzino, A, Bossi, G, Milanesi, O, Azzari, C, Corsello, G, Pignata, C, Aiuti, A, Pietrogrande, M, Marino, B, Ugazio, A, Plebani, A, Rossi, P, Pierani, P, Gabrielli, A, Danieli, M, De Mattia, D, Sisto, C, Dammacco, F, Ranieri, G, Pession, A, Ricci, G, Minelli, P, Lougaris, V, Badolato, R, Cattaneo, R, Airò, P, Mura, R, Cossu, F, Del Giacco, S, Manconi, P, Consarino, C, Dello Russo, A, Miniero, R, Anastasio, E, Marino, S, Russo, G, Paganelli, R, Sperlì, D, Carpino, L, Aricò, M, Gambineri, E, Lippi, F, Canessa, C, Maggi, E, Romagnani, S, Matucci, A, Vultaggio, A, Gattorno, M, Castagnola, E, Nigro, G, Presta, G, Civino, A, Buzi, F, Gambaretto, G, Fasoli, S, Salpietro, C, Gallizzi, R, Dellepiane, R, Panisi, C, Fabio, G, Carrabba, M, Roncarolo, M, Biondi, A, Vallinoto, C, Poggi, V, Menna, G, Di Nardo, R, Sottile, R, Marone, G, Spadaro, G, Carli, M, Basso, G, Putti, C, Semenzato, G, Agostini, C, D'Angelo, P, Izzi, G, Bertolini, P, Zecca, M, Marseglia, G, Maccario, R, Felici, L, Favre, C, Vecchi, V, Sacchini, P, Rinaldi, G, Livadiotti, S, Simonetti, A, Stabile, A, Duse, M, Iacobini, M, Quinti, I, Fiorilli, M, Moschese, V, Cecere, F, D'Ambrosio, A, De Zan, G, Strafella, S, Tamaro, P, Rabusin, M, Tommasini, A, Tovo, P, De Carli, M, De Carli, S, Nespoli, L, Marinoni, M, Porcellini, A, Lunardi, C, Patuzzo, G, Boner, A, Degani, D, Cancrini, C, Puliafito, P, Digilio, Mc, Soresina, A, Martino, S, Rondelli, R, Consolini, R, Ruga, Em, Cardinale, F, Finocchi, A, Romiti, Ml, Martire, B, Bacchetta, R, Albano, V, Carotti, A, Specchia, F, Montin, D, Cirillo, E, Cocchi, G, Trizzino, A, Bossi, G, Milanesi, O, Azzari, C, Corsello, G, Pignata, C, Aiuti, Alessandro, Pietrogrande, Mc, Marino, B, Ugazio, Ag, Plebani, A, Rossi, P., Cancrini, Caterina, Puliafito, Pamela, Digilio, Maria Cristina, Soresina, Annarosa, Martino, Silvana, Rondelli, Roberto, Consolini, Rita, Ruga, Ezia Maria, Cardinale, Fabio, Finocchi, Andrea, Romiti, Maria Luisa, Martire, Baldassarre, Bacchetta, Rosa, Albano, Veronica, Carotti, Adriano, Specchia, Fernando, Montin, Davide, Cirillo, Emilia, Cocchi, Guido, Trizzino, Antonino, Bossi, Grazia, Milanesi, Ornella, Azzari, Chiara, Corsello, Giovanni, Pignata, Claudio, Pietrogrande, Maria Cristina, Marino, Bruno, Ugazio, Alberto Giovanni, Plebani, Alessandro, Rossi, Paolo, Aiuti, A, Rossi, P, Pierani, P, Gabrielli, A, Danieli, Mg, De Mattia, D, Sisto, C, Dammacco, F, Ranieri, G, Pession, A, Ricci, G, Minelli, P, Lougaris, V, Badolato, R, Cattaneo, R, Airò, P, Mura, Rm, Cossu, F, Del Giacco, S, Manconi, Pe, Consarino, C, Dello Russo, Am, Miniero, R, Anastasio, E, Marino, S, Russo, G, Paganelli, R, Sperlì, D, Carpino, L, Aricò, M, Gambineri, E, Lippi, F, Canessa, C, Maggi, E, Romagnani, S, Matucci, A, Vultaggio, A, Gattorno, M, Castagnola, E, Nigro, G, Presta, G, Civino, A, Buzi, F, Gambaretto, G, Fasoli, S, Salpietro, C, Gallizzi, R, Dellepiane, Rm, Panisi, C, Fabio, G, Carrabba, M, Pietrogrande, M, Roncarolo, Mg, Biondi, A, Vallinoto, C, Poggi, V, Menna, G, Di Nardo, R, Sottile, R, Marone, G, Spadaro, G, Carli, M, Basso, G, Putti, C, Semenzato, G, Agostini, C, D'Angelo, P, Izzi, G, Bertolini, P, Zecca, M, Marseglia, G, Maccario, R, Felici, L, Favre, C, Vecchi, V, Sacchini, P, Rinaldi, G, Livadiotti, S, Simonetti, A, Stabile, A, Duse, M, Iacobini, M, Quinti, I, Fiorilli, M, Moschese, V, Cecere, F, D'Ambrosio, A, De Zan, G, Strafella, S, Tamaro, Paolo, Rabusin, M, Tommasini, A, Tovo, P, De Carli, M, De Carli, S, Nespoli, L, Marinoni, M, Porcellini, A, Lunardi, C, Patuzzo, G, Boner, A, Degani, D., Cancrini, C., Pulisfito, P., Digilio, M. C., Soresina, A., Martino, S., Rondelli, R., Consolini, R., Ruga, E. M., C. a. r. d. i. n. a. l. e., F., Finocchi, A., Romiti, M. L., Martire, B., Bacchetta, R., Albano, V., Carotti, A., Specchia, F., Montin, D., Cocchi, G., Trizzino, A., Bossi, G., Milanesi, O., Azzari, C., Corsello, G., Aiuti, A., Pietrogrande, M. C., Marino, B., Ugazio, A. G., Plebani, A., Digilio, MC, Ruga, EM, Romiti, ML, trizzino, A, Aiuti, Pietrogrande, MC, and Ugazio, AG

Subjects
Male, Pediatrics, 22q11.2 deletion, Delayed Diagnosis, Time Factors, Chromosomes, Human, Pair 22, Developmental Disabilities, digeorge syndrome, Sex Factor, Severity of Illness Index, Retrospective Studie, DiGeorge syndrome, Early Diagnosi, Age Factor, Prospective Studies, Neonatal hypocalcemia, Prospective cohort study, Child, medicine.diagnostic_test, Delayed Diagnosi, Primary immune disorders, Age Factors, del 22q, MIM, Abnormalities, Multiple, Adolescent, Adult, Child, Preschool, DiGeorge Syndrome, Early Diagnosis, Female, Follow-Up Studies, Genetic Testing, Humans, Infant, Infant, Newborn, Monitoring, Physiologic, Retrospective Studies, Risk Assessment, Sex Factors, Young Adult, Disease Progression, Cohort, Abnormalities, Multiple, Pediatrics, Perinatology and Child Health, Human, medicine.medical_specialty, Time Factor, Monitoring, Developmental Disabilitie, Italian Association of Pediatric Haematology and Oncology, Context (language use), Chromosomes, Follow-Up Studie, Severity of illness, medicine, 22q11DS, 22q11.2 deletion syndrome, AIEOP, Mendelian Inheritance in Man, Preschool, Physiologic, Genetic testing, Settore MED/38 - Pediatria Generale e Specialistica, business.industry, Retrospective cohort study, medicine.disease, Newborn, Prospective Studie, Pair 22, business
Abstract

Objective To investigate the clinical manifestations at diagnosis and during follow-up in patients with 22q11.2 deletion syndrome to better define the natural history of the disease. Study design A retrospective and prospective multicenter study was conducted with 228 patients in the context of the Italian Network for Primary Immunodeficiencies. Clinical diagnosis was confirmed by cytogenetic or molecular analysis. Results The cohort consisted of 112 males and 116 females; median age at diagnosis was 4 months (range 0 to 36 years 10 months). The diagnosis was made before 2 years of age in 71% of patients, predominantly related to the presence of heart anomalies and neonatal hypocalcemia. In patients diagnosed after 2 years of age, clinical features such as speech and language impairment, developmental delay, minor cardiac defects, recurrent infections, and facial features were the main elements leading to diagnosis. During follow-up (available for 172 patients), the frequency of autoimmune manifestations ( P = .015) and speech disorders ( P = .002) increased. After a median follow-up of 43 months, the survival probability was 0.92 at 15 years from diagnosis. Conclusions Our data show a delay in the diagnosis of 22q11.2 deletion syndrome with noncardiac symptoms. This study provides guidelines for pediatricians and specialists for early identification of cases that can be confirmed by genetic testing, which would permit the provision of appropriate clinical management.

Published
2014

33. Corrigendum to: 'Vaccination in immunocompromised host: Recommendations of Italian Primary Immunodeficiency Network Centers (IPINET)' [Vaccine 36 (2018) Pages 3541–3542]

Author

Martire, Baldassarre, Azzari, Chiara, Badolato, Raffaele, Canessa, Clementina, Cirillo, Emilia, Gallo, Vera, Graziani, Simona, Lorenzini, Tiziana, Milito, Cinzia, Panza, Raffaella, Moschese, Viviana, Pignata, Claudio, Martire, B, Lassandro, G, Panza, R, Vacca, A, Marasco, C, Cardinale, F, Sisto, C, Pession, A, Ricci, G, Rondelli, R, Specchia, F, Plebani, A, Badolato, R, Lougaris, V, Soresina, A, Miniero, R, Anastasio, E, Paganelli, R, Dilizia, Sperli, D, Carpino, L, Cirillo, E, Gallo, V, Giardino, G, Spadaro, G, Pecoraro, A ), Putti, Mc, Agostini, C, Cinetto, F, Trizzino, A, Bertolini, P), Arlotta, A, Marseglia, Gl, Bossi, G, Consolini, R, and Et, Al.

Subjects
ANTIBODY-RESPONSES, Secondary immunodeficiency KeyWords Plus:CHRONIC GRANULOMATOUS-DISEASE, ADVISORY-COMMITTEE, ROTAVIRUS VACCINATION, IMMUNIZATION PRACTICES, Medicine, HUMORAL IMMUNITY, Author Keywords:Vaccination, Primary immunodeficiency, Syndromic immunodeficiency, ACUTE LYMPHOBLASTIC-LEUKEMIA, CALMETTE-GUERIN, POLYSACCHARIDE VACCINATION, MENDELIAN SUSCEPTIBILITY, General Veterinary, General Immunology and Microbiology, business.industry, Public Health, Environmental and Occupational Health, medicine.disease, Virology, Vaccination, Infectious Diseases, Molecular Medicine, business, Host (network)
Published
2018

34. Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study

Author

Elkaim, E, Neven, B, Bruneau, J, Mitsui-Sekinaka, K, Stanislas, A, Heurtier, L, Lucas, CL, Matthews, H, Deau, MC, Sharapova, S, Curtis, J, Reichenbach, J, Glastre, C, Parry, DA, Arumugakani, G, McDermott, E, Kilic, SS, Yamashita, M, Moshous, D, Lamrini, H, Otremba, B, Gennery, A, Coulter, T, Quinti, I, Stephan, JL, Lougaris, V, Brodszki, N, Barlogis, V, Asano, T, Galicier, L, Boutboul, D, Nonoyama, S, Cant, A, Imai, K, Picard, C, Nejentsev, S, Molina, TJ, Lenardo, M, Savic, S, Cavazzana, M, Fischer, A, Durandy, A, and Kracker, S

Subjects
Adult, Male, Adolescent, Genotype, p110δ, Class I Phosphatidylinositol 3-Kinases, activated phosphoinositide 3-kinase δ syndrome, Biopsy, Immunology, CD8-Positive T-Lymphocytes, primary immunodeficiency, APDS2, combined immune deficiency, Cohort Studies, Young Adult, Gene Frequency, T-Lymphocyte Subsets, lymphadenopathy, P110δ-activating mutations causing senescent T cells, Immunology and Allergy, Humans, hyper-IgM, Child, Alleles, and immunodeficiency, Primary immunodeficiency, phosphoinositide 3-kinase, Immunologic Deficiency Syndromes, p85α, adenopathy, Middle Aged, antibody deficiency, Phenotype, Activated phosphoinositide 3-kinase δ syndrome, Adenopathy, And immunodeficiency, Antibody deficiency, Hyper-IgM, Immunodeficiency, Lymphadenopathy, P110δ, P85α, Phosphoinositide 3-kinase, Child, Preschool, Mutation, p110δ-activating mutations causing senescent T cells, Female, RNA Splice Sites, immunodeficiency
Abstract

Background Activated phosphoinositide 3-kinase δ syndrome (APDS) 2 (p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency [PASLI]–R1), a recently described primary immunodeficiency, results from autosomal dominant mutations in PIK3R1, the gene encoding the regulatory subunit (p85α, p55α, and p50α) of class IA phosphoinositide 3-kinases. Objectives We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort. Methods The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed. Results Mutations within splice acceptor and donor sites of exon 11 of the PIK3R1 gene lead to APDS2. Recurrent upper respiratory tract infections (100%), pneumonitis (71%), and chronic lymphoproliferation (89%, including adenopathy [75%], splenomegaly [43%], and upper respiratory tract lymphoid hyperplasia [48%]) were the most common features. Growth retardation was frequently noticed (45%). Other complications were mild neurodevelopmental delay (31%); malignant diseases (28%), most of them being B-cell lymphomas; autoimmunity (17%); bronchiectasis (18%); and chronic diarrhea (24%). Decreased serum IgA and IgG levels (87%), increased IgM levels (58%), B-cell lymphopenia (88%) associated with an increased frequency of transitional B cells (93%), and decreased numbers of naive CD4 and naive CD8 cells but increased numbers of CD8 effector/memory T cells were predominant immunologic features. The majority of patients (89%) received immunoglobulin replacement; 3 patients were treated with rituximab, and 6 were treated with rapamycin initiated after diagnosis of APDS2. Five patients died from APDS2-related complications. Conclusion APDS2 is a combined immunodeficiency with a variable clinical phenotype. Complications are frequent, such as severe bacterial and viral infections, lymphoproliferation, and lymphoma similar to APDS1/PASLI-CD. Immunoglobulin replacement therapy, rapamycin, and, likely in the near future, selective phosphoinositide 3-kinase δ inhibitors are possible treatment options.

Published
2015

35. DIFETTO DI LINFOCITI Ccr4/Ccr6+ IN PAZIENTI CON SINDROME DI IPER IgE CORRELA CON RIDUZIONE DEI LINFOCITI Th17

Author

Guadrini L, Giacomelli M, Moratto M, Caracciolo S, Nigro S, Lougaris V, Pajno G, Porta F. Salpietro A, Monfredini C, Corrente S, Soresina A, Aiuti A, Cancrini C, Ragusa G, Gallizzi R, Tommasini A, Montin D, Specchia G. G, Baraldi E, Nespoli L, Duse M, Plebani A, Badolato R., RICCI, GIAMPAOLO, Guadrini L, Giacomelli M, Moratto M, Caracciolo S, Nigro S, Lougaris V, Pajno G, Porta F. Salpietro A, Monfredini C, Corrente S, Soresina A, Aiuti A, Cancrini C, Ragusa G, Gallizzi R, Tommasini A, Montin D, Ricci G, Specchia G.G, Baraldi E, Nespoli L, Duse M, Plebani A, and Badolato R

Subjects
SINDROME DA IPER IGE, LINFOCITI TH17
Published
2012

36. Reduced NK cell activity and abnormal expression of CCR7 and CXCR1 by NK cells analysis in patients with DOCK8 deficiency

Author

Tabellini, G., Caracciolo, S., Patrizi, O., Benassi, M., Negri, S., Giacomelli, M., Lougaris, V., Plebani, A., Badolato, R., and Parolini, S.

Subjects
primary immunodeficiencies, NK cells, chemokine receptors
Abstract

DOCK8-deficiency is an autosomal recessive primary immunodeficiency that is characterized by multiple abnormalities of the immune system, including a defect of NK cell cytotoxicity which could not be restored after IL2 stimulation. Nevertheless, unanswered questions remain regarding how the absence of DOCK8 leads to predisposition for malignancy, viral, fungal, and bacterial infections. To address these questions we have analyzed NK cell phenotype and functions in patients with DOCK8 deficiency. We observed that NK cells derived from five DOCK8-deficient patients displayed dramatically reduced cytotoxicity which was partially restored after IL-2 stimulation. Analysis of activating and inhibitory NK receptors, including KIRs molecules, chemokine receptors and activation markers on gated CD56+cells by cytofluorimetric analysis showed a substantial defect of CCR7 expression by CD56bright NK cells. Noteworthy, we have also detected the expression of NKG2C and of the chemokine receptor CXCR1 on CD56dull NK cells in DOCK8-deficient cells. Because CCR7 expression by NK cells can be induced after cell culture with IL18 we stimulated NK cells from DOCK-8 deficient patients with IL18. Despite unstimulated CD56bright NK cells from DOCK8 patients showed reduced CCR7 expression, we could not detect any increase of CCR7 on CD56 dull and bright NK cells of DOCK8-deficient patients, whereas CCR7 expression on NK cells derived from healthy donors significantly increased from 5% to 17%.Taken together our results suggest that NK cells of DOCK-8 deficient patients show reduced cytotoxicity and abnormal expression of the chemokine receptors CXCR1 and CCR7 suggesting an abnormal recruitment of these cells to secondary lymphoid organs., Italian Journal of Anatomy and Embryology, Vol 118, No 2 (Supplement) 2013

Published
2014
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38. DELETERIOUS LRBA MUTATIONS IN A NOVEL SYNDROME OF IMMUNE DEFICIENCY AND AUTOIMMUNITY

Author

GABRIELA LOPEZ HERRERA, Tampella, G., Pan-Hammarstrom, Q., Herholz, P., Trujillo-Vargas, C. M., Phadwal, K., Simon, A. K., Moutschen, M., Etzioni, A., Mory, A., Srugo, I., Melamed, D., Hultenby, K., Liu, C., Baronio, M., Vitali, M., Philippet, P., Dideberg, V., Aghamohammadi, A., Rezai, N., Enright, V., Du, L., Salzer, U., Eibel, H., Pfeifer, D., Veelken, H., Stauss, H., Lougaris, V., Plebani, A., Gertz, E. M., Schaeffer, A. A., Hammarstrom, L., and Grimbacher, B.

Published
2012

39. Dock8 deficiency and a diagnostic score to differentiate it from other Hyper-IGE syndromes

Author

Engelhardt, K. R., Gertz, E. M., Keleş, S., Schaeffer, Alejandro A., Ceja, R., Sassi, A., Massaad, M. J., Mellouli, F., Benmustapha, I., Khemiri, M., Etzioni, A., Freeman, A. F., Thiel, J., Schulze, I., Al-Herz, W., Metin, A., Sanal, O., Yeganeh, M., Niehues, T., Siepermann, K., Ünal, E., Patıroğlu, T., Dasouki, M., Yılmaz, Mustafa, Genel, F., Aytekin, C., Kütükçüler, N., Somer, Ayper, Kılıç, M., Reisli, I., Camcıoğlu, Y., Gennery, A. R., Cant, A. J., Jones, A., Gaspar, H. B., Arkwright, P. D., Pietrogrande, M. C., Baz, Z., Al-Tamemi, Salem, Lougaris, V., Lefranc, G., Megarbane, Andre, Boutros, J., Galal, N., Bejaoui, Mohamed, Barbouche, R., Geha, R. S., Chatila, T. A., Grimbacher, B., Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları Anabilim Dalı/Çocuk İmmünolojisi Bölümü., Kılıç, Sara Şebnem, and AAH-1658-2021

Subjects
Immunology
Abstract

Bu çalışma, 3-6 Ekim 2012'de Floransa[İtalya]'da düzenlenen 15. Biennial Meeting European-Society-for-Immunodeficiency (ESID)'de bildiri olarak sunulmuştur. European Soc Immunodeficiency (ESID) Int Nursing Grp Immunodeficiencies (INGID) Int Patient Org Primary Immunodeficiencies (IPOPI)

Published
2012

41. Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease causing from disease modifying TNFRSF13B variants in antibody deficiency syndromes

Author

Salzer, U, Bacchelli, C, Buckridge, S, PAN HAMMARSTROM, Q, Jennings, S, Lougaris, V, Bergbreiter, A, Hagena, T, Birmelin, J, Plebani, Alessandro, Webster, Adb, Peter, Hh, Suez, D, Chapel, H, MACLEAN TOOKE, A, Spickett, Gp, ANOVER SOMBKE, S, Ochs, Hd, Urschel, S, Belohradsky, Bh, Ugrinovich, S, Kumararatne, Lawrence, Tc, Holm, Am, Franco, Jl, Schulze, I, Schneider, P, Gertz, Em, Shaffer, Aa, Hammarstrom, L, Thrasher, Aj, Gaspar, Hb, and Grimbacher, B.

Subjects
TACI mutations, common variable immunodeficiency
Published
2009

42. Relevance of biallelic vs monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes

Author

Salzer, US, Bacchelli, C, Buckridge, S, Pan-Hammar-Strom, Q, Jennings, S, Lougaris, V, Bergbreiter, A, Hagena, T, Birmelin, J, Plebani, A, Webster, ADB, Peter, HH, Suez, D, Chapel, H, Maclean-Tooke, A, Spickett, GP, Anover-Sombke, S, Ochs, HD, Urschel, S, Belohradsky, BH, Ugrinovic, S, Kumararatne, DS, Lawrence, TC, Holm, AM, Franco, JL, Schulze, I, Schneider, P, Gertz, ME, Schaeffer, AA, Hammarstrom, L, and Thrasher, AJ

Published
2008

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