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1. Antibody Deficiency in Patients with Biallelic KARS1 Mutations

Author

Saettini, F, Guerra, F, Fazio, G, Bugarin, C, Mcmillan, H, Ohtake, A, Ardissone, A, Itoh, M, Giglio, S, Cappuccio, G, Giardino, G, Romano, R, Quadri, M, Gasperini, S, Moratto, D, Chiarini, M, Akira, I, Fukuhara, Y, Hayakawa, I, Okazaki, Y, Mauri, M, Piazza, R, Cazzaniga, G, Biondi, A, Saettini F., Guerra F., Fazio G., Bugarin C., McMillan H. J., Ohtake A., Ardissone A., Itoh M., Giglio S., Cappuccio G., Giardino G., Romano R., Quadri M., Gasperini S., Moratto D., Chiarini M., Akira I., Fukuhara Y., Hayakawa I., Okazaki Y., Mauri M., Piazza R., Cazzaniga G., Biondi A., Saettini, F, Guerra, F, Fazio, G, Bugarin, C, Mcmillan, H, Ohtake, A, Ardissone, A, Itoh, M, Giglio, S, Cappuccio, G, Giardino, G, Romano, R, Quadri, M, Gasperini, S, Moratto, D, Chiarini, M, Akira, I, Fukuhara, Y, Hayakawa, I, Okazaki, Y, Mauri, M, Piazza, R, Cazzaniga, G, Biondi, A, Saettini F., Guerra F., Fazio G., Bugarin C., McMillan H. J., Ohtake A., Ardissone A., Itoh M., Giglio S., Cappuccio G., Giardino G., Romano R., Quadri M., Gasperini S., Moratto D., Chiarini M., Akira I., Fukuhara Y., Hayakawa I., Okazaki Y., Mauri M., Piazza R., Cazzaniga G., and Biondi A.

Abstract

Biallelic KARS1 mutations cause KARS-related diseases, a rare syndromic condition encompassing central and peripheral nervous system impairment, heart and liver disease, and deafness. KARS1 encodes the t-RNA synthase of lysine, an aminoacyl-tRNA synthetase, involved in different physiological mechanisms (such as angiogenesis, post-translational modifications, translation initiation, autophagy and mitochondrial function). Although patients with immune-hematological abnormalities have been individually described, results have not been collectively discussed and functional studies investigating how KARS1 mutations affect B cells have not been performed. Here, we describe one patient with severe developmental delay, sensoneurinal deafness, acute disseminated encephalomyelitis, hypogammaglobulinemia and recurrent infections. Pathogenic biallelic KARS1 variants (Phe291Val/ Pro499Leu) were associated with impaired B cell metabolism (decreased mitochondrial numbers and activity). All published cases of KARS-related diseases 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. Seventeen patients with KARS-related diseases were identified. Recurrent/severe infections (9/17) and B cell abnormalities (either B cell lymphopenia [3/9], hypogammaglobulinemia [either IgG, IgA or IgM; 6/15] or impaired vaccine responses [4/7]) were frequently reported. Immunoglobulin replacement therapy was given in five patients. Full immunological assessment is warranted in these patients, who may require detailed investigation and specific supportive treatment.

Published
2023

2. Correction to: Antibody Deficiency in Patients with Biallelic KARS1 Mutations (Journal of Clinical Immunology, (2023), 43, 8, (2115-2125), 10.1007/s10875-023-01584-7)

Author

Saettini F., Saettini, F, Guerra, F, Fazio, G, Bugarin, C, Mcmillan, H, Ohtake, A, Ardissone, A, Itoh, M, Giglio, S, Cappuccio, G, Giardino, G, Romano, R, Quadri, M, Gasperini, S, Moratto, D, Chiarini, M, Ishiguro, A, Fukuhara, Y, Hayakawa, I, Okazaki, Y, Mauri, M, Piazza, R, Cazzaniga, G, Biondi, A, Saettini F., Guerra F., Fazio G., Bugarin C., McMillan H. J., Ohtake A., Ardissone A., Itoh M., Giglio S., Cappuccio G., Giardino G., Romano R., Quadri M., Gasperini S., Moratto D., Chiarini M., Ishiguro A., Fukuhara Y., Hayakawa I., Okazaki Y., Mauri M., Piazza R., Cazzaniga G., Biondi A., Saettini F., Saettini, F, Guerra, F, Fazio, G, Bugarin, C, Mcmillan, H, Ohtake, A, Ardissone, A, Itoh, M, Giglio, S, Cappuccio, G, Giardino, G, Romano, R, Quadri, M, Gasperini, S, Moratto, D, Chiarini, M, Ishiguro, A, Fukuhara, Y, Hayakawa, I, Okazaki, Y, Mauri, M, Piazza, R, Cazzaniga, G, Biondi, A, Saettini F., Guerra F., Fazio G., Bugarin C., McMillan H. J., Ohtake A., Ardissone A., Itoh M., Giglio S., Cappuccio G., Giardino G., Romano R., Quadri M., Gasperini S., Moratto D., Chiarini M., Ishiguro A., Fukuhara Y., Hayakawa I., Okazaki Y., Mauri M., Piazza R., Cazzaniga G., and Biondi A.

Abstract

During the submission of the accepted manuscript, first names and surnames had been inverted. The list of authors has been corrected above. The original version has been corrected.

Published
2023

3. Identical EP300 variant leading to Rubinstein–Taybi syndrome with different clinical and immunologic phenotype

Author

Saettini, F, Fazio, G, Bonati, M, Moratto, D, Massa, V, Di Fede, E, Castiglioni, S, Marchetti, D, Chiarini, M, Sottini, A, Iascone, M, Cazzaniga, G, Imberti, L, Biondi, A, Gervasini, C, Badolato, R, Saettini F., Fazio G., Bonati M. T., Moratto D., Massa V., Di Fede E., Castiglioni S., Marchetti D., Chiarini M., Sottini A., Iascone M., Cazzaniga G., Imberti L., Biondi A., Gervasini C., Badolato R., Saettini, F, Fazio, G, Bonati, M, Moratto, D, Massa, V, Di Fede, E, Castiglioni, S, Marchetti, D, Chiarini, M, Sottini, A, Iascone, M, Cazzaniga, G, Imberti, L, Biondi, A, Gervasini, C, Badolato, R, Saettini F., Fazio G., Bonati M. T., Moratto D., Massa V., Di Fede E., Castiglioni S., Marchetti D., Chiarini M., Sottini A., Iascone M., Cazzaniga G., Imberti L., Biondi A., Gervasini C., and Badolato R.

Abstract

The Rubinstein–Taybi syndrome (RSTS) is a rare developmental disorder characterized by craniofacial dysmorphisms, broad thumbs and toes, intellectual disability, growth deficiency, and recurrent infections. Mutations in the cyclic adenosine monophosphate response element-binding protein (CREB)-binding protein (CREBBP) or in the E1A-associated protein p300 (EP300) genes have been demonstrated in 55% (RSTS1) and up to 8% of the patients (RSTS2), respectively. Dysfunction of immune response has been reported in a subgroup of individuals with RSTS. Here we characterize two patients carrying the same EP300 variant and distinctive RSTS features (including congenital heart abnormalities, short stature, feeding problems, and gastroesophageal reflux). Whole exome sequencing did not support a dual molecular diagnosis hypothesis. Nonetheless, patients showed distinct clinical manifestations and immunological features. The most severe phenotype was associated with reduced T-cell production and diversity. This latter feature was confirmed in a control group of four RSTS patients.

Published
2022

5. When to suspect GATA2 deficiency in pediatric patients: from complete blood count to diagnosis

Author

Saettini, F, Coliva, T, Vendemini, F, Moratto, D, Savoldi, G, Borlenghi, E, Masetti, R, Niemeyer, C, Biondi, A, Balduzzi, A, Bonanomi, S, Saettini F., Coliva T., Vendemini F., Moratto D., Savoldi G., Borlenghi E., Masetti R., Niemeyer C. M., Biondi A., Balduzzi A., Bonanomi S., Saettini, F, Coliva, T, Vendemini, F, Moratto, D, Savoldi, G, Borlenghi, E, Masetti, R, Niemeyer, C, Biondi, A, Balduzzi, A, Bonanomi, S, Saettini F., Coliva T., Vendemini F., Moratto D., Savoldi G., Borlenghi E., Masetti R., Niemeyer C. M., Biondi A., Balduzzi A., and Bonanomi S.

Published
2021

6. Case Report: Hypomorphic Function and Somatic Reversion in DOCK8 Deficiency in One Patient With Two Novel Variants and Sclerosing Cholangitis

Author

Saettini, F, Fazio, G, Moratto, D, Galbiati, M, Zucchini, N, Ippolito, D, Dinelli, M, Imberti, L, Mauri, M, Melzi, M, Bonanomi, S, Gerussi, A, Pinelli, M, Barisani, C, Bugarin, C, Chiarini, M, Giacomelli, M, Piazza, R, Cazzaniga, G, Invernizzi, P, Giliani, S, Badolato, R, Biondi, A, Saettini F., Fazio G., Moratto D., Galbiati M., Zucchini N., Ippolito D., Dinelli M. E., Imberti L., Mauri M., Melzi M. L., Bonanomi S., Gerussi A., Pinelli M., Barisani C., Bugarin C., Chiarini M., Giacomelli M., Piazza R., Cazzaniga G., Invernizzi P., Giliani S. C., Badolato R., Biondi A., Saettini, F, Fazio, G, Moratto, D, Galbiati, M, Zucchini, N, Ippolito, D, Dinelli, M, Imberti, L, Mauri, M, Melzi, M, Bonanomi, S, Gerussi, A, Pinelli, M, Barisani, C, Bugarin, C, Chiarini, M, Giacomelli, M, Piazza, R, Cazzaniga, G, Invernizzi, P, Giliani, S, Badolato, R, Biondi, A, Saettini F., Fazio G., Moratto D., Galbiati M., Zucchini N., Ippolito D., Dinelli M. E., Imberti L., Mauri M., Melzi M. L., Bonanomi S., Gerussi A., Pinelli M., Barisani C., Bugarin C., Chiarini M., Giacomelli M., Piazza R., Cazzaniga G., Invernizzi P., Giliani S. C., Badolato R., and Biondi A.

Abstract

DOCK8 deficiency is a combined immunodeficiency due to biallelic variants in dedicator of cytokinesis 8 (DOCK8) gene. The disease has a wide clinical spectrum encompassing recurrent infections (candidiasis, viral and bacterial infections), virally driven malignancies and immune dysregulatory features, including autoimmune (cytopenia and vasculitis) as well as allergic disorders (eczema, asthma, and food allergy). Hypomorphic function and somatic reversion of DOCK8 has been reported to result in incomplete phenotype without IgE overproduction. Here we describe a case of DOCK8 deficiency in a 8-year-old Caucasian girl. The patient’s disease was initially classified as autoimmune thrombocytopenia, which then evolved toward a combined immunodeficiency phenotype with recurrent infections, persistent EBV infection and lymphoproliferation. Two novel variants (one deletion and one premature stop codon) were characterized, resulting in markedly reduced, but not absent, DOCK8 expression. Somatic reversion of the DOCK8 deletion was identified in T cells. Hypomorphic function and somatic reversion were associated with restricted T cell repertoire, decreased STAT5 phosphorylation and impaired immune synapse functioning in T cells. Although the patient presented with incomplete phenotype (absence of markedly increase IgE and eosinophil count), sclerosing cholangitis was incidentally detected, thus indicating that hypomorphic function and somatic reversion of DOCK8 may delay disease progression but do not necessarily prevent from severe complications.

Published
2021

7. Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency

Author

Saettini, F, Poli, C, Vengoechea, J, Bonanomi, S, Orellana, J, Fazio, G, Rodriguez III, F, Noguera, L, Booth, C, Jarur-Chamy, V, Shams, M, Iascone, M, Vukic, M, Gasperini, S, Quadri, M, Seijas, A, Rivers, E, Mauri, M, Badolato, R, Cazzaniga, G, Bugarin, C, Gaipa, G, Kroes, W, Moratto, D, van Oostaijen-Ten Dam, M, Baas, F, van der Maarel, S, Piazza, R, Coban-Akdemir, Z, Lupski, J, Yuan, B, Chinn, I, Daxinger, L, Biondi, A, Saettini F., Poli C., Vengoechea J., Bonanomi S., Orellana J. C., Fazio G., Rodriguez III F. H., Noguera L. P., Booth C., Jarur-Chamy V., Shams M., Iascone M., Vukic M., Gasperini S., Quadri M., Seijas A. B., Rivers E., Mauri M., Badolato R., Cazzaniga G., Bugarin C., Gaipa G., Kroes W. G. M., Moratto D., van Oostaijen-Ten Dam M. M., Baas F., van der Maarel S., Piazza R., Coban-Akdemir Z. H., Lupski J. R., Yuan B., Chinn I. K., Daxinger L., Biondi A., Saettini, F, Poli, C, Vengoechea, J, Bonanomi, S, Orellana, J, Fazio, G, Rodriguez III, F, Noguera, L, Booth, C, Jarur-Chamy, V, Shams, M, Iascone, M, Vukic, M, Gasperini, S, Quadri, M, Seijas, A, Rivers, E, Mauri, M, Badolato, R, Cazzaniga, G, Bugarin, C, Gaipa, G, Kroes, W, Moratto, D, van Oostaijen-Ten Dam, M, Baas, F, van der Maarel, S, Piazza, R, Coban-Akdemir, Z, Lupski, J, Yuan, B, Chinn, I, Daxinger, L, Biondi, A, Saettini F., Poli C., Vengoechea J., Bonanomi S., Orellana J. C., Fazio G., Rodriguez III F. H., Noguera L. P., Booth C., Jarur-Chamy V., Shams M., Iascone M., Vukic M., Gasperini S., Quadri M., Seijas A. B., Rivers E., Mauri M., Badolato R., Cazzaniga G., Bugarin C., Gaipa G., Kroes W. G. M., Moratto D., van Oostaijen-Ten Dam M. M., Baas F., van der Maarel S., Piazza R., Coban-Akdemir Z. H., Lupski J. R., Yuan B., Chinn I. K., Daxinger L., and Biondi A.

Abstract

Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compoundheterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip12/2 animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.

Published
2021

8. P1450: AUTOLOGOUS STEM CELL TRANSPLANTATION INDUCES HIGHER LEVEL OF EXHAUSTED T-CELLS IN DLBCL PATIENTS BEFORE LEUKAPHERESIS FOR CAR-T CELL THERAPY.

Author

Farina, M., primary, Chiarini, M., additional, Almici, C., additional, Beghin, A., additional, Accorsi Buttini, E., additional, Galvagni, A., additional, Ferrari, E., additional, Bianchetti, A., additional, Zuccalà, F., additional, Piva, S., additional, Volonghi, I., additional, Poli, L., additional, Moratto, D., additional, Leoni, A., additional, Re, F., additional, Bosio, K., additional, Bernardi, S., additional, Polverelli, N., additional, Turra, A., additional, Morello, E., additional, Cattaneo, C., additional, Lanfranchi, A., additional, Malagola, M., additional, Brugnoni, D., additional, Re, A., additional, and Russo, D., additional

Published
2022
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9. 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

13. Generation of induced Pluripotent Stem Cells (UNIBSi008-A, UNIBSi008-B, UNIBSi008-C) from an Ataxia-Telangiectasia (AT) patient carrying a novel homozygous deletion in ATM gene

Author

Masneri, S., primary, Ferraro, R.M., additional, Lanzi, G., additional, Piovani, G., additional, Mori, L., additional, Barisani, C., additional, Moratto, D., additional, Plebani, A., additional, Badolato, R., additional, Soresina, A., additional, and Giliani, S., additional

Published
2019
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18. A novel EP300 mutation associated with Rubinstein-Taybi syndrome type 2 presenting as combined immunodeficiency

Author

Saettini, F, Moratto, D, Grioni, A, Maitz, S, Iascone, M, Rizzari, C, Pavan, F, Spinelli, M, Bettini, L, Biondi, A, Badolato, R, Saettini, Francesco, Moratto, Daniele, Grioni, Andrea, Maitz, Silvia, Iascone, Maria, Rizzari, Carmelo, Pavan, Fabio, Spinelli, Marco, Bettini, Laura Rachele, Biondi, Andrea, Badolato, Raffaele, Saettini, F, Moratto, D, Grioni, A, Maitz, S, Iascone, M, Rizzari, C, Pavan, F, Spinelli, M, Bettini, L, Biondi, A, Badolato, R, Saettini, Francesco, Moratto, Daniele, Grioni, Andrea, Maitz, Silvia, Iascone, Maria, Rizzari, Carmelo, Pavan, Fabio, Spinelli, Marco, Bettini, Laura Rachele, Biondi, Andrea, and Badolato, Raffaele

Published
2018

21. PROSPECTIVE STUDY OF 84 PATIENTS WITH WISKOTT-ALDRICH SYNDROME AND X-RECESSIVE PIASTRINOPENIA: RESULTS OF THE APPLICATION OF COMMON PROTOCOL FOR DIAGNOSIS AND TREATMENT OF WAS/XLT

Author

Soresina, A., Notarangelo, L. D., Ventura, A., Locatelli, F., Dufour, C., Galanello, R., Zanesco, L., Biondi, A., Mattia, D., Aiuti, A., Maurizio Arico', Azzari, C., Cornelli, P. E., Rossi, P., Martino, S., Specchia, F., Pignata, C., Izzi, G., Mazza, C., Moratto, D., Giliani, S., Rondelli, R., Pession, A., Ugazio, A. G., Plebani, A., Pietrogrande, M. C., Porta, F., Soresina, A., Notarangelo, L. D., Ventura, A., Locatelli, F., Dufour, C., Galanello, R., Zanesco, L., Biondi, A., De Mattia, D., Aiuti, A., Arico, M., Azzari, C., Cornelli, P. E., Rossi, P., Martino, S., Specchia, F., Pignata, Claudio, Izzi, G., Mazza, C., Moratto, D., Giliani, S., Rondelli, R., Pession, A., Ugazio, A. G., Plebani, A., Pietrogrande, M. C., and Porta, F.

Published
2012

29. Application of common recommendations for diagnosis and treatment of Wiskott-Aldrich syndrome and X-recessive piastrinopenia: clinical and immunological characteristics of 65 patients with WAS/XLT

Author

Soresina, S. A., Mazzolari, E., Notarangelo, L. D., Ventura, A., Locatelli, F., Dufour, C., Galanello, R., Zanesco, L., Izzi, G., Mattia, D., Azzari, C., Cornelli, P. E., PAOLO ROSSI, Mazza, C., Moratto, D., Giliani, S., Rondelli, R., Pession, A., Ugazio, A. G., and Plebani, A.

Published
2008

37. Presenilin 1 protein directly interacts with Bcl-2.

Author

Alberici, A, Moratto, D, Benussi, L, Gasparini, L, Ghidoni, R, Gatta, L B, Finazzi, D, Frisoni, G B, Trabucchi, M, Growdon, J H, Nitsch, R M, and Binetti, G

Abstract

Presenilin proteins are involved in familial Alzheimer's disease, a neurodegenerative disorder characterized by massive death of neurons. We describe a direct interaction between presenilin 1 (PS1) and Bcl-2, a key factor in the regulation of apoptosis, by yeast two-hybrid interaction system, by co-immunoprecipitation, and by cross-linking experiments. Our data show that PS1 and Bcl-2 assemble into a macromolecular complex, and that they are released from this complex in response to an apoptotic stimulus induced by staurosporine. The results support the idea of cross-talk between these two proteins during apoptosis.

Published
1999

42. Burden of Skin Disease in Selective IgA Deficiency and Common Variable Immunodeficiency

Author

Gualdi G, Lougaris V, Baronio M, Vitali M, Tampella G, Moratto D, Tanghetti P, paola monari, Calzavara-Pinton P, and Plebani A

Subjects
Male, Adolescent, IgA Deficiency, Vitiligo, Alopecia, Dermatitis, Atopic, Cohort Studies, Young Adult, Common Variable Immunodeficiency, Acne Vulgaris, Humans, Psoriasis, Female, Longitudinal Studies, Prospective Studies, Skin Diseases, Infectious, Child

43. Pseudomonas aeruginosa severe skin infection in a toddler with x-linked agammaglobulinemia due to a novel BTK mutation

Author

Niccolo Riccardi, Rotulo, G. A., Favilli, F., Loy, A., Moratto, D., Giliani, S., Mesini, A., Romanini, M. V., Volpi, S., Moscatelli, A., and Castagnola, E.

Subjects
Male, Agammaglobulinemia, Leg Ulcer, Mutation, Pseudomonas aeruginosa, Agammaglobulinaemia Tyrosine Kinase, Humans, Infant, Genetic Diseases, X-Linked, Pseudomonas Infections, Skin Diseases, Bacterial, Negative-Pressure Wound Therapy
Abstract

Agammaglobulinemia is a congenital deficit of humoral immunity characterized by a decreased level or complete absence of immunoglobulins and profound reduction of B-lymphocytes associated with an increased risk of life-threatening bacterial infection. We report a case of invasive Pseudomonas aeruginosa severe skin and soft tissue infection treated with vacuum-assisted closure and antibiotics in a toddler with a previously unreported mutation of the Bruton tyrosin kinase gene.

44. When to suspect GATA2 deficiency in pediatric patients: from complete blood count to diagnosis

Author

Francesco Saettini, Sonia Bonanomi, F Vendemini, Tiziana Coliva, G Savoldi, Adriana Balduzzi, Riccardo Masetti, Daniele Moratto, Charlotte M. Niemeyer, E Borlenghi, Andrea Biondi, Saettini F., Coliva T., Vendemini F., Moratto D., Savoldi G., Borlenghi E., Masetti R., Niemeyer C.M., Biondi A., Balduzzi A., Bonanomi S., Saettini, F, Coliva, T, Vendemini, F, Moratto, D, Savoldi, G, Borlenghi, E, Masetti, R, Niemeyer, C, Biondi, A, Balduzzi, A, and Bonanomi, S

Subjects
Male, medicine.medical_specialty, Adolescent, GATA2 Deficiency, MEDLINE, Immunophenotyping, 03 medical and health sciences, 0302 clinical medicine, Text mining, hemic and lymphatic diseases, Internal medicine, GATA2, medicine, Child, Immunodeficiency, medicine.diagnostic_test, business.industry, Complete blood count, Myeloid leukemia, Hematology, medicine.disease, Blood Cell Count, Oncology, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, Female, Suspect, business, Human, 030215 immunology
Abstract

Heterozygous GATA2 variants cause a highly heterogeneous disorder encompassing myelodysplasia (MDS), acute myeloid leukemia (AML), infection susceptibility, immunodeficiency, pulmonary dysfunction ...

Published
2021
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45. SH2-domain mutations in STAT3 in hyper-IgE syndrome patients result in impairment of IL-10 function

Author

Cristina Bertulli, Alessandro Plebani, Marco A. Cassatella, Daniele Moratto, Raffaele Badolato, Giampaolo Ricci, Mauro Giacomelli, Flavia Bazzoni, Nicola Tamassia, Patrizia Bertolini, Giacomelli, MAURO SIMONE, Tamassia, N, Moratto, D, Bertolini, P, Ricci, G, Bertulli, C, Plebani, A, Cassatella, M, Bazzoni, F, Badolato, R., Giacomelli M., Tamassia N., Moratto D., Bertolini P., Ricci G., Bertulli C., Plebani A., Cassatella M., Bazzoni F., and Badolato R.

Subjects
Lipopolysaccharides, Male, Neutrophils, STAT3, Hyper-IgE syndrome (HIES), IL-10, Suppressor of Cytokine Signaling Proteins, Immunoglobulin E, Monocyte, DC, Monocytes, STAT3, 0302 clinical medicine, DCs, IL-10, IL-1 receptor antagonist, Immunology and Allergy, Myeloid Cells, SOCS3, Phosphorylation, Child, Cells, Cultured, 0303 health sciences, biology, Interleukin-12, 3. Good health, Interleukin-10, Interleukin 10, Child, Preschool, Interleukin 12, Tumor necrosis factor alpha, Female, medicine.symptom, Job Syndrome, Signal Transduction, Adult, STAT3 Transcription Factor, Adolescent, Immunology, Inflammation, Peripheral blood mononuclear cell, src Homology Domains, 03 medical and health sciences, medicine, Humans, Interleukin 8, RNA, Messenger, 030304 developmental biology, Base Sequence, Interleukin-6, Tumor Necrosis Factor-alpha, Gene Expression Profiling, Interleukin-8, Dendritic Cells, Sequence Analysis, DNA, Interleukin 1 Receptor Antagonist Protein, Suppressor of Cytokine Signaling 3 Protein, Hyper-IgE syndrome (HIES), biology.protein, 030215 immunology
Abstract

Autosomal-dominant hyper-IgE syndrome (AD-HIES) is a primary immunodeficiency caused by STAT3 mutations. This inherited condition is characterized by eczema, staphylococcal cold abscesses and recurrent pulmonary infections. Given that STAT3 is involved in IL-10 signaling, we examined the immunoregulatory role of IL-10 in inflammation by studying the effects of IL-10 on monocytes, neutrophils and monocyte-derived DCs from HIES subjects. Analysis of gene expression in PBMCs and neutrophils isolated from HIES patients and stimulated with LPS in the presence of IL-10 showed reduced expression of IL1RN, which encodes IL-1 receptor antagonist (IL-1ra), and SOCS3 mRNA but increased CXCL8 mRNA expression. Moreover, secretion of the anti-inflammatory protein IL-1ra was reduced in AD-HIES patients. DCs from HIES patients secreted higher levels of TNF-α, IL-6 and, to a lesser extent, IL-12 when these cells were cultured in the presence of IL-10. These results suggest that IL-10 activity is affected in myeloid cells (e.g. monocytes, DCs) of HIES patients. Impairment of IL-10 signaling in patients with AD-HIES might result in an altered balance between pro-inflammatory and anti-inflammatory signals and might lead to persistent inflammation and delayed healing after infections.

Published
2011

46. Abnormal B-Cell Maturation and Increased Transitional B Cells in CBL Syndrome

Author

Saettini, Francesco, Coliva, Tiziana Angela, Vendemini, Francesca, Galbiati, Marta, Bugarin, Cristina, Masetti, Riccardo, Moratto, Daniele, Chiarini, Marco, Guerra, Fabiola, Iascone, Maria, Badolato, Raffaele, Cazzaniga, Giovanni, Niemeyer, Charlotte, Flotho, Christian, Biondi, Andrea, Saettini, Francesco, Coliva, Tiziana Angela, Vendemini, Francesca, Galbiati, Marta, Bugarin, Cristina, Masetti, Riccardo, Moratto, Daniele, Chiarini, Marco, Guerra, Fabiola, Iascone, Maria, Badolato, Raffaele, Cazzaniga, Giovanni, Niemeyer, Charlotte, Flotho, Christian, Biondi, Andrea, Saettini, F, Coliva, T, Vendemini, F, Galbiati, M, Bugarin, C, Masetti, R, Moratto, D, Chiarini, M, Guerra, F, Iascone, M, Badolato, R, Cazzaniga, G, Niemeyer, C, Flotho, C, and Biondi, A

Subjects
CBL, splenomegaly, Pediatrics, Perinatology and Child Health, RASopathie, ALPS, RALD, lymphocytosi, BENTA, CARD11
Abstract

CBL syndrome is a Noonan-like RASopathy with heterogeneous clinical phenotype and predisposition to juvenile myelomonocytic leukemia (JMML). Here we describe two patients with identical germline CBL mutation and clinical and immune-hematological overlapping features with autoimmune lymphoproliferative syndrome (ALPS) and B-cell expansion with NF-κB and T-cell anergy (BENTA) syndrome. Increased immature/transitional B cells can be depicted in CBL syndrome, ALPS, and BENTA. Nonetheless, our patients here described showed peculiar B-cell phenotype due to increased immature/transitional CD34+ B cells. This feature differentiates CBL syndrome from BENTA, pointing toward an abnormal proliferation of B-cell early precursors.

Published
2022

47. Identical EP300 variant leading to Rubinstein–Taybi syndrome with different clinical and immunologic phenotype

Author

Francesco Saettini, Grazia Fazio, Maria Teresa Bonati, Daniele Moratto, Valentina Massa, Elisabetta Di Fede, Silvia Castiglioni, Daniela Marchetti, Marco Chiarini, Alessandra Sottini, Maria Iascone, Giovanni Cazzaniga, Luisa Imberti, Andrea Biondi, Cristina Gervasini, Raffaele Badolato, Saettini, F, Fazio, G, Bonati, M, Moratto, D, Massa, V, Di Fede, E, Castiglioni, S, Marchetti, D, Chiarini, M, Sottini, A, Iascone, M, Cazzaniga, G, Imberti, L, Biondi, A, Gervasini, C, and Badolato, R

Subjects
EP300, Rubinstein–Taybi syndrome, inborn errors of immunity, Genetics, CREBBP, syndromic immunodeficiency, Genetics (clinical)
Abstract

The Rubinstein–Taybi syndrome (RSTS) is a rare developmental disorder characterized by craniofacial dysmorphisms, broad thumbs and toes, intellectual disability, growth deficiency, and recurrent infections. Mutations in the cyclic adenosine monophosphate response element-binding protein (CREB)-binding protein (CREBBP) or in the E1A-associated protein p300 (EP300) genes have been demonstrated in 55% (RSTS1) and up to 8% of the patients (RSTS2), respectively. Dysfunction of immune response has been reported in a subgroup of individuals with RSTS. Here we characterize two patients carrying the same EP300 variant and distinctive RSTS features (including congenital heart abnormalities, short stature, feeding problems, and gastroesophageal reflux). Whole exome sequencing did not support a dual molecular diagnosis hypothesis. Nonetheless, patients showed distinct clinical manifestations and immunological features. The most severe phenotype was associated with reduced T-cell production and diversity. This latter feature was confirmed in a control group of four RSTS patients.

Published
2022

48. Immunological Evaluation of Patients Affected with Jacobsen Syndrome Reveals Profound Not Age-Related Lymphocyte Alterations

Author

Canessa Clementina, Raffaele Badolato, Stefano Rossi, Boaz Palterer, Francesco Saettini, Marco Chiarini, Daniele Moratto, Antonio Marzollo, Alessandro Plebani, Lodi Lorenzo, Manuela Baronio, Silvia Ricci, Alessandra Sottini, Luisa Gazzurelli, Luisa Imberti, Daniele Zama, Chiara Gorio, Linda Rossini, Vassilios Lougaris, Baronio M., Saettini F., Gazzurelli L., Rossi S., Marzollo A., Ricci S., Zama D., Palterer B., Clementina C., Lorenzo L., Chiarini M., Sottini A., Imberti L., Gorio C., Rossini L., Badolato R., Plebani A., Moratto D., and Lougaris V.

Subjects
medicine.medical_specialty, CD3, Lymphocyte, Immunology, T lymphocytes, Immunoglobulins, CD16, Gastroenterology, Flow cytometry, Jacobsen syndrome, Internal medicine, White blood cell, medicine, Immunoglobulin, Killer Cells, Immunology and Allergy, Humans, Jacobsen Distal 11q Deletion Syndrome, Lymphocyte Count, Child, Immunodeficiency, B-Lymphocytes, biology, medicine.diagnostic_test, B lymphocyte, business.industry, medicine.disease, Flow Cytometry, Killer Cells, Natural, medicine.anatomical_structure, Natural, biology.protein, B lymphocytes, Antibody, business
Abstract

Purpose Jacobsen syndrome (JS) is a rare form of genetic disorder that was recently classified as a syndromic immunodeficiency. Available detailed immunological data from JS patients are limited. Methods Clinical and immunological presentation of twelve pediatric patients with JS by means of revision of clinical records, flow cytometry, real-time PCR, and lymphocyte functional testing were collected. Results Recurrent infections were registered in 6/12 patients (50%), while bleeding episodes in 2/12 (16.7%). White blood cell and absolute lymphocyte counts were reduced in 8/12 (66.7%) and 7/12 (58.3%) patients, respectively. Absolute numbers of CD3+ and CD4+ T cells were reduced in 8/12 (66.7%) and 7/12 (58.3%), respectively. Of note, recent thymic emigrants (RTE) were reduced in all tested patients (9/9), with T-cell receptor excision circle analysis (TRECs) showing a similar trend in 8/9 patients; naive CD4+ T cells were low only in 5/11 patients (45.4%). Interestingly, B-cell counts, IgM memory B cells, and IgM serum levels were reduced in 10/12 (83.3%) patients. Natural killer (NK) cell counts were mostly normal but the percentages of CD16+CD56low/- cells were expanded in 7/7 patients tested. The observed immunological alterations did not correlate with patients' age. Finally, responses to proliferative stimuli were normal at presentation for all patients, although they may deteriorate over time. Conclusions Our data suggest that patients affected with JS may display important numeric and maturational alterations in the T-, B-, and NK-cell compartments. These findings suggest that JS patients should be regularly monitored from an immunological point of view.

Published
2021

49. Case Report: Hypomorphic Function and Somatic Reversion in DOCK8 Deficiency in One Patient With Two Novel Variants and Sclerosing Cholangitis

Author

Francesco Saettini, Grazia Fazio, Daniele Moratto, Marta Galbiati, Nicola Zucchini, Davide Ippolito, Marco Emilio Dinelli, Luisa Imberti, Mario Mauri, Maria Luisa Melzi, Sonia Bonanomi, Alessio Gerussi, Marinella Pinelli, Chiara Barisani, Cristina Bugarin, Marco Chiarini, Mauro Giacomelli, Rocco Piazza, Giovanni Cazzaniga, Pietro Invernizzi, Silvia Clara Giliani, Raffaele Badolato, Andrea Biondi, Saettini, F, Fazio, G, Moratto, D, Galbiati, M, Zucchini, N, Ippolito, D, Dinelli, M, Imberti, L, Mauri, M, Melzi, M, Bonanomi, S, Gerussi, A, Pinelli, M, Barisani, C, Bugarin, C, Chiarini, M, Giacomelli, M, Piazza, R, Cazzaniga, G, Invernizzi, P, Giliani, S, Badolato, R, and Biondi, A

Subjects
sclerosing cholangitis, Somatic cell, EBV - Epstein-Barr Viru, Immunology, Reversion, Case Report, primary immumunodeficiencie, somatic reversion, thrombocytopenia, Immunoglobulin E, DOCK 8, Immune system, medicine, Immunology and Allergy, Immunodeficiency, Cytopenia, biology, business.industry, RC581-607, primary immumunodeficiencies, lymphopenia, medicine.disease, sclerosing cholangiti, EBV - Epstein-Barr Virus, biology.protein, Immunologic diseases. Allergy, Dock8, DOCK8 Deficiency, business
Abstract

DOCK8 deficiency is a combined immunodeficiency due to biallelic variants in dedicator of cytokinesis 8 (DOCK8) gene. The disease has a wide clinical spectrum encompassing recurrent infections (candidiasis, viral and bacterial infections), virally driven malignancies and immune dysregulatory features, including autoimmune (cytopenia and vasculitis) as well as allergic disorders (eczema, asthma, and food allergy). Hypomorphic function and somatic reversion of DOCK8 has been reported to result in incomplete phenotype without IgE overproduction. Here we describe a case of DOCK8 deficiency in a 8-year-old Caucasian girl. The patient’s disease was initially classified as autoimmune thrombocytopenia, which then evolved toward a combined immunodeficiency phenotype with recurrent infections, persistent EBV infection and lymphoproliferation. Two novel variants (one deletion and one premature stop codon) were characterized, resulting in markedly reduced, but not absent, DOCK8 expression. Somatic reversion of the DOCK8 deletion was identified in T cells. Hypomorphic function and somatic reversion were associated with restricted T cell repertoire, decreased STAT5 phosphorylation and impaired immune synapse functioning in T cells. Although the patient presented with incomplete phenotype (absence of markedly increase IgE and eosinophil count), sclerosing cholangitis was incidentally detected, thus indicating that hypomorphic function and somatic reversion of DOCK8 may delay disease progression but do not necessarily prevent from severe complications.

Published
2021

50. Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency

Author

Lucia Daxinger, Maria Iascone, Fred H. Rodriguez, Monique M van Oostaijen-Ten Dam, Ivan K. Chinn, Julio C Orellana, Rocco Piazza, Sonia Bonanomi, Daniele Moratto, Zeynep H. Coban-Akdemir, Wilma G. M. Kroes, Jaime Vengoechea, Manuel Quadri, Claire Booth, Valentina Jarur-Chamy, Frank Baas, Serena Gasperini, Grazia Fazio, Andrea Biondi, Loreani P Noguera, James R. Lupski, Maja Vukic, Gianni Cazzaniga, Giuseppe Gaipa, Francesco Saettini, Raffaele Badolato, Cecilia Poli, Mario Mauri, Marissa R. Shams, Elizabeth Rivers, Cristina Bugarin, Bo Yuan, Amairelys Barroeta Seijas, Silvère M. van der Maarel, Saettini, F, Poli, C, Vengoechea, J, Bonanomi, S, Orellana, J, Fazio, G, Rodriguez III, F, Noguera, L, Booth, C, Jarur-Chamy, V, Shams, M, Iascone, M, Vukic, M, Gasperini, S, Quadri, M, Seijas, A, Rivers, E, Mauri, M, Badolato, R, Cazzaniga, G, Bugarin, C, Gaipa, G, Kroes, W, Moratto, D, van Oostaijen-Ten Dam, M, Baas, F, van der Maarel, S, Piazza, R, Coban-Akdemir, Z, Lupski, J, Yuan, B, Chinn, I, Daxinger, L, and Biondi, A

Subjects
business.industry, Immunology, Hypertrophic cardiomyopathy, Cardiomyopathy, Cell Biology, Hematology, Consanguinity, Neutropenia, medicine.disease, Biochemistry, Phenotype, Uniparental disomy, Agammaglobulinemia, recurrent infections, hypertrophic cardiomyopathy, gene variant, FNIP1, medicine, business, PI3K/AKT/mTOR pathway, Exome sequencing
Abstract

Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1−/− animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.

Published
2021

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