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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

10. 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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12. 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

16. 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

18. 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

19. 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.

20. 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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21. 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

22. 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

23. 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

24. 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

25. Toll-like receptor-4 genotype in children with respiratory infections

Author

Daniele Moratto, Lucia Dora Notarangelo, Stefania Fontana, L. Barcella, Raffaele Badolato, Carmelita D’Ippolito, Marzia Duse, S. Crovella, Badolato, R, Fontana, S, Barcella, L, Moratto, D, D'Ippolito, C, Crovella, Sergio, Notarangelo, Ld, and Duse, M.

Subjects
Genotype, Immunology, Mannose, Receptors, Cell Surface, chemistry.chemical_compound, Polymorphism (computer science), Immunology and Allergy, Medicine, Humans, Respiratory system, Child, Respiratory Tract Infections, Toll-like receptor, Membrane Glycoproteins, business.industry, Toll-Like Receptors, Infant, Newborn, children, mannose, pneumonia, polymorphism, toll-like receptors, Infant, medicine.disease, Toll-Like Receptor 4, Pneumonia, chemistry, Child, Preschool, business
Published
2004

26. X-chromosome inactivation analysis in a female carrier of FOXP3 mutation

Author

M. Andolina, Lucia Dora Notarangelo, Alberto Tommasini, Simona Ferrari, Raffaele Badolato, Daniele Moratto, Doroti Pirulli, Michele Boniotto, Tommasini, A., Ferrari, S., Moratto, D., Badolato, R., Boniotto, M., Pirulli, D., Notarangelo, L. D., and Andolina, M.

Subjects
Male, Type 1, Diarrhea, Dosage Compensation, DNA Mutational Analysis, Lymphocyte Activation, Clinical Studies, Immunology and Allergy, Cytotoxic T cell, Child, biology, FOXP3, Forkhead Transcription Factors, Syndrome, Missense, Point Mutation, Syndrome, DNA-Binding Proteins, medicine.anatomical_structure, Dosage Compensation, Female, Type 1, Adult, Diarrhea, Heterozygote, Genotype, T cell, Immunology, Mutation, Missense, Endocrine System Diseases, CD19, X-inactivation, Genetic, Endocrine System Diseases, Female, Forkhead Transcription Factors, Genotype, Heterozygote, Humans, Lymphocyte Activation, Lymphocyte Subsets, Lymphoproliferative Disorders, Male, Mutation, Genetic, Dosage Compensation, Genetic, Diabetes Mellitus, medicine, Humans, Point Mutation, Adult, Amino Acid Substitution, Child, DNA Mutational Analysis, DNA-Binding Proteins, Diabetes Mellitu, T lymphocyte, IPEX syndrome, medicine.disease, Molecular biology, Lymphocyte Subsets, Lymphoproliferative Disorders, Diabetes Mellitus, Type 1, Amino Acid Substitution, Mutation, Adult, Amino Acid Substitution, Child, DNA Mutational Analysis, DNA-Binding Proteins, Diabetes Mellitus, biology.protein, Missense, CD8
Abstract

SUMMARYImmune dysregulation, polyendocrinopathy and enteropathy with X-linked inheritance (IPEX) is a serious disease arising from mutations in FOXP3. This gene codifies for a transcription factor whose dysfunction results in hyperactivation of T cells. It is not clear, however, why an intermediate phenotype is not seen in heterozygous females, who are completely healthy. In order to address this question, we investigated X-chromosome inactivation in peripheral blood lymphocytes from a heterozygous female with a child affected by IPEX. No preferential inactivation was shown in freshly sorted CD4+, CD8+, CD19+ cells or in IL-2 cultured CD4 and CD8 T cells, indicating that peripheral blood lymphocytes in these women are randomly selected. Moreover, only one single FOXP3 transcript was expressed by CD4 T cell clones analysed by RT-PCR, confirming that this gene is subject to X- inactivation. We hypothesize that hyper-activation of T cell in carriers of FOXP3 mutations is regulated by the presence of normal regulatory T cells.

27. A distinct human cell type expressing MHCII and RORγt with dual characteristics of dendritic cells and type 3 innate lymphoid cells.

Author

Ulezko Antonova A, Lonardi S, Monti M, Missale F, Fan C, Coates ML, Bugatti M, Jaeger N, Fernandes Rodrigues P, Brioschi S, Trsan T, Fachi JL, Nguyen KM, Nunley RM, Moratto D, Zini S, Kong L, Deguine J, Peeples ME, Xavier RJ, Clatworthy MR, Wang T, Cella M, Vermi W, and Colonna M

Subjects
Humans, Mice, Animals, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, Inflammation metabolism, Dendritic Cells, Lymphocytes, Immunity, Innate
Abstract

Recent studies have characterized various mouse antigen-presenting cells (APCs) expressing the lymphoid-lineage transcription factor RORγt (Retinoid-related orphan receptor gamma t), which exhibit distinct phenotypic features and are implicated in the induction of peripheral regulatory T cells (Tregs) and immune tolerance to microbiota and self-antigens. These APCs encompass Janus cells and Thetis cell subsets, some of which express the AutoImmune REgulator (AIRE). RORγt + MHCII + type 3 innate lymphoid cells (ILC3) have also been implicated in the instruction of microbiota-specific Tregs. While RORγt + APCs have been actively investigated in mice, the identity and function of these cell subsets in humans remain elusive. Herein, we identify a rare subset of RORγt + cells with dendritic cell (DC) features through integrated single-cell RNA sequencing and single-cell ATAC sequencing. These cells, which we term RORγt + DC-like cells (R-DC-like), exhibit DC morphology, express the MHC class II machinery, and are distinct from all previously reported DC and ILC3 subsets, but share transcriptional and epigenetic similarities with DC2 and ILC3. We have developed procedures to isolate and expand them in vitro, enabling their functional characterization. R-DC-like cells proliferate in vitro, continue to express RORγt, and differentiate into CD1c + DC2-like cells. They stimulate the proliferation of allogeneic T cells. The identification of human R-DC-like cells with proliferative potential and plasticity toward CD1c + DC2-like cells will prompt further investigation into their impact on immune homeostasis, inflammation, and autoimmunity., Competing Interests: Competing interests statement:The authors declare no competing interest.

Published
2023
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28. Hennekam Syndrome due to a Novel Homozygous CCBE1 Mutation Presenting as Pediatric-Onset Common Variable Immune Deficiency.

Author

Tessarin G, Baronio M, Gazzurelli L, Rossi S, Chiarini M, Moratto D, Badolato R, and Lougaris V

Subjects
Child, Humans, Mutation, Calcium-Binding Proteins genetics, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Common Variable Immunodeficiency, Lymphangiectasis, Intestinal genetics, Lymphedema genetics
Published
2023
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29. Longitudinal Characterization of Immune Response in a Cohort of Children Hospitalized with Multisystem Inflammatory Syndrome.

Author

Dotta L, Moratto D, Cattalini M, Brambilla S, Giustini V, Meini A, Girelli MF, Cortesi M, Timpano S, Galvagni A, Viola A, Crotti B, Manerba A, Pierelli G, Verzura G, Serana F, Brugnoni D, Garrafa E, Ricci F, Tomasi C, Chiarini M, and Badolato R

Abstract

Background: Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe complication of SARS-CoV-2 infection caused by hyperactivation of the immune system., Methods: this is a retrospective analysis of clinical data, biochemical parameters, and immune cell subsets in 40 MIS-C patients from hospital admission to outpatient long-term follow-up., Results: MIS-C patients had elevated inflammatory markers, associated with T- and NK-cell lymphopenia, a profound depletion of dendritic cells, and altered monocyte phenotype at disease onset, while the subacute phase of the disease was characterized by a significant increase in T- and B-cell counts and a rapid decline in activated T cells and terminally differentiated B cells. Most of the immunological parameters returned to values close to the normal range during the remission phase (20-60 days after hospital admission). Nevertheless, we observed a significantly reduced ratio between recently generated and more differentiated CD8+ T- and B-cell subsets, which partially settled at longer-term follow-up determinations., Conclusions: The characterization of lymphocyte distribution in different phases of MIS-C may help to understand the course of diseases that are associated with dysregulated immune responses and to calibrate prompt and targeted treatments.

Published
2023
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30. Reduced G protein signaling despite impaired internalization and β-arrestin recruitment in patients carrying a CXCR4Leu317fsX3 mutation causing WHIM syndrome.

Author

Kumar R, Milanesi S, Szpakowska M, Dotta L, Di Silvestre D, Trotta AM, Bello AM, Giacomelli M, Benedito M, Azevedo J, Pereira A, Cortesao E, Vacchini A, Castagna A, Pinelli M, Moratto D, Bonecchi R, Locati M, Scala S, Chevigné A, Borroni EM, and Badolato R

Subjects
Humans, beta-Arrestin 1 genetics, beta-Arrestin 1 immunology, Calcium metabolism, MAP Kinase Signaling System genetics, MAP Kinase Signaling System physiology, Mutation, Neutropenia genetics, Neutropenia immunology, Signal Transduction genetics, Signal Transduction physiology, Warts genetics, Warts immunology, beta-Arrestins genetics, beta-Arrestins immunology, GTP-Binding Proteins genetics, GTP-Binding Proteins immunology, Primary Immunodeficiency Diseases genetics, Primary Immunodeficiency Diseases immunology
Abstract

WHIM syndrome is an inherited immune disorder caused by an autosomal dominant heterozygous mutation in CXCR4. The disease is characterized by neutropenia/leukopenia (secondary to retention of mature neutrophils in bone marrow), recurrent bacterial infections, treatment-refractory warts, and hypogammaglobulinemia. All mutations reported in WHIM patients lead to the truncations in the C-terminal domain of CXCR4, R334X being the most frequent. This defect prevents receptor internalization and enhances both calcium mobilization and ERK phosphorylation, resulting in increased chemotaxis in response to the unique ligand CXCL12. Here, we describe 3 patients presenting neutropenia and myelokathexis, but normal lymphocyte count and immunoglobulin levels, carrying what we believe to be a novel Leu317fsX3 mutation in CXCR4, leading to a complete truncation of its intracellular tail. The analysis of the L317fsX3 mutation in cells derived from patients and in vitro cellular models reveals unique signaling features in comparison with R334X mutation. The L317fsX3 mutation impairs CXCR4 downregulation and β-arrestin recruitment in response to CXCL12 and reduces other signaling events - including ERK1/2 phosphorylation, calcium mobilization, and chemotaxis - all processes that are typically enhanced in cells carrying the R334X mutation. Our findings suggest that, overall, the L317fsX3 mutation may be causative of a form of WHIM syndrome not associated with an augmented CXCR4 response to CXCL12.

Published
2023
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31. Timely Leukapheresis May Interfere with the "Fitness" of Lymphocytes Collected for CAR-T Treatment in High Risk DLBCL Patients.

Author

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

Abstract

The development of chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematological diseases. However, approximately 60% of patients relapse after CAR-T cell therapy, and no clear cause for this failure has been identified. The objective of the Bio-CAR-T BS study (ClinicalTrials.gov: NCT05366569) is to improve our understanding of the lymphocyte harvest to maximize the quality of the CAR-T cell product. Of the 14 patients enrolled, 11 were diagnosed with DLBCL, 2 with PMBCL, and 1 with ALL. Five of 11 DLBCL patients met the criteria for "pre-emptive" Lymphocytes-apheresis (being at high risk of second relapse), and 6 were included in the standard-of-care Lymphocytes-apheresis group. Previous autologous stem cell transplantation (ASCT) and age were significantly different between the two groups. At the time of Lymphocyte-apheresis, patients in the "pre-emptive" group had more "fit" lymphocytes (higher CD4+/CD8+ ratio; higher naïve T cells levels) compared with standard group, probably due to the impact of ASCT. At the same time, also being older than 60 years results in a more "exhausted" lymphocyte profile. Overall, "pre-emptive" Ly-apheresis in DLBCL patients at high risk of relapse appears to be feasible and may allow the timely collection of "fit" lymphocytes for CAR-T cell manufacturing.

Published
2022
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32. Abnormal B-Cell Maturation and Increased Transitional B Cells in CBL Syndrome.

Author

Saettini F, Coliva TA, 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

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Saettini, Coliva, Vendemini, Galbiati, Bugarin, Masetti, Moratto, Chiarini, Guerra, Iascone, Badolato, Cazzaniga, Niemeyer, Flotho and Biondi.)

Published
2022
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33. Case Report: Analysis of Inflammatory Cytokines IL-6, CCL2/MCP1, CCL5/RANTES, CXCL9/MIG, and CXCL10/IP10 in a Cystic Fibrosis Patient Cohort During the First Wave of the COVID-19 Pandemic.

Author

Baresi G, Giacomelli M, Moratto D, Chiarini M, Conforti IC, Padoan R, Poli P, Timpano S, Caldarale F, and Badolato R

Abstract

Since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, data registered in the European countries revealed increasing cases of infection in cystic fibrosis (CF) patients. In the course of this pandemic, we enrolled 17 CF patients for a study evaluating inflammatory markers. One of them developed COVID - 19, giving us the possibility to analyze inflammatory markers in the acute phase as compared to levels detected before and after the infectious episode and to levels measured in the other CF patients enrolled to the study who did not experience COVID-19 and 23 patients referred to our center for SARS-CoV-2 infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Baresi, Giacomelli, Moratto, Chiarini, Conforti, Padoan, Poli, Timpano, Caldarale and Badolato.)

Published
2021
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34. 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 ME, Imberti L, Mauri M, Melzi ML, Bonanomi S, Gerussi A, Pinelli M, Barisani C, Bugarin C, Chiarini M, Giacomelli M, Piazza R, Cazzaniga G, Invernizzi P, Giliani SC, Badolato R, and Biondi A

Subjects
Child, Female, Humans, Mutation, Cholangitis, Sclerosing genetics, Guanine Nucleotide Exchange Factors genetics, Primary Immunodeficiency Diseases genetics
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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2021 Saettini, Fazio, Moratto, Galbiati, Zucchini, Ippolito, Dinelli, Imberti, Mauri, Melzi, Bonanomi, Gerussi, Pinelli, Barisani, Bugarin, Chiarini, Giacomelli, Piazza, Cazzaniga, Invernizzi, Giliani, Badolato and Biondi.)

Published
2021
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35. Plasmacytoid Dendritic Cells Depletion and Elevation of IFN-γ Dependent Chemokines CXCL9 and CXCL10 in Children With Multisystem Inflammatory Syndrome.

Author

Caldarale F, Giacomelli M, Garrafa E, Tamassia N, Morreale A, Poli P, Timpano S, Baresi G, Zunica F, Cattalini M, Moratto D, Chiarini M, Cannizzo ES, Marchetti G, Cassatella MA, Taddio A, Tommasini A, and Badolato R

Subjects
Child, Child, Preschool, Female, Humans, Infant, Male, Retrospective Studies, COVID-19 immunology, Chemokine CXCL10 immunology, Chemokine CXCL9 immunology, Dendritic Cells immunology, Interferon-gamma immunology, Plasma Cells immunology, SARS-CoV-2 immunology, Systemic Inflammatory Response Syndrome immunology
Abstract

Background: SARS-CoV-2 occurs in the majority of children as COVID-19, without symptoms or with a paucisymptomatic respiratory syndrome, but a small proportion of children develop the systemic Multi Inflammatory Syndrome (MIS-C), characterized by persistent fever and systemic hyperinflammation, with some clinical features resembling Kawasaki Disease (KD)., Objective: With this study we aimed to shed new light on the pathogenesis of these two SARS-CoV-2-related clinical manifestations., Methods: We investigated lymphocyte and dendritic cells subsets, chemokine/cytokine profiles and evaluated the neutrophil activity mediators, myeloperoxidase (MPO), and reactive oxygen species (ROS), in 10 children with COVID-19 and 9 with MIS-C at the time of hospital admission., Results: Patients with MIS-C showed higher plasma levels of C reactive protein (CRP), MPO, IL-6, and of the pro-inflammatory chemokines CXCL8 and CCL2 than COVID-19 children. In addition, they displayed higher levels of the chemokines CXCL9 and CXCL10, mainly induced by IFN-γ. By contrast, we detected IFN-α in plasma of children with COVID-19, but not in patients with MIS-C. This observation was consistent with the increase of ISG15 and IFIT1 mRNAs in cells of COVID-19 patients, while ISG15 and IFIT1 mRNA were detected in MIS-C at levels comparable to healthy controls. Moreover, quantification of the number of plasmacytoid dendritic cells (pDCs), which constitute the main source of IFN-α, showed profound depletion of this subset in MIS-C, but not in COVID-19., Conclusions: Our results show a pattern of immune response which is suggestive of type I interferon activation in COVID-19 children, probably related to a recent interaction with the virus, while in MIS-C the immune response is characterized by elevation of the inflammatory cytokines/chemokines IL-6, CCL2, and CXCL8 and of the chemokines CXCL9 and CXL10, which are markers of an active Th1 type immune response. We believe that these immunological events, together with neutrophil activation, might be crucial in inducing the multisystem and cardiovascular damage observed in MIS-C., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Caldarale, Giacomelli, Garrafa, Tamassia, Morreale, Poli, Timpano, Baresi, Zunica, Cattalini, Moratto, Chiarini, Cannizzo, Marchetti, Cassatella, Taddio, Tommasini and Badolato.)

Published
2021
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36. Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency.

Author

Saettini F, Poli C, Vengoechea J, Bonanomi S, Orellana JC, Fazio G, Rodriguez FH, Noguera LP, Booth C, Jarur-Chamy V, Shams M, Iascone M, Vukic M, Gasperini S, Quadri M, Barroeta Seijas A, Rivers E, Mauri M, Badolato R, Cazzaniga G, Bugarin C, Gaipa G, Kroes WGM, Moratto D, van Oostaijen-Ten Dam MM, Baas F, van der Maarel S, Piazza R, Coban-Akdemir ZH, Lupski JR, Yuan B, Chinn IK, Daxinger L, and Biondi A

Subjects
Adult, Animals, B-Lymphocytes metabolism, Child, Child, Preschool, Chromosomes, Human, Pair 5 genetics, Codon, Nonsense, Consanguinity, Crohn Disease genetics, DNA Copy Number Variations, Developmental Disabilities genetics, Disease Models, Animal, Disease Susceptibility, Female, Heart Defects, Congenital genetics, Humans, Infections etiology, Loss of Function Mutation, Male, Mice, Neutropenia genetics, Pedigree, Uniparental Disomy, Exome Sequencing, Agammaglobulinemia genetics, B-Lymphocytes pathology, Cardiomyopathy, Hypertrophic genetics, Carrier Proteins genetics, Immunologic Deficiency Syndromes genetics, Lymphopenia genetics
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., (© 2021 by The American Society of Hematology.)

Published
2021
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37. Case Report: A Case of X-Linked Agammaglobulinemia With High Serum IgE Levels and Allergic Rhinitis.

Author

Cinicola B, Uva A, Leonardi L, Moratto D, Giliani S, Carsetti R, Ferrari S, Zicari AM, and Duse M

Subjects
Agammaglobulinemia complications, Agammaglobulinemia genetics, Cell Differentiation, Child, Genetic Diseases, X-Linked complications, Genetic Diseases, X-Linked genetics, Humans, Male, Mutation genetics, Phenotype, Rhinitis, Allergic complications, Rhinitis, Allergic genetics, Up-Regulation, Agammaglobulinaemia Tyrosine Kinase genetics, Agammaglobulinemia diagnosis, B-Lymphocytes pathology, Genetic Diseases, X-Linked diagnosis, Immunoglobulin E blood, Rhinitis, Allergic diagnosis
Abstract

X-linked Agammaglobulinemia (XLA) is a rare genetic disorder of B-lymphocyte differentiation, characterized by the absence or paucity of circulating B cells, markedly reduced levels of all serum immunoglobulin isotypes and lack of specific antibody production. Bruton Tyrosine Kinase ( BTK ) gene encodes a cytoplasmic tyrosine kinase involved in the B cell maturation and its mutation, blocking B cell differentiation at the pre-B cell stage, and is responsible for XLA. All domains may be affected by the mutation, and the many genotypes are associated with a wide range of clinical presentations. Little is known about genotype-phenotype correlation in this disorder, and factors influencing the phenotype of XLA are not clearly understood. In this report we present a unique case of a young patient affected by XLA. The disease was genetically diagnosed at birth due to a family history of XLA, but during follow up, it was characterized by a CD19+ B cell percentage consistently greater than 2%. He never suffered severe infections, but at two years of age, he developed persistent rhinitis. Thus, total serum IgE levels were measured and detected over the normal range, and specific allergic investigations showed sensitization to dust mites. Further immunological tests (BTK expression, functional " in vitro " B cell proliferation upon CpG stimulation, B cell subset analysis) explained these findings as possible manifestations of a mild XLA phenotype. XLA patients rarely present with allergic manifestations, which could warrant further investigation. High serum IgE levels could be a sign of a mild phenotype, but their role and the mechanisms underlying their production in XLA need to be clarified., (Copyright © 2020 Cinicola, Uva, Leonardi, Moratto, Giliani, Carsetti, Ferrari, Zicari and Duse.)

Published
2020
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38. Activated Phosphoinositide 3-Kinase Delta Syndrome 1: Clinical and Immunological Data from an Italian Cohort of Patients.

Author

Tessarin G, Rossi S, Baronio M, Gazzurelli L, Colpani M, Benvenuto A, Zunica F, Cardinale F, Martire B, Brescia L, Costagliola G, Luti L, Casazza G, Menconi MC, Saettini F, Palumbo L, Girelli MF, Badolato R, Lanzi G, Chiarini M, Moratto D, Meini A, Giliani S, Bondioni MP, Plebani A, and Lougaris V

Abstract

Activated phosphoinositide 3-kinase delta syndrome 1 (APDS-1) is a recently described inborn error of immunity caused by monoallelic gain-of-function mutations in the PIK3CD gene. We reviewed for the first time medical records and laboratory data of eight Italian APDS-1 patients. Recurrent sinopulmonary infections were the most common clinical feature at onset of disease. Seven patients presented lymphoproliferative disease, at onset or during follow-up, one of which resembled hemophagocytic lymphohistiocytosis (HLH). Genetic analysis of the PIK3CD gene revealed three novel mutations: functional testing confirmed their activating nature. In the remaining patients, the previously reported variants p .E1021K ( n = 4) and p .E525A ( n = 1) were identified. Six patients were started on immunoglobulin replacement treatment (IgRT). One patient successfully underwent hematopoietic stem cell transplantation (HSCT), with good chimerism and no GVHD at 21 months post-HSCT. APDS-1 is a combined immune deficiency with a wide variety of clinical manifestations and a complex immunological presentation. Besides IgRT, specific therapies targeting the PI3Kδ pathway will most likely become a valid aid for the amelioration of patients' clinical management and their quality of life.

Published
2020
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39. Plasmacytoid Dendritic Cell Impairment in Metastatic Melanoma by Lactic Acidosis.

Author

Monti M, Vescovi R, Consoli F, Farina D, Moratto D, Berruti A, Specchia C, and Vermi W

Abstract

The introduction of targeted therapies and immunotherapies has significantly improved the outcome of metastatic melanoma (MM) patients. These approaches rely on immune functions for their anti-melanoma response. Plasmacytoid dendritic cells (pDCs) exhibit anti-tumor function by production of effector molecules, type I interferons (I-IFNs), and cytokines. Tissue and blood pDCs result compromised in MM, although these findings are still partially conflicting. This study reports that blood pDCs were dramatically depleted in MM, particularly in patients with high lactate dehydrogenase (LDH) and high tumor burden; the reduced pDC frequency was associated with poor overall survival. Circulating pDCs resulted also in significant impairment in interferon alpha (IFN-α) and C-X-C motif chemokine 10 (CXCL10) production in response to toll-like receptor (TLR)-7/8 agonists; on the contrary, the response to TLR-9 agonist remained intact. In the BRAF V600+ subgroup, no recovery of pDC frequency could be obtained by BRAF and MEK inhibitors (BRAFi; MEKi), whereas their function was partially rescued. Mechanistically, in vitro exposure to lactic acidosis impaired both pDC viability and function. In conclusion, pDCs from MM patients were found to be severely impaired, with a potential role for lactic acidosis. Short-term responses to treatments were not associated with pDC recovery, suggesting long-lasting effects on their compartment.

Published
2020
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40. Transient Decrease of Circulating and Tissular Dendritic Cells in Patients With Mycobacterial Disease and With Partial Dominant IFNγR1 Deficiency.

Author

Dotta L, Vairo D, Giacomelli M, Moratto D, Tamassia N, Vermi W, Lonardi S, Casanova JL, Bustamante J, Giliani S, and Badolato R

Subjects
Child, Preschool, Female, Genetic Predisposition to Disease genetics, Humans, Mutation, Primary Immunodeficiency Diseases genetics, Receptors, Interferon genetics, Interferon gamma Receptor, Dendritic Cells immunology, Mycobacterium avium-intracellulare Infection immunology, Primary Immunodeficiency Diseases immunology, Receptors, Interferon deficiency
Abstract

Interferon-γ receptor 1 (IFNγR1) deficiency is one of the inborn errors of IFN-γ immunity underlying Mendelian Susceptibility to Mycobacterial Disease (MSMD). This molecular circuit plays a crucial role in regulating the interaction between dendritic cells (DCs) and T lymphocytes, thus affecting DCs activation, maturation, and priming of T cells involved in the immune response against intracellular pathogens. We studied a girl who developed at the age of 2.5 years a Mycobacterium avium infection characterized by disseminated necrotizing granulomatous lymphadenitis, and we compared her findings with other patients with the same genetic condition. The patient carried a heterozygous 818del4 mutation in the IFNGR1 gene responsible of autosomal dominant (AD) partial IFNγR1 deficiency. During the acute infection blood cells immunophenotyping showed a marked reduction in DCs counts, including both myeloid (mDCs) and plasmacytoid (pDCs) subsets, that reversed after successful prolonged antimicrobial therapy. Histology of her abdomen lymph node revealed a profound depletion of tissue pDCs, as compared to other age-matched granulomatous lymphadenitis of mycobacterial origin. Circulating DCs depletion was also observed in another patient with AD partial IFNγR1 deficiency during mycobacterial infection. To conclude, AD partial IFNγR1 deficiency can be associated with a transient decrease in both circulating and tissular DCs during acute mycobacterial infection, suggesting that DCs counts monitoring might constitute a useful marker of treatment response., (Copyright © 2020 Dotta, Vairo, Giacomelli, Moratto, Tamassia, Vermi, Lonardi, Casanova, Bustamante, Giliani and Badolato.)

Published
2020
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41. Multisystem autoimmune disease caused by increased STAT3 phosphorylation and dysregulated gene expression.

Author

Todaro F, Tamassia N, Pinelli M, Moratto D, Dotta L, Grassi A, Consonni F, Giacomelli M, Lionetti P, Gardiman E, Cassatella MA, Gambineri E, Canani RB, and Badolato R

Subjects
Autoimmune Diseases metabolism, Autoimmune Diseases pathology, Child, Humans, Male, Multiple Organ Failure metabolism, Multiple Organ Failure pathology, Mutation, Phosphorylation, Prognosis, STAT3 Transcription Factor genetics, Autoimmune Diseases etiology, Gene Expression Regulation, Multiple Organ Failure etiology, STAT3 Transcription Factor metabolism
Published
2019
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42. Pseudomonas aeruginosa severe skin infection in a toddler with X-linked agammaglobulinemia due to a novel BTK mutation.

Author

Riccardi N, Rotulo GA, Favilli F, Loy A, Moratto D, Giliani S, Mesini A, Romanini MV, Volpi S, Moscatelli A, and Castagnola E

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

Published
2019

43. Corrigendum: Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56 bright NKG2A +++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content.

Author

Dobbs K, Tabellini G, Calzoni E, Patrizi O, Martinez P, Giliani SC, Moratto D, Al-Herz W, Cancrini C, Cowan M, Bleesing J, Booth C, Buchbinder D, Burns SO, Chatila TA, Chou J, Daza-Cajigal V, Ott de Bruin LM, de la Morena MT, Di Matteo G, Finocchi A, Geha R, Goyal RK, Hayward A, Holland S, Huang CH, Kanariou MG, King A, Kaplan B, Kleva A, Kuijpers TW, Lee BW, Lougaris V, Massaad M, Meyts I, Morsheimer M, Neven B, Pai SY, Parvaneh N, Plebani A, Prockop S, Reisli I, Soh JY, Somech R, Torgerson TR, Kim YJ, Walter JE, Gennery AR, Keles S, Manis JP, Marcenaro E, Moretta A, Parolini S, and Notarangelo LD

Abstract

[This corrects the article on p. 798 in vol. 8, PMID: 28769923.].

Published
2017
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44. Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56 bright NKG2A +++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content.

Author

Dobbs K, Tabellini G, Calzoni E, Patrizi O, Martinez P, Giliani SC, Moratto D, Al-Herz W, Cancrini C, Cowan M, Bleesing J, Booth C, Buchbinder D, Burns SO, Chatila TA, Chou J, Daza-Cajigal V, Ott de Bruin LM, de la Morena M, Di Matteo G, Finocchi A, Geha R, Goyal RK, Hayward A, Holland S, Huang CH, Kanariou MG, King A, Kaplan B, Kleva A, Kuijpers TW, Lee BW, Lougaris V, Massaad M, Meyts I, Morsheimer M, Neven B, Pai SY, Parvaneh N, Plebani A, Prockop S, Reisli I, Soh JY, Somech R, Torgerson TR, Kim YJ, Walter JE, Gennery AR, Keles S, Manis JP, Marcenaro E, Moretta A, Parolini S, and Notarangelo LD

Abstract

Mutations of the recombinase-activating genes 1 and 2 ( RAG1 and RAG2 ) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag -/- natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in RAG and in non-homologous end joining (NHEJ) genes. Here, we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56 bright CD16 -/int CD57 - cells, yet increased degranulation and high perforin content. Correlation was observed between in vitro recombinase activity of the mutant proteins, NK cell abnormalities, and in vivo clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT.

Published
2017
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45. Impairment of dendritic cell functions in patients with adaptor protein-3 complex deficiency.

Author

Prandini A, Salvi V, Colombo F, Moratto D, Lorenzi L, Vermi W, De Francesco MA, Notarangelo LD, Porta F, Plebani A, Facchetti F, Sozzani S, and Badolato R

Subjects
Adaptor Protein Complex 3 immunology, Antigens, CD genetics, Antigens, CD immunology, Cell Adhesion Molecules, Neuronal genetics, Cell Adhesion Molecules, Neuronal immunology, Cytokines genetics, Cytokines immunology, Dendritic Cells pathology, Female, GPI-Linked Proteins genetics, GPI-Linked Proteins immunology, Granzymes genetics, Granzymes immunology, Hermanski-Pudlak Syndrome genetics, Hermanski-Pudlak Syndrome pathology, Herpesvirus 1, Human immunology, Humans, Immunoglobulins genetics, Immunoglobulins immunology, Male, Membrane Glycoproteins genetics, Membrane Glycoproteins immunology, Monocytes pathology, T-Lymphocytes immunology, T-Lymphocytes pathology, CD83 Antigen, Adaptor Protein Complex 3 deficiency, Dendritic Cells immunology, Gene Expression Regulation immunology, Hermanski-Pudlak Syndrome immunology, Monocytes immunology
Abstract

Hermansky-Pudlak syndrome type 2 (HPS2) is a primary immunodeficiency due to adaptor protein-3 (AP-3) complex deficiency. HPS2 patients present neutropenia, partial albinism, and impaired lysosomal vesicles formation in hematopoietic cells. Given the role of dendritic cells (DCs) in the immune response, we studied monocyte-derived DCs (moDCs) and plasmacytoid DCs (pDCs) in two HPS2 siblings. Mature HPS2 moDCs showed impaired expression of CD83 and DC-lysosome-associated membrane protein (LAMP), low levels of MIP1-β/CCL4, MIG/CXCL9, and severe defect of interleukin-12 (IL-12) secretion. DCs in lymph-node biopsies from the same patients showed a diffuse cytoplasm reactivity in a large fraction of DC-LAMP(+) cells, instead of the classical dot-like stain. In addition, analysis of pDC-related functions of blood-circulating mononuclear cells revealed reduced interferon-α secretion in response to herpes simplex virus-1 (HSV-1), whereas granzyme-B induction upon IL-3/IL-10 stimulation was normal. Finally, T-cell costimulatory activity, as measured by mixed lymphocyte reaction assay, was lower in patients, suggesting that function and maturation of DCs is abnormal in patients with HPS2., (© 2016 by The American Society of Hematology.)

Published
2016
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46. Proteus syndrome: evaluation of the immunological profile.

Author

Lougaris V, Salpietro V, Cutrupi M, Baronio M, Moratto D, Pizzino MR, Mankad K, Briuglia S, Salpietro C, and Plebani A

Subjects
Adolescent, B-Lymphocytes immunology, Female, Humans, Proteus Syndrome complications, Pulmonary Embolism diagnosis, Pulmonary Embolism etiology, Pulmonary Embolism immunology, T-Lymphocytes immunology, Proteus Syndrome diagnosis, Proteus Syndrome immunology
Abstract

Proteus syndrome (PS) is an extremely rare and complex disease characterized by malformations and overgrowth of different tissues. Prognosis of affected patients may be complicated by premature death, mostly due to pulmonary embolism and respiratory failure. To date, immunological data in Proteus syndrome are scarse.We report on the novel immunologic findings of a 15 years old girl affected with PS. Detailed T and B cell evaluation revealed maturational alterations for both subsets and functional hyperactivation for the latter. Such findings have not been reported previously in PS and may be the spy of more complex immune abnormalities in this syndrome.

Published
2016
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47. Evaluation of a novel human IgG1 anti-claudin3 antibody that specifically recognizes its aberrantly localized antigen in ovarian cancer cells and that is suitable for selective drug delivery.

Author

Romani C, Cocco E, Bignotti E, Moratto D, Bugatti A, Todeschini P, Bandiera E, Tassi R, Zanotti L, Pecorelli S, Sartori E, Odicino FE, de Marco A, Santin AD, Ravaggi A, and Mitola S

Subjects
Animals, Antibody Affinity, Antineoplastic Agents pharmacology, Blotting, Western, Cell Line, Tumor, Drug Carriers pharmacology, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Humans, Mice, Mice, SCID, Microscopy, Confocal, Microscopy, Fluorescence, RNA, Small Interfering, Real-Time Polymerase Chain Reaction, Surface Plasmon Resonance, Transfection, Xenograft Model Antitumor Assays, Antibodies, Neoplasm pharmacology, Claudin-3 immunology, Drug Delivery Systems methods, Immunoglobulin G pharmacology, Ovarian Neoplasms immunology
Abstract

Membrane protein claudin3 has been recently suggested as a marker for biologically aggressive tumors and a possible target for the therapeutic delivery of active anti-cancer compounds. Claudin3-binding molecules such as the Clostridium perfringens enterotoxin (CPE), CPE-related molecules, and murine and chimeric antibodies have shown promising antitumor efficacy in preclinical oncological settings. We first engineered a fully human anti-claudin3 IgG1 antibody (IgGH6) by fusing the human IgG1 Fc-domain to the anti-claudin3 scFvH6 previously isolated from a pre-immune phage display library. The construct was expressed in mammalian cells and specifically targeted claudin3 endogenously expressed on the surface of different human ovarian cancer cell lines. No detectable cross-reactivity with other homologous claudins was observed. The epitope recognized by IgGH6 is located within the minor extracellular domain of claudin3 and becomes accessible only in tumor cells characterized by incomplete junction formation. Confocal microscopy experiments demonstrated that IgGH6 was actively internalized in tumor cells after binding to native claudin3 and co-localized, likely within intracellular vesicles, with the C-CPE peptide. Preliminary results indicate that IgGH6 accumulated in vivo in free claudin3 ovarian carcinoma xenografts. For its selective uptake in tumor cells and its human nature, IgGH6 represents a valuable candidate for antibody-drug conjugate therapeutic applications in ovarian cancer patients.

Published
2015
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48. 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, Monari P, Calzavara-Pinton P, and Plebani A

Subjects
Acne Vulgaris immunology, Adolescent, Alopecia epidemiology, Alopecia immunology, Child, Cohort Studies, Common Variable Immunodeficiency immunology, Dermatitis, Atopic immunology, Female, Humans, IgA Deficiency immunology, Longitudinal Studies, Male, Prospective Studies, Psoriasis immunology, Skin Diseases, Infectious immunology, Vitiligo epidemiology, Vitiligo immunology, Young Adult, Acne Vulgaris epidemiology, Common Variable Immunodeficiency epidemiology, Dermatitis, Atopic epidemiology, IgA Deficiency epidemiology, Psoriasis epidemiology, Skin Diseases, Infectious epidemiology
Published
2015

49. Occurrence of nodular lymphocyte-predominant hodgkin lymphoma in hermansky-pudlak type 2 syndrome is associated to natural killer and natural killer T cell defects.

Author

Lorenzi L, Tabellini G, Vermi W, Moratto D, Porta F, Notarangelo LD, Patrizi O, Sozzani S, de Saint Basile G, Latour S, Pace D, Lonardi S, Facchetti F, Badolato R, and Parolini S

Subjects
Adolescent, Adult, Aged, Biopsy, CD56 Antigen metabolism, Child, Child, Preschool, Cytotoxicity, Immunologic, Female, Hermanski-Pudlak Syndrome diagnosis, Hodgkin Disease diagnosis, Humans, Immunohistochemistry, Immunophenotyping, Interferon-gamma biosynthesis, Killer Cells, Natural metabolism, Lymph Nodes pathology, Lymphocyte Count, Lymphocyte Subsets immunology, Lymphocyte Subsets metabolism, Lysosomal-Associated Membrane Protein 1 metabolism, Male, Middle Aged, Natural Killer T-Cells metabolism, Phenotype, Siblings, Tetraspanin 30 metabolism, Young Adult, Hermanski-Pudlak Syndrome complications, Hermanski-Pudlak Syndrome immunology, Hodgkin Disease complications, Hodgkin Disease immunology, Killer Cells, Natural immunology, Natural Killer T-Cells immunology
Abstract

Hermansky Pudlak type 2 syndrome (HPS2) is a rare autosomal recessive primary immune deficiency caused by mutations on β3A gene (AP3B1 gene). The defect results in the impairment of the adaptor protein 3 (AP-3) complex, responsible for protein sorting to secretory lysosomes leading to oculo-cutaneous albinism, bleeding disorders and immunodeficiency. We have studied peripheral blood and lymph node biopsies from two siblings affected by HPS2. Lymph node histology showed a nodular lymphocyte predominance type Hodgkin lymphoma (NLPHL) in both HPS2 siblings. By immunohistochemistry, CD8 T-cells from HPS2 NLPHL contained an increased amount of perforin (Prf) + suggesting a defect in the release of this granules-associated protein. By analyzing peripheral blood immune cells we found a significant reduction of circulating NKT cells and of CD56(bright)CD16(-) Natural Killer (NK) cells subset. Functionally, NK cells were defective in their cytotoxic activity against tumor cell lines including Hodgkin Lymphoma as well as in IFN-γ production. This defect was associated with increased baseline level of CD107a and CD63 at the surface level of unstimulated and IL-2-activated NK cells. In summary, these results suggest that a combined and profound defect of innate and adaptive effector cells might explain the susceptibility to infections and lymphoma in these HPS2 patients.

Published
2013
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50. A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP.

Author

Lanzi G, Moratto D, Vairo D, Masneri S, Delmonte O, Paganini T, Parolini S, Tabellini G, Mazza C, Savoldi G, Montin D, Martino S, Tovo P, Pessach IM, Massaad MJ, Ramesh N, Porta F, Plebani A, Notarangelo LD, Geha RS, and Giliani S

Subjects
Base Sequence, Cytoskeletal Proteins genetics, Cytoskeletal Proteins immunology, Female, Gene Expression Regulation, Gene Order, Humans, Infant, Newborn, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins immunology, Mutation, T-Lymphocytes immunology, T-Lymphocytes metabolism, Wiskott-Aldrich Syndrome Protein genetics, Cytoskeletal Proteins deficiency, Intracellular Signaling Peptides and Proteins deficiency, Wiskott-Aldrich Syndrome genetics, Wiskott-Aldrich Syndrome immunology
Abstract

A female offspring of consanguineous parents, showed features of Wiskott-Aldrich syndrome (WAS), including recurrent infections, eczema, thrombocytopenia, defective T cell proliferation and chemotaxis, and impaired natural killer cell function. Cells from this patient had undetectable WAS protein (WASP), but normal WAS sequence and messenger RNA levels. WASP interacting protein (WIP), which stabilizes WASP, was also undetectable. A homozygous c.1301C>G stop codon mutation was found in the WIPF1 gene, which encodes WIP. Introduction of WIP into the patient's T cells restored WASP expression. These findings indicate that WIP deficiency should be suspected in patients with features of WAS in whom WAS sequence and mRNA levels are normal.

Published
2012
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