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San Raffaele Cimena, Italy

Cypowyj S.,Rockefeller University | Picard C.,University of Paris Descartes | Picard C.,Study Center for Primary Immunodeficiencies | Marodi L.,Debrecen University | And 4 more authors.
European Journal of Immunology | Year: 2012

Mice with defective IL-17 immunity display a broad vulnerability to various infectious agents at diverse mucocutaneous surfaces. In humans, the study of patients with various primary immunodeficiencies, including autosomal dominant hyper-IgE syndrome caused by dominant-negative STAT3 mutations and autosomal recessive autoimmune polyendocrinopathy syndrome type 1 caused by null mutations in AIRE, has suggested that IL-17A, IL-17F and/or IL-22 are essential for mucocutaneous immunity to Candida albicans. This hypothesis was confirmed by the identification of rare patients with chronic mucocutaneous candidiasis (CMC) due to autosomal recessive IL-17RA deficiency and autosomal dominant IL-17F deficiency. Heterozygosity for gain-of-function mutations in STAT1 in additional patients with CMC was recently shown to inhibit the development of IL-17 T cells. Although the infectious phenotype of patients with CMC and inborn errors of IL-17 immunity remains to be finely delineated, it appears that human IL-17A and IL-17F display redundancy for protective immunity in natural conditions that is not seen in their mouse orthologs in experimental conditions. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Crequer A.,Rockefeller University | Crequer A.,University of Paris Descartes | Troeger A.,Dana-Farber Cancer Institute | Troeger A.,Heinrich Heine University Dusseldorf | And 31 more authors.
Journal of Clinical Investigation | Year: 2012

Epidermodysplasia verruciformis (EV) is a rare genetic disorder characterized by increased susceptibility to specific human papillomaviruses, the betapapillomaviruses. These EV-HPVs cause warts and increase the risk of skin carcinomas in otherwise healthy individuals. Inactivating mutations in epidermodysplasia verruciformis 1 (EVER1) or EVER2 have been identified in most, but not all, patients with autosomal recessive EV. We found that 2 young adult siblings presenting with T cell deficiency and various infectious diseases, including persistent EV-HPV infections, were homozygous for a mutation creating a stop codon in the ras homolog gene family member H (RHOH) gene. RHOH encodes an atypical Rho GTPase expressed predominantly in hematopoietic cells. Patients' circulating T cells contained predominantly effector memory T cells, which displayed impaired TCR signaling. Additionally, very few circulating T cells expressed the β7 integrin subunit, which homes T cells to specific tissues. Similarly, Rhoh-null mice exhibited a severe overall T cell defect and abnormally small numbers of circulating β7-positive cells. Expression of the WT, but not of the mutated RHOH, allele in Rhoh -/- hematopoietic stem cells corrected the T cell lymphopenia in mice after bone marrow transplantation. We conclude that RHOH deficiency leads to T cell defects and persistent EV-HPV infections, suggesting that T cells play a role in the pathogenesis of chronic EV-HPV infections. Source


Lorioli L.,San Raffaele Telethon Institute for Gene Therapy | Lorioli L.,Pediatric Immunohematology Unit | Lorioli L.,San Raffaele Scientific Institute | Lorioli L.,Vita-Salute San Raffaele University | And 4 more authors.
Expert Opinion on Orphan Drugs | Year: 2015

Metachromatic leukodystrophy (MLD) is a rare, fatal, inherited lysosomal storage disorder caused by the deficiency of arylsulfatase A (ARSA). The enzymatic defect results in the accumulation of the ARSA substrate, mainly in myelin forming cells, leading to progressive demyelination and dysfunction in the CNS and peripheral nervous system. The severity of the disease and the absence of approved treatments stimulate testing innovative therapeutic strategies.Areas covered: Among diverse experimental approaches, hematopoietic stem cell (HSC) transplantation (HSCT) from healthy compatible donors, and very recently, gene therapy based on transplantation of autologous HSCs transduced with a lentiviral vector encoding for the ARSA cDNA have been applied to MLD patients. State of the development of these HSC-based strategies is here analyzed, based on a review of the scientific literature, focusing on the outcomes of allogeneic HSCT, and on its potential clinical benefit and limitations.Expert opinion: HSC-based approaches would require the evaluation of long-term follow-up on neurological and transplant-related outcomes of larger cohorts of patients, in order to rationally define indication to treatment for MLD patients. © 2015 Informa UK, Ltd. Source


Lorioli L.,San Raffaele Telethon Institute for Gene Therapy HSR TIGET | Lorioli L.,Pediatric Immunohematology Unit | Lorioli L.,Vita-Salute San Raffaele University | Cicalese M.P.,San Raffaele Telethon Institute for Gene Therapy HSR TIGET | And 19 more authors.
Molecular Genetics and Metabolism | Year: 2015

Metachromatic Leukodystrophy (MLD; MIM# 250100) is a rare inherited lysosomal storage disorder caused by the deficiency of Arylsulfatase A (ARSA). The enzymatic defect results in the accumulation of the ARSA substrate that is particularly relevant in myelin forming cells and leads to progressive dysmyelination and dysfunction of the central and peripheral nervous system. Sulfatide accumulation has also been reported in various visceral organs, although little is known about the potential clinical consequences of such accumulation. Different forms of MLD-associated gallbladder disease have been described, and there is one reported case of an MLD patient presenting with functional consequences of sulfatide accumulation in the kidney.Here we describe a wide cohort of MLD patients in whom a tendency to sub-clinical metabolic acidosis was observed. Furthermore in some of them we report episodes of metabolic acidosis of different grades of severity developed in acute clinical conditions of various origin. Importantly, we finally show how a careful acid-base balance monitoring and prompt correction of imbalances might prevent severe consequences of acidosis. © 2015 Elsevier Inc.. Source

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