المؤلفون: Jane C. Stinchcombe, Alessandra Santoro, Lorenzo Moretta, Concetta Micalizzi, Giuseppa Bruno, Francesco Dieli, Cesare Danesino, Daniela Pende, Lucia Dora Notarangelo, Federico Gallo, Sonia Cannella, Antonino Trizzino, Gillian M. Griffiths, Maurizio Aricò, C De Fusco, Giovanna Bossi

المساهمون: SANTORO A, CANNELLA S, TRIZZINO A, GALLO F, PENDE D, DIELI F, BRUNO G, MICALIZZI C, DE FUSCO C, DANESINO C, MORETTA L, NOTARANGELO LD, GRIFFITHS G, ARIC M

المصدر: Journal of Medical Genetics. 43:953-960

مصطلحات موضوعية: EXPRESSION, Male, PRF1, Adolescent, FHL, Blotting, Western, DNA Mutational Analysis, Hepatosplenomegaly, DONORS, Prenatal diagnosis, Biology, medicine.disease_cause, Lymphohistiocytosis, Hemophagocytic, Genetics, medicine, PERFORIN GENE-MUTATIONS, Humans, UNC13D, Child, Genetics (clinical), Family Health, SPECTRUM, Hemophagocytic lymphohistiocytosis, Mutation, Cytopenia, Microscopy, Confocal, IDENTIFICATION, Genetic heterogeneity, Infant, Newborn, CYTOTOXIC T-LYMPHOCYTES, Infant, Membrane Proteins, medicine.disease, BONE-MARROW-TRANSPLANTATION, Transplantation, Microscopy, Electron, Child, Preschool, Immunology, Female, medicine.symptom, Letter to JMG, T-Lymphocytes, Cytotoxic

الوصف: Familial haemophagocytic lymphohistiocytosis (FHL) is a genetically heterogeneous disorder characterised by constitutive defects in cellular cytotoxicity resulting in fever, hepatosplenomegaly and cytopenia, and the outcome is fatal unless treated by chemoimmunotherapy followed by haematopoietic stem‐cell transplantation. Since 1999, mutations in the perforin gene giving rise to this disease have been identified; however, these account only for 40% of cases. Lack of a genetic marker hampers the diagnosis, suitability for transplantation, selection of familial donors, identification of carriers, genetic counselling and prenatal diagnosis. Mutations in the Munc13–4 gene have recently been described in patients with FHL. We sequenced the Munc13–4 gene in all patients with haemophagocytic lymphohistiocytosis not due to PRF1 mutations. In 15 of the 30 families studied, 12 novel and 4 known Munc13–4 mutations were found, spread throughout the gene. Among novel mutations, 2650C→T introduced a stop codon; 441del A, 532del C, 3082del C and 3226ins G caused a frameshift, and seven were mis sense mutations. Median age of diagnosis was 4 months, but six patients developed the disease after 5 years of age and one as a young adult of 18 years. Involvement of central nervous system was present in 9 of 15 patients, activity of natural killer cells was markedly reduced or absent in 13 of 13 tested patients. Chemo‐immunotherapy was effective in all patients. Munc13–4 mutations were found in 15 of 30 patients with FHL without PRF1 mutations. Because these patients may develop the disease during adolescence or even later, haematologists should include FHL2 and FHL3 in the differential diagnosis of young adults with fever, cytopenia, splenomegaly and hypercytokinaemia.

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::be968a79ccc972b5268d678b3a5fef1a
https://doi.org/10.1136/jmg.2006.041863

المؤلفون: Moretta L; Department of Experimental Medicine, University of Genova, Genova, Italy. lorenzomoretta@ospedale-gaslini.ge.it, Locatelli F, Moretta A

المصدر: Annals of the rheumatic diseases [Ann Rheum Dis] 2008 Dec; Vol. 67 Suppl 3, pp. iii39-43.

نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Review

بيانات الدورية: Publisher: BMJ Country of Publication: England NLM ID: 0372355 Publication Model: Print Cited Medium: Internet ISSN: 1468-2060 (Electronic) Linking ISSN: 00034967 NLM ISO Abbreviation: Ann Rheum Dis Subsets: MEDLINE

مواضيع طبية MeSH: Hematopoietic Stem Cell Transplantation/*methods , Killer Cells, Natural/*immunology , Leukemia/*therapy, Histocompatibility Antigens Class I/immunology ; Humans ; Immunoglobulin Allotypes/immunology ; Leukemia/immunology ; Receptors, KIR/blood ; Receptors, Natural Killer Cell/immunology

مستخلص: Natural killer (NK) cells express surface receptors that regulate potent effector functions, such as cytolytic activity and release of cytokines, which play a central role in inflammatory response and immunoregulation. In this paper, major advances are outlined from the original discovery of HLA-class I-specific inhibitory receptors in humans to recent, particularly successful, clinical applications in the cure of high-risk, otherwise fatal leukaemias. The central role of donor-derived "alloreactive" NK cells in eradicating leukaemic cells in the T-cell-depleted haploidentical haematopoietic stem cell transplantation setting became evident. Since alloreactive NK cells seem to play a key role also in preventing graft rejection and graft-vs-host disease, they may be an ideal tool to treat high-risk leukaemias in the haematopoietic stem cell transplantation setting.