title: Familial hemophagocytic lymphohistiocytosis: when rare diseases shed light on immune system functioning.
abstract: The human immune system depends on the activity of cytotoxic T lymphocytes (CTL), natural killer (NK) cells, and NKT cells in order to fight off a viral infection. Understanding the molecular mechanisms during this process and the role of individual proteins was greatly improved by the study of familial hemophagocytic lymphohistiocytosis (FHL). Since 1999, genetic sequencing is the gold standard to classify patients into different subgroups of FHL. The diagnosis, once based on a clinical constellation of abnormalities, is now strongly supported by the results of a functional flow-cytometry screening, which directs the genetic study. A few additional congenital immune deficiencies can also cause a resembling or even identical clinical picture to FHL. As in many other rare human disorders, the collection and analysis of a relatively large number of cases in registries is crucial to draw a complete picture of the disease. The conduction of prospective therapeutic trials allows investigators to increase the awareness of the disease and to speed up the diagnostic process, but also provides important functional and genetic confirmations. Children with confirmed diagnosis may undergo hematopoietic stem cell transplantation, which is the only cure known to date. Moreover, detailed characterization of these rare patients helped to understand the function of individual proteins within the exocytic machinery of CTL, NK, and NKT cells. Moreover, identification of these genotypes also provides valuable information on variant phenotypes, other than FHL, associated with biallelic and monoallelic mutations in the FHL-related genes. In this review, we describe how detailed characterization of patients with genetic hemophagocytic lymphohistiocytosis has resulted in improvement in knowledge regarding contribution of individual proteins to the functional machinery of cytotoxic T- and NK-cells. The review also details how identification of these genotypes has provided valuable information on variant phenotypes.
authors.affiliation: Department Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer Children Hospital , Florence , Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Sieni
authors.affiliation: Department Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer Children Hospital , Florence , Italy ; Pediatric Hematology Oncology Network, Istituto Toscano Tumori (I.T.T.) , Florence , Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cetica
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge Biomedical Campus , Cambridge , UK.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Hackmann
authors.affiliation: Department Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer Children Hospital , Florence , Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Coniglio
authors.affiliation: Department Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer Children Hospital , Florence , Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Da Ros
authors.affiliation: Department Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer Children Hospital , Florence , Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Ciambotti
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro , Genoa , Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pende
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge Biomedical Campus , Cambridge , UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: Griffiths
authors.affiliation: Pediatric Hematology Oncology Network, Istituto Toscano Tumori (I.T.T.) , Florence , Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Aricò
keywords: cellular cytotoxicity; hemophagocytosis; mutation analysis; natural killer