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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.

SUBMITTER: Sieni E

PROVIDER: S-EPMC3997030 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Familial hemophagocytic lymphohistiocytosis: when rare diseases shed light on immune system functioning.

Sieni Elena E Cetica Valentina V Hackmann Yvonne Y Coniglio Maria Luisa ML Da Ros Martina M Ciambotti Benedetta B Pende Daniela D Griffiths Gillian G Aricò Maurizio M

Frontiers in immunology 20140416

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 constel ...[more]

PMID: 24795715

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Project description:Background: Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders. The lack of comprehensive disease-specific mutation databases may hinder or delay classification of the genetic variants found in samples from these patients. This is especially true for familial hemophagocytic lymphohistiocytosis (FHL), a life-threatening PID classically considered an autosomal recessive condition, but with increasingly demonstrated genetic heterogeneity. Objective: The aim of this study was to build an open-access repository to collect detailed information on the known genetic variants reported in FHL. Methods: We manually reviewed more than 120 articles to identify all reported variants related to FHL. We retrieved relevant information about the allelic status, the number of patients with the same variant, and whether functional assays were done. We stored all the data retrieved in a PostgreSQL database and then built a website on top of it, using the Django framework. Results: The database designed (FHLdb) (https://www.biotoclin.org/FHLdb) contains comprehensive information on reported variants in the 4 genes related to FHL (PRF1, UNC13D, STXBP2, STX11). It comprises 240 missense, 69 frameshift, 51 nonsense, 51 splicing, 10 in-frame indel, 7 deep intronic, and 5 large rearrangement variants together with their allelic status, carrier(s) information, and functional evidence. All genetic variants have been classified as pathogenic, likely pathogenic, uncertain significance, likely benign or benign, according to the American College of Medical Genetics guidelines. Additionally, it integrates information from other relevant databases: clinical evidence from ClinVar and UniProt, population allele frequency from ExAC and gnomAD, and pathogenicity predictions from well-recognized tools (e.g., PolyPhen-2, SIFT). Finally, a diagram depicts the location of the variant relative to the gene exon and protein domain structures. Conclusion: FHLdb includes a broad range of data on the reported genetic variants in familial HLH genes. It is a free-access and easy-to-use resource that will facilitate the interpretation of molecular results of FHL patients, and it illustrates the potential value of disease-specific databases for other PIDs.

Dataset Information

Familial hemophagocytic lymphohistiocytosis: when rare diseases shed light on immune system functioning.

Publications

Familial hemophagocytic lymphohistiocytosis: when rare diseases shed light on immune system functioning.

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