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.
Highlights
Defense of an organism against pathogens and cancer is accomplished by the cooperation between different cell types of the human immune system, in particular cytotoxic T lymphocytes (CTL), natural killer (NK) cells, and NKT cells [1]
In this review we will address some features of the NK cells, because they are suitable for rapid diagnostic assays, it is important to recognize that T-cells share most of these features and have great relevance in most of the human disease related to impairment of this machinery
NK cells originate in the bone marrow and are released into the bloodstream upon maturation, being able to respond to stimuli such as pathogen molecules, cytokines, or by the interaction with any target cell that expresses ligands for activating NK cell receptors
Summary
Defense of an organism against pathogens and cancer is accomplished by the cooperation between different cell types of the human immune system, in particular cytotoxic T lymphocytes (CTL), natural killer (NK) cells, and NKT cells [1]. Accumulation of reported cases and investigation of consanguineous families allowed to define that the familial form of HLH is a congenital immune deficiency; to date, four subtypes are defined by mutations in the following genes: PRF1 in familial hemophagocytic lymphohistiocytosis type 2 (FHL2), UNC13D in familial hemophagocytic lymphohistiocytosis type 3 (FHL3), STX11 in familial hemophagocytic lymphohistiocytosis type 4 (FHL4), and STXBP2 in familial hemophagocytic lymphohistiocytosis type 5 (FHL5). These subtypes will be described below in more details. Accumulation of a sufficient number of cases helped to establish connections between specific mutations and particular ethnic groups: c.1122G > A (p.W374X) was found to have a high
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