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.

The cytotoxic T lymphocyte immune synapse at a glance

“…Mouse models of these conditions show that upon pathogen challenge, the genetic mutation impairs the secretion of pro-apoptotic factors from CTL (and natural killer) granules, whereas the production of cytokines and their release through a different secretory pathway appears to be enhanced (Brisse et al, 2015;de Saint Basile et al, 2015 preprint;Jenkins et al, 2015;Reefman et al, 2010). The inability of CTLs and natural killer cells to clear the infection whilst continuously secreting cytokines promotes the activity of effector immune cells, leading to a life-threatening hyperinflammatory state (haemophagocytic lymphohistiocytosis, HLH) that requires immunosuppressive therapy and ultimately bonemarrow transplantation (Sieni et al, 2014). To date, four FHLassociated proteins have been identified and a fifth disease-linked genetic locus awaits further investigation (Côte et al, 2009;Feldmann et al, 2003;Ohadi et al, 1999;Stepp et al, 1999;zur Stadt et al, 2009zur Stadt et al, , 2005.…”

Mouse model for acute Epstein–Barr virus infection

“…Although the healthy human immune system is able to control EBV infection, a number of primary immunodeficiencies predispose patients to fatal EBVassociated hematological diseases (5,6). Among those primary immunodeficiencies are inactivating mutations of perforin, a protein that is required for Granzyme-mediated T-cell killing.…”

“…Although an EBV infection is harmless to most people, immunocompromised individuals can develop severe complications. Genetic defects that lead to impaired T-cell function predispose to EBV-driven lymphoproliferative diseases, such as familial hemophagocytic lymphohistiocytosis (FHL) (5,6). FHL presents in infants and is characterized by persistent fever, hemophagocytosis, and cytokine storms.…”

Deconstructing the diagnosis of hemophagocytic lymphohistiocytosis using illustrative cases

“…While the genetic defects identified to date compromise the cytotoxic function of NK and CD8+ T cells, neutrophil and platelet degranulation can also be affected, which explains an association in some cases with inflammatory bowel disease and bruising/bleeding. Table 2 summarizes the genes, types of mutations, proteins they encode and associated features in genetically determined HLH [1,[3][4][5][6][7][8][9][10][11][12][13].…”