Familial hemophagocytic lymphohistiocytosis: a model for understanding the human machinery of cellular cytotoxicity

Abstract

Cytotoxic T lymphocytes, natural killer cells, and NKT cells are effector cells able to kill infected cells. In some inherited human disorders, a defect in selected proteins involved in the cellular cytotoxicity mechanism results in specific clinical syndromes, grouped under the name of familial hemophagocytic lymphohistiocytosis. Recent advances in genetic studies of these patients has allowed the identification of different genetic subsets. Additional genetic immune deficiencies may also induce a similar clinical picture. International cooperation and prospective trials resulted in refining the diagnostic and therapeutic approach to these rare diseases with improved outcome but also with improved knowledge of the mechanisms underlying granule-mediated cellular cytotoxicity in humans.

Hemophagocytic lymphohistiocytosis (HLH): A heterogeneous spectrum of cytokine-driven immune disorders

“…Type 1 fHLH encompasses all fHLH patients for whom no specific mutation has been described yet and is thought to represent approximately 10% of all forms of fHLH. In some patients gene mapping has allowed to demarcate a 7.8 cM region on chromosome 9q21.3-22 that is closely linked to disease susceptibility, but the specific gene and corresponding protein are yet to be characterized [7,8,12].…”

“…Secondary HLH associated with the latter two is also referred to as 'macrophage activation syndrome' (MAS). Clinical manifestations in both primary and secondary HLH are often precipitated by an infectious trigger, including viral, bacterial, fungal and protozoan infections, and can possibly be facilitated by immune-modulating therapies [2,3,[6][7][8]. Taken together, HLH comprises a heterogeneous spectrum of etiologically different disorders (Fig.…”

Reduced frequency of CD56dim CD16pos natural killer cells in pediatric systemic inflammatory response syndrome/sepsis patients

“…Through granule-dependent exocytosis, NK cells are able to deliver its various cytotoxic proteins, including perforin, granzymes, granulysin and other lysosomal enzymes, to the target cell. Ultimately, defects in any of the steps, or absence of key proteins, can lead to dysfunctional cellular cytotoxicity (18) and can result in familial hemophagocytic lymphohistiocytosis (FHL) or other syndromes in which hemophagocytic lymphohistiocytosis can be seen. To date, the underlying genetic defect of FHL has been described for four loci, whereas other syndromes have also been shown to have defects of the exocytosis process.…”

Deconstructing the diagnosis of hemophagocytic lymphohistiocytosis using illustrative cases

“…Boys should be tested for signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) and X-linked inhibitor of apoptosis protein (XIAP) encoded by SH2D1A and BIRC4 and mutated in XLP-1 and XLP-2, respectively [15,16], and if SAP and XIAP are normal, CD107a mobilization should be performed next. CD107a (also known as lysosomal-associated membrane protein 1, or LAMP1) colocalizes with perforin in the lytic granules of both 5. Hemophagocytosis in the bone marrow, spleen, lymph nodes, or liver 6.…”

“…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].…”