Insights into the cellular pathophysiology of familial hemophagocytic lymphohistiocytosis

Abstract

Familial hemophagocytic lymphohistiocytosis (fHLH) encompasses a group of rare inherited immune dysregulation disorders characterized by loss-of-function mutations in one of several genes involved in the assembly, exocytosis, and function of cytotoxic granules within CD8+ T cells and natural killer (NK) cells. The resulting defect in cytotoxicity allows these cells to be appropriately stimulated in response to an antigenic trigger, and also impairs their ability to effectively mediate and terminate the immune response. Consequently, there is sustained lymphocyte activation, resulting in the secretion of excessive amounts of pro-inflammatory cytokines that further activate other cells of the innate and adaptive immune systems. Together, these activated cells and pro-inflammatory cytokines mediate tissue damage that leads to multi-organ failure in the absence of treatment aimed at controlling hyperinflammation. In this article, we review these mechanisms of hyperinflammation in fHLH at the cellular level, focusing primarily on studies performed in murine models of fHLH that have provided insight into how defects in the lymphocyte cytotoxicity pathway mediate rampant and sustained immune dysregulation.

Innate immunity in rickettsial infections

“…Genetic forms of HPS result from mutations of genes encoding proteins involved in signaling perforin or granzyme delivery for cytolysis of target cells resulting in impaired cytotoxic lymphocyte (CTL) function, often among NK cells ( Schulert et al., 2016 ; Schulert and Cron, 2020 ). Similarly, infection-associated HLH is characterized by defects in CTLs, either by NK lymphopenia or NK cell defects in perforin delivery, although HLH has been observed in humans and animal models with defects in CD8 T cells as well ( Steen et al., 2023 ). The explanation for the relentless progression with HLH and MAS is that the APC-cytotoxic cell synapse through TCR–MHC class I interaction leads to activation of CTLs and production of IL12, IL18, IL15, and IL2, resulting in lymphoproliferation and IFNγ generation.…”

“…IFNγ activates macrophage effector production (nitric oxide, reactive oxygen species, TNFα, phagocytosis). However, the inability of CTLs to deliver perforin to the APC presenting a cognate ligand frees the cascade from regulation by loss of cytolysis of the APC, exacerbating disease due to unremitting APC activation and cytokine stimulation ( Steen et al., 2023 ). This supports the concept of impaired cytotoxicity of innate and adaptive immune CTLs that are unable to exert homeostatic control of APCs following antigen processing and MHC class I expression to these CTLs.…”

A degranulation assay using Vγ9Vδ2 T cells for the rapid diagnosis of familial hemophagocytic syndromes

“…Many different diseases can lead to HLH. Most forms of primary (or familial) HLH are caused by pathogenic genetic variants in the lymphocyte’s cytotoxic machinery ( 3 , 4 ). Other genetic causes for HLH and macrophage activation syndrome (which are distinct from deficiencies in cytotoxicity) have been discovered recently ( 5 ).…”