TITLE:
The Cell Biology of Systemic Hyperinflammation Resulting from Failed Cytolytic Target Cell Killing
AUTHORS:
Bor Luen Tang
KEYWORDS:
Cytokine Storms, Cytolytic T Lymphocytes (CTLs), Familial Hemophagocytic Lymphohistiocytosis (FHL), Natural Killer (NK) Cells, Hyperinflammation
JOURNAL NAME:
CellBio,
Vol.4 No.3,
December
22,
2015
ABSTRACT: Mutations in genes encoding a key component of cytotoxic granules, or the machinery for their release,
underlie the systemic hyperiflammatory symptoms of familial hemophagocytic lymphohistiocytosis
(FHL), a typically pediatric onset autosomal recessive disorder with five known genetic
subtypes (FHL1 - 5). FHL1 mutations have been mapped to chromosome 9, while the respective
genes mutated in FHL2 (PRF1), FHL3 (UNC13D/Munc13-4), FHL4 (STX11) and FHL5 (STXBP2/
Munc18b/Munc18-2) have been identified. Perforin gene mutation directly affected the cytolytic activity
of the cytotoxic granules. All the other FHL mutations appear to affect some aspect of cytotoxic
granule exocytosis, resulting in impaired target cell killing by cytolytic T lymphocytes (CTLs) and/or
natural killer (NK) cells. Recent findings suggest that failure to kill and detach from target cells, and
prolonged synapse connection time, promote cytokine hypersecretion by the defective CTLs and NKs,
which in turn result in systemic inflammation. Deciphering the genetics of FHL has contributed towards
our understanding of the cell biology of hyperinflammatory responses and hemophagocytic
lymphohistiocytosis accompanying pathological conditions such as cancer and viral infections.