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.
Highlights
Diseased cells, those that express tumor markers and viral antigens, are constantly picked up byHow to cite this paper: Tang, B.L. (2015) The Cell Biology of Systemic Hyperinflammation Resulting from Failed Cytolytic Target Cell Killing
Target cell killing in the vertebrate adaptive and innate immune responses to cancerous or infected cells is mediated by the action of cytolytic T lymphocytes (CTLs) and natural killer (NK) cells [1]
Both CTLs and NK cells kill diseased target cells using cytotoxic or lytic granules containing the complement component 9 (C9)-like pore-forming protein perforin [2]-[4], programmed cell death inducing molecules such as Fas Ligand (FasL) and serine proteases known as granzymes [5] [6]
Summary
Those that express tumor markers and viral antigens, are constantly picked up by. NK cells could be activated by antibodies that bind to disease associated antigens via its FcΥRIII (CD16) receptors Both CTLs and NK cells kill diseased target cells using cytotoxic or lytic granules containing the complement component 9 (C9)-like pore-forming protein perforin [2]-[4], programmed cell death inducing molecules such as Fas Ligand (FasL) and serine proteases known as granzymes [5] [6]. These granules are secretory lysosomes [7] that are generated and secreted via a specialized mode of regulated secretion in cytotoxic killer cells [8]. These advances are described and discussed in the paragraphs below
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