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Mutations in genes encoding a key component of cytotoxic granules, or the machinery for their release,underlie the systemic hyperiflammatory symptoms of familial hemophagocytic lymphohistiocytosisFHL, a typically pediatric onset autosomal recessive disorder with five known geneticsubtypes FHL1 - 5. FHL1 mutations have been mapped to chromosome 9, while the respectivegenes 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 activityof the cytotoxic granules. All the other FHL mutations appear to affect some aspect of cytotoxicgranule exocytosis, resulting in impaired target cell killing by cytolytic T lymphocytes CTLs and-ornatural killer NK cells. Recent findings suggest that failure to kill and detach from target cells, andprolonged 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 towardsour understanding of the cell biology of hyperinflammatory responses and hemophagocyticlymphohistiocytosis accompanying pathological conditions such as cancer and viral infections.

KEYWORDS

Cytokine Storms, Cytolytic T Lymphocytes CTLs, Familial Hemophagocytic Lymphohistiocytosis FHL, Natural Killer NK Cells, Hyperinflammation

Cite this paper

Tang, B. 2015 The Cell Biology of Systemic Hyperinflammation Resulting from Failed Cytolytic Target Cell Killing. CellBio, 4, 37-45. doi: 10.4236-cellbio.2015.43005.





Autor: Bor Luen Tang

Fuente: http://www.scirp.org/



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