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Edward M Behrens, Randy Q Cron, Kill or Be Killed, The Journal of Immunology, Volume 194, Issue 11, June 2015, Pages 5041–5043, https://doi.org/10.4049/jimmunol.1500774
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Hemophagocytic lymphohistiocytosis (HLH) refers to a group of rare genetic disorders characterized by a massive proinflammatory cytokine storm resulting in coagulopathy, CNS dysfunction, increased hemophagocytosis, pancytopenia, multiorgan failure, and death (1). Defects in cytolytic function are typical in the immune cells of these infants, and without early aggressive immunosuppression and bone marrow transplantation, familial HLH (fHLH) is a uniformly fatal condition that affects 1 in 50,000 live births (2). Even with bone marrow transplantation, 5-y survival rates are ∼50% (3). Most of the familial cases of HLH are associated with autosomal recessive disorders. The first of these genes to be identified as a cause of fHLH was perforin (4).
In 1999, Stepp et al. (4) connected two important facts, that defects in cytotoxic function had been regularly associated with fHLH, and that the 10q21–22 locus had been consistently linked to multiple families with fHLH in their pedigrees. They hypothesized that the missing link connecting these two associations was that the gene encoding perforin, a critical effector molecule of cytotoxic function, mapped to the 10q21–22 locus. In their landmark paper (4), they went on to more finely map perforin to the centromeric end of the 10q21 locus, and then showed that eight of eight unrelated fHLH patients studied with 10q21–22 linkage had mutations in their perforin genes. To demonstrate that perforin-mediated cytotoxicity was indeed defective in these patients, they used a Fas-deficient target cell in combination with a Fas-blocking Ab in an anti-CD3 Ab-mediated cell killing assay to eliminate the possibility that Fas–Fas ligand interactions might confound killing measurements. T lymphocytes from patients harboring a nonsense mutation mediated no killing in this assay, and cells from patients with a missense mutation had dramatically reduced killing, suggesting that the genetic alterations in perforin in these patients did indeed result in loss of perforin-mediated killing. The authors then went on to demonstrate loss of perforin protein in these patients by immunofluoresence, showing no, or greatly reduced, perforin staining in granzyme B+ vesicles. Thus, the genetic lesions in perforin were linked to both protein level and function in these patients, supporting loss of perforin as a functional cause of fHLH in these patients.
