Chromosome Transfer Activates and Delineates a Locus Control Region for Perforin

Pipkin, Matthew E.; Ljutic, Belma; Cruz-Guilloty, Fernando; Nouzová, Marcela; Rao, Anjana; Zúñiga‐Pflücker, Juan Carlos; Lichtenheld, Mathias G.

doi:10.1016/j.immuni.2006.11.009

Cited by 36 publications

(65 citation statements)

References 48 publications

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“…Therefore, we have no indications so far that this variant in the 5 0 -upstream region of PRF1 contributes to decreased levels of perforin in NK cells of SoJIA patients. However, the transcriptional regulation of PRF1 is complex [42], and recently it was shown that the induction of perforin in activated cytotoxic lymphocytes is under control of distal cis-acting locus control regions (LCRs) upstream of PRF1 [43]. Future studies may be aimed at the identification of mutations in these distal LCRs as putative candidates affecting perforin expression in SoJIA patients.…”

Section: Discussionmentioning

confidence: 99%

Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis

et al. 2009

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Objective. Macrophage activation syndrome (MAS) in systemic onset juvenile idiopathic arthritis (SoJIA) is considered to be an acquired form of familial haemophagocytic lymphohistiocytosis (fHLH). FHLH is an autosomal recessive disorder, characterized by diminished NK cell function and caused by mutations in the perforin gene (PRF1) in 20-50% of patients. Interestingly, SoJIA patients display decreased levels of perforin in NK cells and diminished NK cell function as well. Here, we analysed PRF1 and its putative promoter in SoJIA patients with or without a history of MAS.Methods. DNA of 56 SoJIA patients (41 Italian and 15 Dutch) was isolated. Of these, 15 (27%) had a confirmed history of MAS. We sequenced PRF1 and 1.5 kb of the 5 0 -upstream region. DNA sequence variations in the promoter region were functionally tested in transfection experiments using a human NK cell line.Results. We detected a previously undescribed sequence variation (À499 C > T) in the promoter of PRF1 in 18% of the SoJIA patients. However, transfection experiments did not show functional implications of this variation. Secondly, we found that 11 of 56 (20%) SoJIA patients were heterozygous for missense mutations in PRF1. In particular, we found a high prevalence of the Ala91Val mutation, a variant known to result in defective function of perforin. Interestingly, the prevalence of Ala91Val in SoJIA patients with a history of MAS (20%) was increased compared with SoJIA patients without MAS (9.8%). One SoJIA patient, heterozygous for Ala91Val, showed profound decreased perforin levels at the time of MAS.Conclusions. These findings suggest that PRF1 mutations play a role in the development of MAS in SoJIA patients.

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Section: Discussionmentioning

confidence: 99%

Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis

et al. 2009

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“…A recent study has shown that transcriptional regulation of the PRF1 gene is controlled by a 150 kb-long active chromatin domain. 29 Polymorphisms in this region have never been investigated in relation to the level of perforin expression under normal or pathological conditions. We postulate that the observed variations in the levels of perforin expression and CTL/NK cell cytotoxicity in healthy populations may partly be due to differences in the efficiency of PRF1 transcription.…”

Section: Discussionmentioning

confidence: 99%

Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function

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et al. 2007

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Perforin (PRF), a pore-forming protein expressed in cytotoxic lymphocytes, plays a key role in immune surveillance and immune homeostasis. The A91V substitution has a prevalence of 8% to 9% in population studies. While this variant has been suspected of predisposing to various disorders of immune homeostasis, its effect on perforin's function has not been elucidated. Here we complemented, for the first time, the cytotoxic function of perforin-deficient primary cytotoxic T lymphocytes (CTLs) with wild-type (hPRF-WT) and A91V mutant (hPRF-A91V) perforin. The cytotoxicity of hPRF-A91V-expressing cells was about half that of hPRF-WT-expressing counterparts and coincided with a moderate reduction in hPRF-A91V expression. By contrast, the reduction in cytotoxic function was far more pronounced (more than 10-fold) when purified proteins were tested directly on target cells. The A91V substitution can therefore be manifested by abnormalities at both the lymphocyte (presynaptic) and target cell (postsynaptic) levels. However, the severe intrinsic defect in activity can be partly rescued by expression in the physiological setting of an intact CTL. These findings provide the first direct evidence that hPRF-A91V is functionally abnormal and provides a rationale for why it may be responsible for IntroductionPerforin (PRF; encoded by the PRF1 gene) is a pore-forming protein stored in secretory granules of cytotoxic lymphocytes (CLs) comprising cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. CLs destroy virus-infected or -transformed target cells predominantly through the "granule exocytosis" mechanism, in which the contents of cytotoxic secretory granules are released into the synapse formed between the CL and the target cell. There, perforin synergizes with other granule components, among which are the proapoptotic serine proteases (granzymes) to deliver a lethal hit to the target cell. 1,2 The key role of perforin in immune surveillance has been extensively investigated using perforin knockout (PRF-KO) mice, which display a high sensitivity to several viral infections; develop spontaneous, aggressive disseminated B-cell lymphoma; and fail to optimally reject many transplanted tumors. [3][4][5][6] The first description of an inherited perforin deficiency in humans was in 1999, manifested as a hemophagocytic syndrome termed type 2 familial hemophagocytic lymphohistiocytosis (FHL2). 7 Most missense PRF1 mutations in FHL2 patients result in loss of function at the "presynaptic" level, most commonly due to unfolding and/or faulty trafficking of the protein. 8,9 Recently, mutations in vesicular trafficking proteins such as Munc13-4 10 and Syntaxin 11 11 have also been shown to play a causative role in the disease. Collectively, mutations affecting Munc 13-4, Syntaxin 11, and perforin are responsible for only 30% to 70% cases of the disease, depending on sanguinity, suggesting that other genetic defects leading or predisposing to FHL remain to be identified.The rarity of FHL (estimated to be 1 in 50 000 live births f...

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“…The regulation of PRF1 gene expression is complex and has been revealed only recently in an elegant study by Lichtenheld and coworkers. 11 The study showed a Locus Control Region that regulates cell lineage-and activation signal-specific expression of PRF1. Such a heterochromatin-dependent regulation may enable exogenous stimuli or endogenous transcription-regulating factors to induce PRF1 transcription in other cell types.…”

Section: Perforin Biologymentioning

confidence: 97%

Perforin deficiency and susceptibility to cancer

et al. 2010

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Cytotoxic lymphocytes (CLs) are the killer cells that destroy intracellular pathogen-infected and transformed cells, predominantly through the cytotoxic granule-mediated death pathway. Soluble cytotoxic granule components, including pore-forming perforin and pro-apoptotic serine proteases, granzymes, synergize to induce unscheduled apoptosis of the target cell. A complete loss of CL function results in an aggressive immunoregulatory disorder, familial hemophagocytic lymphohistiocytosis, whereas a partial loss of function seems to be a factor strongly predisposing to hematological malignancies. This review discusses the pathological manifestations of CL deficiencies due to impaired perforin function and describes novel aspects of perforin biology. Cell Death and Differentiation (2010) 17, 607-615; doi:10.1038/cdd.2009; published online 15 January 2010Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, collectively called cytotoxic lymphocytes (CLs), kill virusinfected and transformed cells through a number of contactdependent mechanisms. 1,2 Engagement of death receptors by membrane-bound members of the TNF superfamily of death ligands is critical for maintaining lymphoid homeostasis in the host. By contrast, studies of gene deficiencies indicate that defects of the granule exocytosis pathway result in a failure to eliminate infected cells or those that pose a risk of subsequent malignancy. Although cytotoxic granules contain diverse toxins that together contribute to apoptosis induction, this review will deal exclusively with the critical role of the pore-forming protein perforin (PRF) as an essential enabler of target-cell apoptosis, and its more recently described role as a potential 'extrinsic' tumor suppressor.Perforin is a 67-kDa pore-forming protein that is stored and released from the secretory granules (SGs) of CLs along with a number of pro-apoptotic serine protease granzymes that display broad substrate specificities. 3 Following exocytic release, PRF and the granzymes are exposed to the neutral pH and calciumrich environment of the immune synapse. 4 After binding calcium through their C2 domains, PRF monomers acquire the ability to bind generic lipids in the target cell membrane, 5 and then coalesce into large transmembrane pores that permit the granzymes to access key death substrates in the cytosol. [6][7][8] Although the diverse apoptotic pathways triggered by granzymes have been extensively studied and are now understood in considerable detail, it is only of late that insights into the molecular and cellular functions of PRF have been even partly addressed.In this review, we will re-examine the pathological consequences of PRF deficiency, both in mice and humans. In doing so, important differences in PRF biology between these species will be described. We will discuss the pathogenic effect of a number of recently described missense mutations of human PRF. In particular, although the complete absence of PRF function typically results in an aggressive, fatal immunoregulatory disorder of ea...

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Chromosome Transfer Activates and Delineates a Locus Control Region for Perforin

Cited by 36 publications

References 48 publications

Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis

Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis

Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function

Perforin deficiency and susceptibility to cancer

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