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Perforinopathy: A Spectrum of Human Immune Disease Caused by Defective Perforin Delivery or Function

Congenital perforin deficiency is considered a rare cause of human immunopathology and immune dysregulation, and classically presents as a fatal illness early in infancy. However, we propose that a group of related disorders in which killer lymphocytes deliver only partially active perforin or a red...

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Autores principales: Voskoboinik, Ilia, Trapani, Joseph A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3860100/
https://www.ncbi.nlm.nih.gov/pubmed/24376445
http://dx.doi.org/10.3389/fimmu.2013.00441
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author Voskoboinik, Ilia
Trapani, Joseph A.
author_facet Voskoboinik, Ilia
Trapani, Joseph A.
author_sort Voskoboinik, Ilia
collection PubMed
description Congenital perforin deficiency is considered a rare cause of human immunopathology and immune dysregulation, and classically presents as a fatal illness early in infancy. However, we propose that a group of related disorders in which killer lymphocytes deliver only partially active perforin or a reduced quantum of wild-type perforin to the immune synapse should be considered part of an extended syndrome with overlapping but more variable clinical features. Apart from the many rare mutations scattered over the coding sequences, up to 10% of Caucasians carry the severely hypomorphic PRF1 allele C272 > T (leading to A91V mutation) and the overall prevalence of the homozygous state for A91V is around 1 in 600 individuals. We therefore postulate that the partial loss of perforin function and its clinical consequences may be more common then currently suspected. An acute clinical presentation is infrequent in A91V heterozygous individuals, but we postulate that the partial loss of perforin function may potentially be manifested in childhood or early adulthood as “idiopathic” inflammatory disease, or through increased cancer susceptibility – either hematological malignancy or multiple, independent primary cancers. We suggest the new term “perforinopathy” to signify the common functional endpoints of all the known consequences of perforin deficiency and failure to deliver fully functional perforin.
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spelling pubmed-38601002013-12-27 Perforinopathy: A Spectrum of Human Immune Disease Caused by Defective Perforin Delivery or Function Voskoboinik, Ilia Trapani, Joseph A. Front Immunol Immunology Congenital perforin deficiency is considered a rare cause of human immunopathology and immune dysregulation, and classically presents as a fatal illness early in infancy. However, we propose that a group of related disorders in which killer lymphocytes deliver only partially active perforin or a reduced quantum of wild-type perforin to the immune synapse should be considered part of an extended syndrome with overlapping but more variable clinical features. Apart from the many rare mutations scattered over the coding sequences, up to 10% of Caucasians carry the severely hypomorphic PRF1 allele C272 > T (leading to A91V mutation) and the overall prevalence of the homozygous state for A91V is around 1 in 600 individuals. We therefore postulate that the partial loss of perforin function and its clinical consequences may be more common then currently suspected. An acute clinical presentation is infrequent in A91V heterozygous individuals, but we postulate that the partial loss of perforin function may potentially be manifested in childhood or early adulthood as “idiopathic” inflammatory disease, or through increased cancer susceptibility – either hematological malignancy or multiple, independent primary cancers. We suggest the new term “perforinopathy” to signify the common functional endpoints of all the known consequences of perforin deficiency and failure to deliver fully functional perforin. Frontiers Media S.A. 2013-12-12 /pmc/articles/PMC3860100/ /pubmed/24376445 http://dx.doi.org/10.3389/fimmu.2013.00441 Text en Copyright © 2013 Voskoboinik and Trapani. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Voskoboinik, Ilia
Trapani, Joseph A.
Perforinopathy: A Spectrum of Human Immune Disease Caused by Defective Perforin Delivery or Function
title Perforinopathy: A Spectrum of Human Immune Disease Caused by Defective Perforin Delivery or Function
title_full Perforinopathy: A Spectrum of Human Immune Disease Caused by Defective Perforin Delivery or Function
title_fullStr Perforinopathy: A Spectrum of Human Immune Disease Caused by Defective Perforin Delivery or Function
title_full_unstemmed Perforinopathy: A Spectrum of Human Immune Disease Caused by Defective Perforin Delivery or Function
title_short Perforinopathy: A Spectrum of Human Immune Disease Caused by Defective Perforin Delivery or Function
title_sort perforinopathy: a spectrum of human immune disease caused by defective perforin delivery or function
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3860100/
https://www.ncbi.nlm.nih.gov/pubmed/24376445
http://dx.doi.org/10.3389/fimmu.2013.00441
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