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Papillon-Lefevre syndrome patient reveals species-dependent requirements for neutrophil defenses

Sørensen, Ole E LU ; Clemmensen, Stine N.; Dahl, Sara L.; Ostergaard, Ole; Heegaard, Niels H.; Glenthoj, Andreas; Nielsen, Finn Cilius and Borregaard, Niels (2014) In Journal of Clinical Investigation 124(10). p.4539-4548
Abstract
Papillon-Lefevre syndrome (PLS) results from mutations that inactivate cysteine protease cathepsin C (CTSC), which processes a variety of serine proteases considered essential for antimicrobial defense. Despite serine protease-deficient immune cell populations, PLS patients do not exhibit marked immunodeficiency. Here, we characterized a 24-year-old woman who had suffered from severe juvenile periodontal disease, but was otherwise healthy, and identified a homozygous missense mutation in CTSC indicative of PLS. Proteome analysis of patient neutrophil granules revealed that several proteins that normally localize to azurophil granules, including the major serine proteases, elastase, cathepsin G, and proteinase 3, were absent. Accordingly,... (More)
Papillon-Lefevre syndrome (PLS) results from mutations that inactivate cysteine protease cathepsin C (CTSC), which processes a variety of serine proteases considered essential for antimicrobial defense. Despite serine protease-deficient immune cell populations, PLS patients do not exhibit marked immunodeficiency. Here, we characterized a 24-year-old woman who had suffered from severe juvenile periodontal disease, but was otherwise healthy, and identified a homozygous missense mutation in CTSC indicative of PLS. Proteome analysis of patient neutrophil granules revealed that several proteins that normally localize to azurophil granules, including the major serine proteases, elastase, cathepsin G, and proteinase 3, were absent. Accordingly, neutrophils from this patient were incapable of producing neutrophil extracellular traps (NETs) in response to ROS and were unable to process endogenous cathelicidin hCAP-18. into the antibacterial peptide LL-37 in response to ionomycin. In immature myeloid cells from patient bone marrow, biosynthesis of CTSC and neutrophil serine proteases appeared normal along with initial processing and sorting to cellular storage. In contrast, these proteins were completely absent in mature neutrophils, indicating that CTSC mutation promotes protease degradation in more mature hematopoietic subsets, but does not affect protease production in progenitor cells. Together, these data indicate CTSC protects serine proteases from degradation in mature immune cells and suggest that neutrophil serine proteases are dispensable for human immunoprotection. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Journal of Clinical Investigation
volume
124
issue
10
pages
4539 - 4548
publisher
The Journal of Clinical Investigation
external identifiers
  • wos:000342649900045
  • scopus:84907486038
ISSN
0021-9738
DOI
10.1172/JCI76009
language
English
LU publication?
yes
id
2cc7823b-e94e-4e9c-b978-e66792419992 (old id 4803471)
date added to LUP
2014-12-01 07:34:32
date last changed
2017-11-05 04:02:39
@article{2cc7823b-e94e-4e9c-b978-e66792419992,
  abstract     = {Papillon-Lefevre syndrome (PLS) results from mutations that inactivate cysteine protease cathepsin C (CTSC), which processes a variety of serine proteases considered essential for antimicrobial defense. Despite serine protease-deficient immune cell populations, PLS patients do not exhibit marked immunodeficiency. Here, we characterized a 24-year-old woman who had suffered from severe juvenile periodontal disease, but was otherwise healthy, and identified a homozygous missense mutation in CTSC indicative of PLS. Proteome analysis of patient neutrophil granules revealed that several proteins that normally localize to azurophil granules, including the major serine proteases, elastase, cathepsin G, and proteinase 3, were absent. Accordingly, neutrophils from this patient were incapable of producing neutrophil extracellular traps (NETs) in response to ROS and were unable to process endogenous cathelicidin hCAP-18. into the antibacterial peptide LL-37 in response to ionomycin. In immature myeloid cells from patient bone marrow, biosynthesis of CTSC and neutrophil serine proteases appeared normal along with initial processing and sorting to cellular storage. In contrast, these proteins were completely absent in mature neutrophils, indicating that CTSC mutation promotes protease degradation in more mature hematopoietic subsets, but does not affect protease production in progenitor cells. Together, these data indicate CTSC protects serine proteases from degradation in mature immune cells and suggest that neutrophil serine proteases are dispensable for human immunoprotection.},
  author       = {Sørensen, Ole E and Clemmensen, Stine N. and Dahl, Sara L. and Ostergaard, Ole and Heegaard, Niels H. and Glenthoj, Andreas and Nielsen, Finn Cilius and Borregaard, Niels},
  issn         = {0021-9738},
  language     = {eng},
  number       = {10},
  pages        = {4539--4548},
  publisher    = {The Journal of Clinical Investigation},
  series       = {Journal of Clinical Investigation},
  title        = {Papillon-Lefevre syndrome patient reveals species-dependent requirements for neutrophil defenses},
  url          = {http://dx.doi.org/10.1172/JCI76009},
  volume       = {124},
  year         = {2014},
}