Papillon-Lefèvre syndrome patient reveals species-dependent requirements for neutrophil defenses
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Papillon-Lefèvre syndrome patient reveals species-dependent requirements for neutrophil defenses. / Sørensen, Ole E.; Clemmensen, Stine N; Dahl, Sara L; Østergaard, Ole; Heegaard, Niels H H; Glenthøj, Andreas; Nielsen, Finn Cilius; Borregaard, Niels.
In: The Journal of Clinical Investigation, Vol. 124, No. 10, 2014, p. 4539-48.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Papillon-Lefèvre syndrome patient reveals species-dependent requirements for neutrophil defenses
AU - Sørensen, Ole E.
AU - Clemmensen, Stine N
AU - Dahl, Sara L
AU - Østergaard, Ole
AU - Heegaard, Niels H H
AU - Glenthøj, Andreas
AU - Nielsen, Finn Cilius
AU - Borregaard, Niels
PY - 2014
Y1 - 2014
N2 - Papillon-Lefèvre 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.
AB - Papillon-Lefèvre 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.
KW - Adult
KW - Antimicrobial Cationic Peptides
KW - Bone Marrow
KW - Cathepsin C
KW - Cell Separation
KW - Defensins
KW - Female
KW - Flow Cytometry
KW - Homozygote
KW - Humans
KW - Immune System
KW - Ionomycin
KW - Mutation, Missense
KW - Neutrophils
KW - Papillon-Lefevre Disease
KW - Proteome
KW - Reactive Oxygen Species
KW - Serine Proteases
KW - Subcellular Fractions
U2 - 10.1172/JCI76009
DO - 10.1172/JCI76009
M3 - Journal article
C2 - 25244098
VL - 124
SP - 4539
EP - 4548
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 10
ER -
ID: 135549691