Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

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

Research output: Contribution to journalJournal articleResearchpeer-review

DOI

  1. Leukemogenic nucleophosmin mutation disrupts the transcription factor hub regulating granulo-monocytic fates

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Hypoglycemia unawareness in type 1 diabetes suppresses brain responses to hypoglycemia

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Breaking down brain barrier breaches in cerebral malaria

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Neutrophil extracellular traps - the dark side of neutrophils

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. The Number of Signaling Pathways Altered by Driver Mutations in Chronic Lymphocytic Leukemia Impacts Disease Outcome

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Blodsygdomme

    Research output: Chapter in Book/Report/Conference proceedingBook chapterCommunication

  4. Variant in ERAP1 promoter region is associated with low expression in a patient with a Behçet-like MHC-I-opathy

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Shared heritability and functional enrichment across six solid cancers

    Research output: Contribution to journalJournal articleResearchpeer-review

View graph of relations

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.

Original languageEnglish
JournalThe Journal of clinical investigation
Volume124
Issue number10
Pages (from-to)4539-48
Number of pages10
ISSN0021-9738
DOIs
Publication statusPublished - 1 Oct 2014

ID: 44846525