| 1. |
- Sørensen, Ole E, et al.
(author)
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Papillon-Lefevre syndrome patient reveals species-dependent requirements for neutrophil defenses
- 2014
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In: Journal of Clinical Investigation. - 0021-9738. ; 124:10, s. 4539-4548
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Journal article (peer-reviewed)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.
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| 2. |
- Holst, Birgitte, et al.
(author)
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G Protein-Coupled Receptor 39 Deficiency Is Associated with Pancreatic Islet Dysfunction
- 2009
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In: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 150, s. 2577-2585
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Journal article (peer-reviewed)abstract
- G protein-coupled receptor (GPR)-39 is a seven-transmembrane receptor expressed mainly in endocrine and metabolic tissues that acts as a Zn++ sensor signaling mainly through the G(q) and G(12/13) pathways. The expression of GPR39 is regulated by hepatocyte nuclear factor (HNF)-1 alpha and HNF-4 alpha, and in the present study, we addressed the importance of GPR39 for glucose homeostasis and pancreatic islets function. The expression and localization of GPR39 were characterized in the endocrine pancreas and pancreatic cell lines. Gpr39(-/-) mice were studied in vivo, especially in respect of glucose tolerance and insulin sensitivity, and in vitro in respect of islet architecture, gene expression, and insulin secretion. Gpr39 was down-regulated on differentiation of the pluripotent pancreatic cell line AR42J cells toward the exocrine phenotype but was along with Pdx-1 strongly up-regulated on differentiation toward the endocrine phenotype. Immunohistochemistry demonstrated that GRP39 is localized selectively in the insulin-storing cells of the pancreatic islets as well as in the duct cells of the exocrine pancreas. Gpr39(-/-) mice displayed normal insulin sensitivity but moderately impaired glucose tolerance both during oral and iv glucose tolerance tests, and Gpr39(-/-) mice had decreased plasma insulin response to oral glucose. Islet architecture was normal in the Gpr39 null mice, but expression of Pdx-1 and Hnf-1 alpha was reduced. Isolated, perifused islets from Gpr39 null mice secreted less insulin in response to glucose stimulation than islets from wild-type littermates. It is concluded that GPR39 is involved in the control of endocrine pancreatic function, and it is suggested that this receptor could be a novel potential target for the treatment of diabetes. (Endocrinology 150: 2577-2585, 2009)
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| 3. |
- Nielsen, Christoffer T, et al.
(author)
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Increased IgG on cell-derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation.
- 2012
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In: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 64:4, s. 1227-1236
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Journal article (peer-reviewed)abstract
- OBJECTIVE.: To quantify immunoglobulin and C1q on circulating cell-derived microparticles (MPs) in systemic lupus erythematosus (SLE) and to correlate this with clinical and serological parameters. METHODS.: Sixty-eight clinically well-characterized SLE patients, 38 healthy controls (HC), 6 systemic sclerosis (SSc), and 6 rheumatoid arthritis (RA) patients were included. The numbers of annexin V-binding MPs displaying IgG, IgM or C1q were enumerated by flow cytometry. MP protein levels were determined by mass spectrometry in clinically defined subsets of SLE patients and controls. The MP-IgG load was determined by flow cytometry of all SLE and HC samples. RESULTS.: SLE patients had significantly increased total and relative numbers of IgG-positive MPs (p = 0.0004) with a much higher average IgG-load/MP (p < 0.0001) than HCs. Quantitative mass spectrometry of purified MPs verified significantly increased IgG, IgM, and C1q in SLE. In RA and SSc the average IgG/MP was significantly lower than in SLE (p = 0.006 and 0.05, respectively). Also, IgM/MP and C1q/MP were higher in SLE than in controls (p < 0.05) except for IgM in the RA-group. IgG-positive MPs were significantly associated with the presence of anti-dsDNA, anti-ENA, and anti-histone antibodies, with total IgG, and with decreased leukocyte counts. Average IgG/MP was associated with lower concentrations of MPs, the presence of anti-C1q antibodies, and with complement consumption. CONCLUSIONS.: Circulating cell-derived MPs in SLE carry increased loads of IgG, IgM, and C1q and IgG-MPs are associated with autoantibodies and complement activation. The findings link immunological reactions on MPs with the etiopathology of SLE. © 2012 American College of Rheumatology.
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