Publications by authors named "Robin Kahn"

28 Publications

  • Page 1 of 1

Low Intra-Individual Variation in Mean Platelet Volume Over Time in Systemic Lupus Erythematosus.

Front Med (Lausanne) 2021 20;8:638750. Epub 2021 Apr 20.

Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.

Platelets have recently emerged as important immune modulators in systemic lupus erythematosus (SLE), in addition to their role in thrombosis and cardiovascular disease. However, studies investigating mean platelet volume (MPV) in SLE are often scarce, conflicting and cross-sectional. In this study, MPV was measured in clinical routine throughout a defined time-period to quantify both individual MPV fluctuations and investigate if such variations are associated with disease activity and clinical phenotypes of SLE. Of our 212 patients, 34 patients had only one MPV value reported with the remaining 178 patients having between 2 and 19 visits with recorded MPV values. The intra-individual MPV variation was low, with a median variation of 0.7 fL. This was further supported by the finding that 84% of patients stayed within their reference interval category (i.e., small, normal or large) over time. In our cohort, no correlation between disease activity and MPV neither cross-sectionally nor longitudinally was found. Mean platelet volume values were significantly smaller in SLE patients (mean 10.5 fL) compared to controls (mean 10.8 fL), < 0.0001. Based on the reference interval, 2.4% ( = 5) of patients had large-sized platelets, 84.4% ( = 179) had normal-sized and 13.2% ( = 28) had small-sized. A larger proportion (85.7%) of patients with small-sized platelets met the anti-dsDNA criterion (ACR10b; = 0.003) compared to patients with normal and large (57.6%) sized platelets. In conclusion, the intra-individual MPV variation was of low magnitude and fluctuations in disease activity did not have any significant impact on MPV longitudinally. This lack of variability in MPV over time indicates that measuring MPV at any time-point is sufficient. Further studies are warranted to evaluate MPV as a possible biomarker in SLE, as well as to determine the underlying mechanisms influencing platelet size in SLE.
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http://dx.doi.org/10.3389/fmed.2021.638750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093559PMC
April 2021

Synovial fluid neutrophils in oligoarticular juvenile idiopathic arthritis have an altered phenotype and impaired effector functions.

Arthritis Res Ther 2021 Apr 9;23(1):109. Epub 2021 Apr 9.

Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden.

Background: Neutrophils are the most prevalent immune cells in the synovial fluid in inflamed joints of children with oligoarticular juvenile idiopathic arthritis (JIA). Despite this, little is known about neutrophil function at the site of inflammation in JIA and how local neutrophils contribute to disease pathogenesis. This study aimed to characterize the phenotype and function of synovial fluid neutrophils in oligoarticular JIA.

Methods: Neutrophils obtained from paired blood and synovial fluid from patients with active oligoarticular JIA were investigated phenotypically (n = 17) and functionally (phagocytosis and oxidative burst, n = 13) by flow cytometry. In a subset of patients (n = 6), blood samples were also obtained during inactive disease at a follow-up visit. The presence of CD206-expressing neutrophils was investigated in synovial biopsies from four patients by immunofluorescence.

Results: Neutrophils in synovial fluid had an activated phenotype, characterized by increased CD66b and CD11b levels, and most neutrophils had a CD16 CD62Laged phenotype. A large proportion of the synovial fluid neutrophils expressed CD206, a mannose receptor not commonly expressed by neutrophils but by monocytes, macrophages, and dendritic cells. CD206-expressing neutrophils were also found in synovial tissue biopsies. The synovial fluid neutrophil phenotype was not dependent on transmigration alone. Functionally, synovial fluid neutrophils had reduced phagocytic capacity and a trend towards impaired oxidative burst compared to blood neutrophils. In addition, the effector functions of the synovial fluid neutrophils correlated negatively with the proportion of CD206 neutrophils.

Conclusions: Neutrophils in the inflamed joint in oligoarticular JIA were altered, both regarding phenotype and function. Neutrophils in the synovial fluid were activated, had an aged phenotype, had gained monocyte-like features, and had impaired phagocytic capacity. The impairment in phagocytosis and oxidative burst was associated with the phenotype shift. We speculate that these neutrophil alterations might play a role in the sustained joint inflammation seen in JIA.
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http://dx.doi.org/10.1186/s13075-021-02483-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034063PMC
April 2021

High risk of coronary artery aneurysm in Kawasaki disease.

Rheumatology (Oxford) 2021 Apr;60(4):1910-1914

Section of Pediatrics, Pediatrics, Department of Clinical Sciences Lund, Skåne University Hospital, Lund University, Lund, Sweden.

Objective: Kawasaki disease (KD) is a vasculitis of unknown aetiology with a high risk of coronary aneurysms if untreated. Timely treatment with intravenous immunoglobulin decreases the risk for coronary artery aneurysms (CAA). In this study, we set out to elucidate the factors associated with the risk of developing CAA.

Methods: Records of all KD-diagnosed children in Skåne between 2004 and 2014 were collected and clinical and demographic data were compiled. KD is defined according to the revised American Heart Association diagnostic criteria and classified as either complete KD (cKD) or incomplete KD (iKD).

Results: KD was diagnosed in 77 children and CAA was found in 31% (n = 24). Children with CAA were younger compared with children without (median; 20 vs 34 months) and intravenous immunoglobulin treatment within 10 days was less likely to be received (75% vs 91%). In children presenting with iKD, 47% developed CAA compared with 21% in cKD patients. Using multivariate analysis, an association between the risk of CAA with low age in children with iKD was observed.

Conclusion: The risk of CAA development is disturbingly high in young children with iKD. This highlights the importance of rapid intense treatment and vigilance in infants, who are the most difficult to diagnose, in order to reduce the frequency of CAA.
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http://dx.doi.org/10.1093/rheumatology/keaa512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023999PMC
April 2021

Mismatch between circulating cytokines and spontaneous cytokine production by leukocytes in hyperinflammatory COVID-19.

J Leukoc Biol 2021 01 13;109(1):115-120. Epub 2020 Aug 13.

Skåne University Hospital, Lund and Malmö, Sweden.

The disease COVID-19 has developed into a worldwide pandemic. Hyperinflammation and high levels of several cytokines, for example, IL-6, are observed in severe COVID-19 cases. However, little is known about the cellular origin of these cytokines. Here, we investigated whether circulating leukocytes from patients with COVID-19 had spontaneous cytokine production. Patients with hyperinflammatory COVID-19 (n = 6) and sepsis (n = 3) were included at Skåne University Hospital, Sweden. Healthy controls were also recruited (n = 5). Cytokines were measured in COVID-19 and sepsis patients using an Immulite immunoassay system. PBMCs were cultured with brefeldin A to allow cytokine accumulation. In parallel, LPS was used as an activator. Cells were analyzed for cytokines and surface markers by flow cytometry. High levels of IL-6 and measurable levels of IL-8 and TNF, but not IL-1β, were observed in COVID-19 patients. Monocytes from COVID-19 patients had spontaneous production of IL-1β and IL-8 (P = 0.0043), but not of TNF and IL-6, compared to controls. No spontaneous cytokine production was seen in lymphocytes from either patients or controls. Activation with LPS resulted in massive cytokine production by monocytes from COVID-19 patients and healthy controls, but not from sepsis patients. Finally, monocytes from COVID-19 patients produced more IL-1β than from healthy controls (P = 0.0087) when activated. In conclusion, monocytes contribute partly to the ongoing hyperinflammation by production of IL-1β and IL-8. Additionally, they are responsive to further activation. This data supports the notion of IL-1β blockade in treatment of COVID-19. However, the source of the high levels of IL-6 remains to be determined.
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http://dx.doi.org/10.1002/JLB.5COVBCR0720-310RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436862PMC
January 2021

Children with oligoarticular juvenile idiopathic arthritis have skewed synovial monocyte polarization pattern with functional impairment-a distinct inflammatory pattern for oligoarticular juvenile arthritis.

Arthritis Res Ther 2020 08 12;22(1):186. Epub 2020 Aug 12.

Department of Pediatrics, Clinical Sciences Lund, Lund University, BMC B13, Klinikgatan 26, 22185, Lund, Sweden.

Background: Juvenile idiopathic arthritis (JIA) is an umbrella term of inflammatory joint diseases in children. Oligoarthritis is the most common form in the Western world, representing roughly 60% of all patients. Monocytes and macrophages play an important role in adult arthritides, but their role in oligoarticular JIA is less studied. Polarization highly influences monocytes' and macrophages' effector functions, broadly separated into pro-inflammatory M1 or anti-inflammatory M2 phenotypes. Here, we set out to investigate the polarization pattern and functional aspects of synovial monocytes in oligoarticular juvenile idiopathic arthritis (JIA).

Methods: Paired synovial fluid, blood samples (n = 13), and synovial biopsies (n = 3) were collected from patients with untreated oligoarticular JIA. Monocytes were analyzed for polarization markers by flow cytometry and qPCR. Effector function was analyzed by a phagocytosis assay. Polarization of healthy monocytes was investigated by stimulation with synovial fluid in vitro. Monocyte/macrophage distribution, polarization, and mRNA expression were investigated in biopsies by immunohistochemistry, immunofluorescence, and in situ hybridization.

Results: Children with oligoarticular JIA have polarized synovial fluid monocytes of a specific M1(IFNγ)/M2(IL-4)-like pattern. This was evidenced by increased surface expression of CD40 (p < 0.001), CD86 (p < 0.001), and CD206 (p < 0.001), but not CD163, as compared to paired circulating monocytes. Additionally, polarization was extensively explored at the mRNA level and synovial fluid monocytes differentially expressed classical markers of M1(IFNγ)/M2(IL-4) polarization compared to circulating monocytes. Synovial fluid monocytes were functionally affected, as assessed by reduced capacity to phagocytose (p < 0.01). Synovial fluid induced M2 markers (CD16 and CD206), but not M1 (CD40) or CD86 in healthy monocytes and did not induce cytokine production. Single and co-expression of surface CD40 and CD206, as well as mRNA expression of IL-10 and TNF, was observed in monocytes/macrophages in synovial biopsies.

Conclusion: Children with untreated oligoarticular JIA have similar and distinct synovial fluid monocyte polarization pattern of mixed pro- and anti-inflammatory features. This pattern was not exclusively a result of the synovial fluid milieu as monocytes/macrophages in the synovial membrane show similar patterns. Our study highlights a distinct polarization pattern in oligoarticular JIA, which could be utilized for future treatment strategies.
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http://dx.doi.org/10.1186/s13075-020-02279-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425414PMC
August 2020

NCF1-339 polymorphism is associated with altered formation of neutrophil extracellular traps, high serum interferon activity and antiphospholipid syndrome in systemic lupus erythematosus.

Ann Rheum Dis 2020 02 8;79(2):254-261. Epub 2019 Nov 8.

Department of Clinical Sciences Lund, Section of Rheumatology, Lunds University Faculty of Medicine, Lund, Skane, Sweden.

​OBJECTIVES: A single nucleotide polymorphism in the NCF1 gene (NCF1-339, rs201802880), encoding NADPH oxidase type II subunit NCF1/p47, reducing production of reactive oxygen species (ROS) is strongly associated with the development of systemic lupus erythematosus (SLE). This study aimed at characterising NCF1-339 effects on neutrophil extracellular trap (NET) formation, type I interferon activity and antibody profile in patients with SLE. ​METHODS: Neutrophil NET-release pathways (n=31), serum interferon (n=141) and finally antibody profiles (n=305) were investigated in SLE subjects from Lund, genotyped for NCF1-339. Then, 1087 SLE subjects from the rheumatology departments of four Swedish SLE centres, genotyped for NCF1-339, were clinically characterised to validate these findings. ​RESULTS: Compared with patients with normal-ROS NCF1-339 genotypes, neutrophils from patients with SLE with low-ROS NCF1-339 genotypes displayed impaired NET formation (p<0.01) and increased dependence on mitochondrial ROS (p<0.05). Low-ROS patients also had increased frequency of high serum interferon activity (80% vs 21.4%, p<0.05) and positivity for anti-β2 glycoprotein I (p<0.01) and anticardiolipin antibodies (p<0.05) but were not associated with other antibodies. We confirmed an over-representation of having any antiphospholipid antibody, OR 1.40 (95% CI 1.01 to 1.95), anti-β2 glycoprotein I, OR 1.82 (95% CI 1.02 to 3.24) and the antiphospholipid syndrome (APS), OR 1.74 (95% CI 1.19 to 2.55) in all four cohorts (n=1087). ​CONCLUSIONS: The NCF1-339 SNP mediated decreased NADPH oxidase function, is associated with high interferon activity and impaired formation of NETs in SLE, allowing dependence on mitochondrial ROS. Unexpectedly, we revealed a striking connection between the ROS deficient NCF1-339 genotypes and the presence of phospholipid antibodies and APS.
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http://dx.doi.org/10.1136/annrheumdis-2019-215820DOI Listing
February 2020

Outcome in juvenile idiopathic arthritis: a population-based study from Sweden.

Arthritis Res Ther 2019 10 28;21(1):218. Epub 2019 Oct 28.

Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.

Background: As the treatment arsenal for children with juvenile idiopathic arthritis (JIA) has expanded during the last decades, follow-up studies are needed on children diagnosed in the era of biological treatment to evaluate if this has improved the outcome. Our aim was to study the epidemiology and outcome of JIA in southern Sweden using a population-based cohort of children with a validated diagnosis of JIA collected over 9 years.

Methods: Potential cases of JIA between 2002 and 2010 were collected after a database search, using the ICD codes M08-M09. The study area was Skåne, the southernmost county of Sweden (population 1.24 million; 17.6% aged < 16 years). The JIA diagnosis was validated and subcategorized through medical record review based on the criteria defined by the International League of Associations for Rheumatism (ILAR). Parameters on disease activity and pharmacologic treatment were recorded annually until the end of the study period (December 31, 2015).

Results: In total, 251 cases of JIA were confirmed. The mean annual incidence rate for JIA was estimated to be 12.8/100,000 children < 16 years, with the highest age-specific annual incidence at the age of 2 years (36/100,000). Oligoarthritis was the largest subgroup (44.7%), and systemic JIA was the smallest subgroup (2.8%). Methotrexate was the most common disease-modifying anti-rheumatic drug prescribed (60.6%). Tumor necrosis factor alpha inhibitors were used as treatment for 23.9% of the children. Only 40.0% of the follow-up years, with a median follow-up time of 8 years, were free of arthritis or uveitis. Uveitis occurred in 10.8% of the children (8.0% chronic uveitis), and the need for joint corrective orthopedic surgery was 9.2%.

Conclusions: The incidence of JIA in this well-defined, population-based cohort is slightly lower than in previously published studies from Scandinavia. The need for orthopedic surgery and the presence of uveitis are diminished compared to studies with patients diagnosed more than 20 years ago. Children with JIA however still experience disease activity more than 50% of the time. In conclusion, we still have long-term challenges in the care for children with JIA, in spite of state-of-the-art treatment.
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http://dx.doi.org/10.1186/s13075-019-1994-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816211PMC
October 2019

Blockade of the kallikrein-kinin system reduces endothelial complement activation in vascular inflammation.

EBioMedicine 2019 Sep 20;47:319-328. Epub 2019 Aug 20.

Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden. Electronic address:

Background: The complement and kallikrein-kinin systems (KKS) are activated during vascular inflammation. The aim of this study was to investigate if blockade of the KKS can affect complement activation on the endothelium during inflammation.

Methods: Complement deposition on endothelial microvesicles was assayed in vasculitis patient plasma samples and controls. Plasma was perfused over glomerular endothelial cells and complement deposition assayed by flow cytometry. The effect of the kinin system was assessed using kinin receptor antagonists and C1-inhibitor. The in vivo effect was assessed in kidney sections from mice with nephrotoxic serum-induced glomerulonephritis treated with a kinin receptor antagonist.

Findings: Vasculitis patient plasma had significantly more C3- and C9-positive endothelial microvesicles than controls. Perfusion of patient acute-phase plasma samples over glomerular endothelial cells induced the release of significantly more complement-positive microvesicles, in comparison to remission or control plasma. Complement activation on endothelial microvesicles was reduced by kinin B1- and B2-receptor antagonists or by C1-inhibitor (the main inhibitor of the classical pathway and the KKS). Likewise, perfusion of glomerular endothelial cells with C1-inhibitor-depleted plasma induced the release of complement-positive microvesicles, which was significantly reduced by kinin-receptor antagonists or C1-inhibitor. Mice with nephrotoxic serum-induced glomerulonephritis exhibited significantly reduced glomerular C3 deposition when treated with a B1-receptor antagonist.

Interpretation: Excessive complement deposition on the endothelium will promote endothelial injury and the release of endothelial microvesicles. This study demonstrates that blockade of the KKS can reduce complement activation and thereby the inflammatory response on the endothelium.

Funding: Full details are provided in the Acknowledgements/Funding section.
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http://dx.doi.org/10.1016/j.ebiom.2019.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796560PMC
September 2019

Low plasma concentrations of apolipoprotein M are associated with disease activity and endothelial dysfunction in systemic lupus erythematosus.

Arthritis Res Ther 2019 05 2;21(1):110. Epub 2019 May 2.

Department of Rheumatology, Clinical Sciences, Lund University, SE-22185, Lund, Sweden.

Background: Apolipoprotein M (apoM) is a 25-kDa apolipoprotein present in 5% of high-density lipoprotein (HDL) particles. It is suggested to be anti-atherogenic and to play a key role in sustaining endothelial barrier integrity. SLE patients have increased cardiovascular disease risk, and we aimed to investigate if apoM levels reflect endothelial function in SLE. Since apoM plasma levels decrease during inflammatory conditions, our aim was also to determine the impact of SLE disease activity on apoM plasma levels.

Methods: Plasma concentrations of apoM were measured by ELISA in two patient groups with systemic lupus erythematosus (SLE) and in 79 healthy control individuals. In patient group I (n = 84), evaluation time points were selected with the objective to include a wide range of clinical and laboratory variables reflecting disease activity which was measured as SLEDAI. In patient group II consisting of 140 consecutive patients, endothelial function was measured by a finger plethysmograph. A low Reactive Hyperemia Index (RHI) value indicates endothelial dysfunction.

Results: SLE patients had decreased levels of apoM compared to healthy controls (p < 0.01), with apoM levels correlating inversely with SLEDAI (r = - 0.31, p < 0.01) as well as with levels of CRP (r = - 0.26, p = 0.02) and positively with levels of C3 (r = 0.29, p < 0.01). ApoM levels were particularly low in patients with active disease from the kidney and skin and in patients with leukopenia or positive anti-dsDNA antibody test (p < 0.05). ApoM levels correlated with RHI values in young SLE patients (r = 0.32, p = 0.01), consistent with the important role of apoM in regulating endothelial integrity.

Conclusions: ApoM levels may be regulated by SLE-related inflammatory processes and could be a marker of disease activity and endothelial dysfunction, in particular in young SLE patients. Further studies are needed to investigate the predictive value of apoM in the development of a cardiovascular disease.
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http://dx.doi.org/10.1186/s13075-019-1890-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498515PMC
May 2019

Heparin-Binding Protein as a Prognostic Biomarker of Sepsis and Disease Severity at the Emergency Department.

Shock 2019 12;52(6):e135-e145

Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden.

Objective: Rapid and early detection of patients at risk to develop sepsis remains demanding. Heparin-binding protein (HBP) has previously demonstrated good prognostic properties in detecting organ dysfunction among patients with suspected infections. This study aimed to evaluate the plasma levels of HBP as a prognostic biomarker for infection-induced organ dysfunction among patients seeking medical attention at the emergency department.

Design: Prospective, international multicenter, convenience sample study.

Setting: Four general emergency departments at academic centers in Sweden, Switzerland, and Canada.

Patients: All emergency encounters among adults where one of the following criteria were fulfilled: respiratory rate >25 breaths per minute; heart rate >120 beats per minute; altered mental status; systolic blood pressure <100 mm Hg; oxygen saturation <90% without oxygen; oxygen saturation <93% with oxygen; reported oxygen saturation <90%.

Intervention: None.

Measurements And Main Results: A total of 524 emergency department patients were prospectively enrolled, of these 236 (45%) were eventually adjudicated to have a noninfectious disease. Three hundred forty-seven patients (66%) had or developed organ dysfunction within 72 h, 54 patients (10%) were admitted to an intensive care unit, and 23 patients (4%) died within 72 h. For the primary outcome, detection of infected-related organ dysfunction within 72 h, the area under the receiver operating curve (AUC) for HBP was 0.73 (95% CI 0.68-0.78) among all patients and 0.82 (95% CI 0.76-0.87) among patients confidently adjudicated to either infection or no infection. Against the secondary outcome, infection leading to admittance to the ICU, death or a persistent high SOFA-score due to an infection (SOFA-score ≥5 at 12-24 h) HBP had an AUC of 0.87 (95% CI 0.79-0.95) among all patients and 0.88 (95% CI 0.77-0.99) among patients confidently adjudicated to either infection or noninfection.

Conclusions: Among patients at the emergency department, HBP demonstrated good prognostic and discriminatory properties in detecting the most severely ill patients with infection.
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http://dx.doi.org/10.1097/SHK.0000000000001332DOI Listing
December 2019

Human G protein-coupled receptor 30 is -glycosylated and N-terminal domain asparagine 44 is required for receptor structure and activity.

Biosci Rep 2019 02 26;39(2). Epub 2019 Feb 26.

Department of Experimental Medical Science, Lund University, Lund 22184, Sweden

G protein-coupled receptor 30 (GPR30), or G protein-coupled estrogen receptor (GPER), is a G protein-coupled receptor (GPCR) that is currently attracting considerable attention in breast cancer and cardiometabolic regulation. The receptor was reported to be a novel membrane estrogen receptor mediating rapid non-genomic responses. However, questions remain about both the cognate ligand and the subcellular localization of receptor activity. Here, we used human embryonic kidney (HEK) 293 (HEK293) cells ectopically expressing N-terminally FLAG-tagged human GPR30 and three unique antibodies (Ab) specifically targetting the receptor N-terminal domain (N-domain) to investigate the role of -glycosylation in receptor maturation and activity, the latter assayed by constitutive receptor-stimulated extracellular-regulated protein kinase (ERK) 1/2 (ERK1/2) activity. GPR30 expression was complex with receptor species spanning from approximately 40 kDa to higher molecular masses and localized in the endoplasmatic reticulum (ER), the plasma membrane (PM), and endocytic vesicles. The receptor contains three conserved asparagines, Asn, Asn, and Asn, in consensus -glycosylation motifs, all in the N-domain, and PNGase F treatment showed that at least one of them is -glycosylated. Mutating Asn to isoleucine inactivated the receptor, yielding a unique receptor species at approximately 20 kDa that was recognized by Ab only in a denatured state. On the other hand, mutating Asn or Asn either individually or in combination, or truncating successively N-domain residues 1-42, had no significant effect either on receptor structure, maturation, or activity. Thus, Asn in the GPR30 N-domain is required for receptor structure and activity, whereas N-domain residues 1-42, including specifically Asn and Asn, do not play any major structural or functional role(s).
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http://dx.doi.org/10.1042/BSR20182436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390128PMC
February 2019

Exosomes and microvesicles in normal physiology, pathophysiology, and renal diseases.

Pediatr Nephrol 2019 01 27;34(1):11-30. Epub 2017 Nov 27.

Department of Pediatrics, Clinical Sciences Lund, Lund University, 22185, Lund, Sweden.

Extracellular vesicles are cell-derived membrane particles ranging from 30 to 5,000 nm in size, including exosomes, microvesicles, and apoptotic bodies. They are released under physiological conditions, but also upon cellular activation, senescence, and apoptosis. They play an important role in intercellular communication. Their release may also maintain cellular integrity by ridding the cell of damaging substances. This review describes the biogenesis, uptake, and detection of extracellular vesicles in addition to the impact that they have on recipient cells, focusing on mechanisms important in the pathophysiology of kidney diseases, such as thrombosis, angiogenesis, tissue regeneration, immune modulation, and inflammation. In kidney diseases, extracellular vesicles may be utilized as biomarkers, as they are detected in both blood and urine. Furthermore, they may contribute to the pathophysiology of renal disease while also having beneficial effects associated with tissue repair. Because of their role in the promotion of thrombosis, inflammation, and immune-mediated disease, they could be the target of drug therapy, whereas their favorable effects could be utilized therapeutically in acute and chronic kidney injury.
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http://dx.doi.org/10.1007/s00467-017-3816-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244861PMC
January 2019

Endothelial dysfunction is associated with activation of the type I interferon system and platelets in patients with systemic lupus erythematosus.

RMD Open 2017 25;3(2):e000508. Epub 2017 Oct 25.

Department of Rheumatology, Clinical Sciences Lund, Lunds University, Lund, Sweden.

Objectives: Endothelial dysfunction may be connected to cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). Type I interferons (IFNs) are central in SLE pathogenesis and are suggested to induce both endothelial dysfunction and platelet activation. In this study, we investigated the interplay between endothelial dysfunction, platelets and type I IFN in SLE.

Methods: We enrolled 148 patients with SLE and 79 sex-matched and age-matched healthy controls (HCs). Type I IFN activity was assessed with a reporter cell assay and platelet activation by flow cytometry. Endothelial dysfunction was assessed using surrogate markers of endothelial activation, soluble vascular cell adhesion molecule-1 (sVCAM-1) and endothelial microparticles (EMPs), and finger plethysmograph to determine Reactive Hyperaemia Index (RHI).

Results: In patients with SLE, type I IFN activity was associated with endothelial activation, measured by high sVCAM-1 (OR 1.68, p<0.01) and elevated EMPs (OR 1.40, p=0.03). Patients with SLE with high type I IFN activity had lower RHI than HCs (OR 2.61, p=0.04), indicating endothelial dysfunction.Deposition of complement factors on platelets, a measure of platelet activation, was seen in patients with endothelial dysfunction. High levels of sVCAM-1 were associated with increased deposition of C4d (OR 4.57, p<0.01) and C1q (OR 4.10, p=0.04) on platelets. High levels of EMPs were associated with C4d deposition on platelets (OR 3.64, p=0.03).

Conclusions: Endothelial dysfunction was associated with activation of platelets and the type I IFN system. We suggest that an interplay between the type I IFN system, injured endothelium and activated platelets may contribute to development of CVD in SLE.
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http://dx.doi.org/10.1136/rmdopen-2017-000508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663269PMC
October 2017

G protein-coupled estrogen receptor 1 (GPER1)/GPR30 increases ERK1/2 activity through PDZ motif-dependent and -independent mechanisms.

J Biol Chem 2017 06 27;292(24):9932-9943. Epub 2017 Apr 27.

From the Departments of Experimental Medical Science,

G protein-coupled receptor 30 (GPR30), also called G protein-coupled estrogen receptor 1 (GPER1), is thought to play important roles in breast cancer and cardiometabolic regulation, but many questions remain about ligand activation, effector coupling, and subcellular localization. We showed recently that GPR30 interacts through the C-terminal type I PDZ motif with SAP97 and protein kinase A (PKA)-anchoring protein (AKAP) 5, which anchor the receptor in the plasma membrane and mediate an apparently constitutive decrease in cAMP production independently of G Here, we show that GPR30 also constitutively increases ERK1/2 activity. Removing the receptor PDZ motif or knocking down specifically AKAP5 inhibited the increase, showing that this increase also requires the PDZ interaction. However, the increase was inhibited by pertussis toxin as well as by wortmannin but not by AG1478, indicating that G and phosphoinositide 3-kinase (PI3K) mediate the increase independently of epidermal growth factor receptor transactivation. FK506 and okadaic acid also inhibited the increase, implying that a protein phosphatase is involved. The proposed GPR30 agonist G-1 also increased ERK1/2 activity, but this increase was only observed at a level of receptor expression below that required for the constitutive increase. Furthermore, deleting the PDZ motif did not inhibit the G-1-stimulated increase. Based on these results, we propose that GPR30 increases ERK1/2 activity via two G-mediated mechanisms, a PDZ-dependent, apparently constitutive mechanism and a PDZ-independent G-1-stimulated mechanism.
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http://dx.doi.org/10.1074/jbc.M116.765875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473245PMC
June 2017

C1-Inhibitor Decreases the Release of Vasculitis-Like Chemotactic Endothelial Microvesicles.

J Am Soc Nephrol 2017 Aug 13;28(8):2472-2481. Epub 2017 Mar 13.

Departments of Pediatrics and

The kinin system is activated during vasculitis and may contribute to chronic inflammation. C1-inhibitor is the main inhibitor of the kinin system. In this study, we investigated the presence of the kinin B1 receptor on endothelial microvesicles and its contribution to the inflammatory process. Compared with controls (=15), patients with acute vasculitis (=12) had markedly higher levels of circulating endothelial microvesicles, identified by flow cytometry analysis, and significantly more microvesicles that were positive for the kinin B1 receptor (<0.001). Compared with microvesicles from wild-type cells, B1 receptor-positive microvesicles derived from transfected human embryonic kidney cells induced a significant neutrophil chemotactic effect, and a B1 receptor antagonist blocked this effect. Likewise, patient plasma induced neutrophil chemotaxis, an effect decreased by reduction of microvesicle levels and by blocking the B1 receptor. We used a perfusion system to study the effect of patient plasma (=6) and control plasma (=6) on the release of microvesicles from glomerular endothelial cells. Patient samples induced the release of significantly more B1 receptor-positive endothelial microvesicles than control samples, an effect abrogated by reduction of the microvesicles in the perfused samples. Perfusion of C1-inhibitor-depleted plasma over glomerular endothelial cells promoted excessive release of B1 receptor-positive endothelial microvesicles compared with normal plasma, an effect significantly decreased by addition of C1-inhibitor or B1 receptor-antagonist. Thus, B1 receptor-positive endothelial microvesicles may contribute to chronic inflammation by inducing neutrophil chemotaxis, and the reduction of these microvesicles by C1-inhibitor should be explored as a potential treatment for neutrophil-induced inflammation.
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http://dx.doi.org/10.1681/ASN.2016060637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533224PMC
August 2017

Decreased platelet size is associated with platelet activation and anti-phospholipid syndrome in systemic lupus erythematosus.

Rheumatology (Oxford) 2017 03;56(3):408-416

Department of Clinical Sciences Lund, Section of Rheumatology, Lund, Sweden.

Objectives: . SLE is an autoimmune disease with increased cardiovascular morbidity and platelet activation. In the general population, increased platelet size predicts platelet reactivity and cardiovascular disease. The aim of this study was to investigate whether platelet size related to platelet activation and cardiovascular disease in SLE.

Methods: . Fresh blood samples from SLE patients ( n = 148), healthy volunteers ( n = 79) and disease controls ( n = 40) were analysed for platelet size and activation by flow cytometry, ELISA and cell count. Associations to manifest cardiovascular disease, venous thrombosis and APS were adjusted for traditional cardiovascular risk factors using logistic regression analysis.

Results: . SLE patients had decreased platelet size as compared with healthy controls ( P = 0.003). In SLE, decreased platelet size was related to increased platelet activation, in particular microparticle formation ( P < 0.0001, r = -0.46) and release of serotonin from dense granules ( P < 0.001, r = 0.57). SLE patients with aCL had decreased platelet size ( P = 0.02) and aCL decreased platelet size in vitro ( P = 0.007). In contrast to the general population, increased platelet size was not associated with cardiovascular disease. Instead, decreased platelet size was associated with secondary APS, even after adjusting for traditional cardiovascular risk factors ( P = 0.01, odds ratio 3.58).

Conclusion: . Platelet size is decreased in SLE patients and associated with microparticle formation and APS. Future studies are needed to determine the underlying mechanism(s) as well as the potential predictive value of small platelets for disease complications in SLE.
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http://dx.doi.org/10.1093/rheumatology/kew437DOI Listing
March 2017

Microvesicle transfer of kinin B1-receptors is a novel inflammatory mechanism in vasculitis.

Kidney Int 2017 01 1;91(1):96-105. Epub 2016 Dec 1.

Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden. Electronic address:

During vasculitis, activation of the kinin system induces inflammation, whereby the kinin B1-receptor is expressed and activated after ligand binding. Additionally, activated blood cells release microvesicles into the circulation. Here we determined whether leukocyte-derived microvesicles bear B1-kinin receptors during vasculitis, and if microvesicles transfer functional B1-receptors to recipient cells, thus promoting inflammation. By flow cytometry, plasma from patients with vasculitis were found to contain high levels of leukocyte-derived microvesicles bearing B1-receptors. Importantly, renal biopsies from two patients with vasculitis showed leukocyte-derived microvesicles bearing B1-receptors docking on glomerular endothelial cells providing in vivo relevance. Microvesicles derived from B1-receptor-transfected human embryonic kidney cells transferred B1-receptors to wild-type human embryonic kidney cells, lacking the receptor, and to glomerular endothelial cells. The transferred B1-receptors induced calcium influx after B1-receptor agonist stimulation: a response abrogated by a specific B1-receptor antagonist. Microvesicles derived from neutrophils also transferred B1-receptors to wild-type human embryonic kidney cells and induced calcium influx after stimulation. Thus, we found a novel mechanism by which microvesicles transfer functional receptors and promote kinin-associated inflammation.
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http://dx.doi.org/10.1016/j.kint.2016.09.023DOI Listing
January 2017

Platelet-Derived S100A8/A9 and Cardiovascular Disease in Systemic Lupus Erythematosus.

Arthritis Rheumatol 2016 08;68(8):1970-80

Lund University and Skåne University Hospital, Lund, Sweden.

Objective: Levels of S100A8/A9, a proinflammatory and prothrombotic protein complex, are increased in several diseases, and high levels predispose to cardiovascular disease (CVD). Recently, platelet S100A8/A9 synthesis was described in mice and humans in relation to CVD. The aim of this study was to investigate the role of platelet S100A8/A9 in systemic lupus erythematosus (SLE), a disease with markedly increased cardiovascular morbidity, as well as the exact platelet distribution of the S100A8/A9 proteins.

Methods: The occurrence and distribution of platelet S100A8/A9 protein were detected by enzyme-linked immunosorbent assay, electron microscopy, Western blotting, and flow cytometry in healthy controls (n = 79) and in 2 individual cohorts of SLE patients (n = 148 and n = 318, respectively) and related to cardiovascular morbidity.

Results: We observed that human platelets expressed S100A8/A9 proteins, and that these were localized in close proximity to intracellular membranes and granules as well as on the cell surface upon activation with physiologic and pathophysiologic stimuli. Interestingly, S100A8/A9 was enriched at sites of membrane interactions, indicating a role of S100A8/A9 in cell-cell communication. S100A8/A9 levels were highly regulated by interferon-α, both in vivo and in vitro. Patients with SLE had increased platelet S100A8/A9 content compared with healthy individuals. Increased levels of platelet S100A8/A9 were associated with CVD, particularly myocardial infarction (odds ratio 4.8, 95% confidence interval 1.5-14.9, P = 0.032 [adjusted for age, sex, and smoking]).

Conclusion: Platelets contain S100A8/A9 in membrane-enclosed vesicles, enabling rapid cell surface deposition upon activation. Furthermore, platelet S100A8/A9 protein levels were increased in SLE patients, particularly in those with CVD, and may be a future therapeutic target.
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http://dx.doi.org/10.1002/art.39656DOI Listing
August 2016

Circulating complexes between tumour necrosis factor-alpha and etanercept predict long-term efficacy of etanercept in juvenile idiopathic arthritis.

Acta Paediatr 2016 Apr 1;105(4):427-32. Epub 2016 Feb 1.

Department of Rheumatology, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden.

Aim: The relationship between tumour necrosis factor-alpha (TNF-α) and drug survival had not been studied in juvenile idiopathic arthritis (JIA), and there were no laboratory tests to predict the long-term efficacy of biological drugs for JIA. We studied whether serum levels of TNF-α, free or bound to etanercept, could predict long-term efficacy of etanercept in children with JIA.

Methods: We included 41 biologic-naïve patients with JIA who started treatment with etanercept at Skåne University Hospital between 1999 and 2010. Serum taken at the start of treatment and at the six-week follow-up were analysed for TNF-α and the long-term efficacy of etanercept was assessed using the drug survival time.

Results: Levels of TNF-α increased significantly at the six-week follow-up, and this was almost exclusively comprised of TNF-α in complex with etanercept. The increase in TNF-α showed a dose-dependent correlation to long-term drug survival (p < 0.01).

Conclusion: Increasing levels of circulating TNF-α at treatment initiation predicted long-term efficacy of etanercept in children with JIA, which may have been due to different pathophysiological mechanisms of inflammation. Our result may provide a helpful clinical tool, as high levels of circulating TNF-α/etanercept complexes could be used as a marker for the long-term efficacy of etanercept.
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http://dx.doi.org/10.1111/apa.13319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066673PMC
April 2016

Complement Interactions with Blood Cells, Endothelial Cells and Microvesicles in Thrombotic and Inflammatory Conditions.

Adv Exp Med Biol 2015 ;865:19-42

Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden,

The complement system is activated in the vasculature during thrombotic and inflammatory conditions. Activation may be associated with chronic inflammation on the endothelial surface leading to complement deposition. Complement mutations allow uninhibited complement activation to occur on platelets, neutrophils, monocytes, and aggregates thereof, as well as on red blood cells and endothelial cells. Furthermore, complement activation on the cells leads to the shedding of cell derived-microvesicles that may express complement and tissue factor thus promoting inflammation and thrombosis. Complement deposition on red blood cells triggers hemolysis and the release of red blood cell-derived microvesicles that are prothrombotic. Microvesicles are small membrane vesicles ranging from 0.1 to 1 μm, shed by cells during activation, injury and/or apoptosis that express components of the parent cell. Microvesicles are released during inflammatory and vascular conditions. The repertoire of inflammatory markers on endothelial cell-derived microvesicles shed during inflammation is large and includes complement. These circulating microvesicles may reflect the ongoing inflammatory process but may also contribute to its propagation. This overview will describe complement activation on blood and endothelial cells and the release of microvesicles from these cells during hemolytic uremic syndrome, thrombotic thrombocytopenic purpura and vasculitis, clinical conditions associated with enhanced thrombosis and inflammation.
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http://dx.doi.org/10.1007/978-3-319-18603-0_2DOI Listing
December 2015

Type I interferon-mediated skewing of the serotonin synthesis is associated with severe disease in systemic lupus erythematosus.

PLoS One 2015 21;10(4):e0125109. Epub 2015 Apr 21.

Department of Clinical Sciences Lund, Section of Rheumatology, Lund University and Skåne University Hospital, Lund, Sweden.

Serotonin, a highly pro-inflammatory molecule released by activated platelets, is formed by tryptophan. Tryptophan is also needed in the production of kynurenine, a process mediated by the type I interferon (IFN)-regulated rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO). The aim of this study was to investigate levels of serotonin in patients with the autoimmune disease systemic lupus erythematosus (SLE), association to clinical phenotype and possible involvement of IDO in regulation of serotonin synthesis. Serotonin levels were measured in serum and plasma from patients with SLE (n=148) and healthy volunteers (n=79) by liquid chromatography and ELISA, as well as intracellularly in platelets by flow cytometry. We found that SLE patients had decreased serotonin levels in serum (p=0.01) and platelets (p<0.0001) as compared to healthy individuals. SLE patients with ongoing type I IFN activity, as determined by an in-house reporter assay, had decreased serum levels of serotonin (p=0.0008) as well as increased IDO activity (p<0.0001), as determined by the kynurenine/tryptophan ratio measured by liquid chromatography. Furthermore, SLE sera induced IDO expression in WISH cells in a type I IFN-dependent manner (p=0.008). Also platelet activation contributed to reduce overall availability of serotonin levels in platelets and serum (p<0.05). Decreased serum serotonin levels were associated with severe SLE with presence of anti-dsDNA antibodies and nephritis. In all, reduced serum serotonin levels in SLE patients were related to severe disease phenotype, including nephritis, suggesting involvement of important immunopathological processes. Further, our data suggest that type I IFNs, present in SLE sera, are able to up-regulate IDO expression, which may lead to decreased serum serotonin levels.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0125109PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405357PMC
March 2016

G protein-coupled receptor 30 (GPR30) forms a plasma membrane complex with membrane-associated guanylate kinases (MAGUKs) and protein kinase A-anchoring protein 5 (AKAP5) that constitutively inhibits cAMP production.

J Biol Chem 2014 Aug 24;289(32):22117-27. Epub 2014 Jun 24.

From the Departments of Experimental Medical Science,

GPR30, or G protein-coupled estrogen receptor, is a G protein-coupled receptor reported to bind 17β-estradiol (E2), couple to the G proteins Gs and Gi/o, and mediate non-genomic estrogenic responses. However, controversies exist regarding the receptor pharmacological profile, effector coupling, and subcellular localization. We addressed the role of the type I PDZ motif at the receptor C terminus in receptor trafficking and coupling to cAMP production in HEK293 cells and CHO cells ectopically expressing the receptor and in Madin-Darby canine kidney cells expressing the native receptor. GPR30 was localized both intracellularly and in the plasma membrane and subject to limited basal endocytosis. E2 and G-1, reported GPR30 agonists, neither stimulated nor inhibited cAMP production through GPR30, nor did they influence receptor localization. Instead, GPR30 constitutively inhibited cAMP production stimulated by a heterologous agonist independently of Gi/o. Moreover, siRNA knockdown of native GPR30 increased cAMP production. Deletion of the receptor PDZ motif interfered with inhibition of cAMP production and increased basal receptor endocytosis. GPR30 interacted with membrane-associated guanylate kinases, including SAP97 and PSD-95, and protein kinase A-anchoring protein (AKAP) 5 in the plasma membrane in a PDZ-dependent manner. Knockdown of AKAP5 or St-Ht31 treatment, to disrupt AKAP interaction with the PKA RIIβ regulatory subunit, decreased inhibition of cAMP production, and St-Ht31 increased basal receptor endocytosis. Therefore, GPR30 forms a plasma membrane complex with a membrane-associated guanylate kinase and AKAP5, which constitutively attenuates cAMP production in response to heterologous agonists independently of Gi/o and retains receptors in the plasma membrane.
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http://dx.doi.org/10.1074/jbc.M114.566893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139225PMC
August 2014

Idiopathic angioedema and urticarial vasculitis in a patient with a history of acquired haemophilia.

Acta Derm Venereol 2015 Feb;95(2):227-8

Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Biomedical center B14, Tornavägen 10, SE-221 84 Lund, Sweden.

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http://dx.doi.org/10.2340/00015555-1909DOI Listing
February 2015

Kinin system activation in vasculitis.

Acta Paediatr 2011 Jul 8;100(7):950-7. Epub 2011 Apr 8.

Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.

Unlabelled: Vasculitis is a systemic autoimmune inflammatory disease, characterized by inflammation in and around vessel walls leading to perturbed vessel patency and tissue damage. Many different organs may be involved. In this review, pathogenetic mechanisms of vasculitis are discussed, with special reference to activation of the kinin system. Mechanisms of kinin system activation are described, ultimately leading to release of kinins from high molecular weight kininogen. These vasoactive peptides promote inflammation.

Conclusion:   Kinin system activation during vasculitis promotes inflammation.
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http://dx.doi.org/10.1111/j.1651-2227.2011.02266.xDOI Listing
July 2011

The contact/kinin and complement systems in vasculitis.

APMIS Suppl 2009 Jun(127):48-54

Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.

Vasculitides are a group of conditions with marked inflammation in and around vessel walls and vascular leakage. These conditions may involve the presence of auto-antibodies such as ANCA or may be mediated by other autoimmune or pathogenic mechanisms. Regardless of the primary trigger, vasculitides entail activation of the complement system as well as the contact/kinin system. In vivo and in vitro data support the involvement of these systems showing activation of the alternative, classical and lectin complement pathways as well as release of bradykinin at sites of vascular inflammation. This short review will summarize some of the data regarding the participation of these systems and the interplay between the complement and kinin systems as well as their interaction with the endothelium and neutrophils. Although these systems do not play a primary role in induction of vasculitis, the peptides released contribute to inflammation and vascular leakage and may thus be identified as potential therapeutic targets.
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http://dx.doi.org/10.1111/j.1600-0463.2009.02477.xDOI Listing
June 2009

Neutrophil-derived proteinase 3 induces kallikrein-independent release of a novel vasoactive kinin.

J Immunol 2009 Jun;182(12):7906-15

Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.

The kinin-forming pathway is activated on endothelial cells and neutrophils when high-molecular weight kininogen (HK) is cleaved by plasma kallikrein liberating bradykinin, a potent mediator of inflammation. Kinins are released during inflammatory conditions such as vasculitis, associated with neutrophil influx around blood vessels. Some patients with vasculitis have elevated plasma levels of neutrophil-derived proteinase 3 (PR3) and anti-PR3 Abs. This study investigated if neutrophil-derived PR3 could induce activation of the kinin pathway. PR3 incubated with HK, or a synthetic peptide derived from HK, induced breakdown and release of a novel tridecapeptide termed PR3-kinin, NH(2)-MKRPPGFSPFRSS-COOH, consisting of bradykinin with two additional amino acids on each terminus. The reaction was specific and inhibited by anti-PR3 and alpha(1)-antitrypsin. Recombinant wild-type PR3 incubated with HK induced HK breakdown, whereas mutated PR3, lacking enzymatic activity, did not. PR3-kinin bound to and activated human kinin B(1) receptors, but did not bind to B(2) receptors, expressed by transfected HEK293 cells in vitro. In human plasma PR3-kinin was further processed to the B(2) receptor agonist bradykinin. PR3-kinin exerted a hypotensive effect in vivo through both B(1) and B(2) receptors as demonstrated using wild-type and B(1) overexpressing rats as well as wild-type and B(2) receptor knockout mice. Neutrophil extracts from vasculitis patients and healthy controls contained comparable amounts of PR3 and induced HK proteolysis, an effect that was abolished when PR3 was immunoadsorbed. Neutrophil-derived PR3 can proteolyze HK and liberate PR3-kinin, thereby initiating kallikrein-independent activation of the kinin pathway.
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http://dx.doi.org/10.4049/jimmunol.0803624DOI Listing
June 2009

Contact-system activation in children with vasculitis.

Lancet 2002 Aug;360(9332):535-41

Department of Paediatrics, Lund University, Lund, Sweden.

Background: The contact system triggers the kallikrein-kinin cascade, liberating bradykinin from high-molecular-weight kininogen. Effectors of the contact system have proinflammatory and vasoactive properties. Vasculitis is a condition characterised by inflammation around vessel walls, leading to secondary tissue damage for which the underlying molecular mechanisms are poorly understood. Our aim was to investigate contact-system activation in children with vasculitis.

Methods: We compared 17 children, aged 4-19 years, with vasculitis, engaging the skin, joints, intestines, or kidneys, with 21 controls, aged 2-18 years. We analysed proteolysis of high-molecular-weight kininogen by immunoblotting. Plasma bradykinin concentrations were quantified by ELISA. Kidney and skin biopsies were stained in situ for kinins. Concentrations of heparin binding protein (HBP) were quantified by ELISA.

Findings: We noted extensive proteolysis of high-molecular-weight kininogen in the plasma of 13 of 17 patients, but in only one of 21 controls (p<0.0001). Bradykinin concentrations were higher in the patients' plasma (median 320 ng/L, range <1-19680) than in plasma from controls (11 ng/L, <1-304; p=0.0004). Patients had local release of kinins at sites of inflammation in kidney and skin biopsies. HBP values were raised in patients (17.4 microg/L, 5.4-237.6) compared with controls (6 microg/L, 2.5-43.4; p=0.008).

Interpretation: Activation of the contact system could play a part in the pathogenesis of vasculitis, and explain the inflammation, pain, vasodilatation, and oedema seen in patients.
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http://dx.doi.org/10.1016/S0140-6736(02)09743-XDOI Listing
August 2002