84 results on '"Birgitta Gullstrand"'
Search Results
2. O18 Data-driven clustering of cerebrospinal fluid proteome reflects clinical phenotypes of systemic lupus erythematosus
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Andreas Jönsen, Robin Kahn, Anders A Bengtsson, Pia C Sundgren, Birgitta Gullstrand, Elsa Grenmyr, Jessika Nystedt, Petra C Nilsson, Kristoffer Zervides, Seyed Morteza Najibi, and Charlotte Welinder
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2024
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3. Plasma and cerebrospinal fluid neurofilament light concentrations reflect neuronal damage in systemic lupus Erythematosus
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Kristoffer A. Zervides, Shorena Janelidze, Jessika Nystedt, Birgitta Gullstrand, Petra Nilsson, Pia C. Sundgren, Anders A. Bengtsson, Oskar Hansson, and Andreas Jönsen
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Neurofilament light ,Systemic lupus erythematosus ,Neuropsychiatric ,Biomarker ,Plasma ,Cerebrospinal fluid ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Neuronal damage in systemic lupus erythematosus (SLE) is common, but the extent and mechanisms are unclear. Neurofilament light (NfL) concentrations rise in plasma and cerebrospinal fluid (CSF) during neuronal damage in various neurological disorders. In this cross-sectional study, plasma and CSF concentrations of NfL were explored as a marker of neuronal damage in SLE. Methods Seventy-two consecutive SLE out-patients and 26 healthy controls, all female, aged
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- 2022
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4. Serum S100A8/A9 concentrations are associated with neuropsychiatric involvement in systemic lupus erythematosus: a cross-sectional study
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Kristoffer A. Zervides, Andreas Jern, Jessika Nystedt, Birgitta Gullstrand, Petra C. Nilsson, Pia C. Sundgren, Anders A. Bengtsson, and Andreas Jönsen
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Systemic lupus erythematosus ,Neuropsychiatric systemic lupus erythematosus ,S100A8/A9 ,Fatigue ,Inflammation ,Serum ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Abstract Background Neuropsychiatric (NP) involvement and fatigue are major problems in systemic lupus erythematosus (SLE). S100A8/A9 is a marker of inflammation and responds to therapy in SLE patients. S100A8/A9 has an immunopathogenic role in various neurological diseases. We investigated S100A8/A9 in relation to NP-involvement and fatigue in SLE. Methods 72 consecutive SLE outpatients at a tertiary centre and 26 healthy controls were included in this cross-sectional study. NPSLE was determined by specialists in rheumatology and neurology and defined according to three attribution models: “ACR”, “SLICC A” and “SLICC B”. Cerebral MRI was assessed by a neuroradiologist and neurocognitive testing by a neuropsychologist. The individuals were assessed by scores of pain (VAS), fatigue (VAS and FSS), and depression (MADRS-S). Concentrations of S100A8/A9 in serum and cerebrospinal fluid were measured with ELISA. Statistical calculations were performed using non-parametric methods. Results Serum concentrations of S100A8/A9 were higher in SLE patients compared with controls (medians 1230 ng/ml; 790 ng/ml, p = 0.023). The concentrations were higher in NPSLE patients compared with non-NPSLE patients when applying the SLICC A and ACR models, but not significant when applying the SLICC B model (medians 1400 ng/ml; 920 ng/ml, p = 0.011; 1560 ng/ml; 1090 ng/ml, p = 0.050; 1460 ng/ml; 1090 ng/ml, p = 0.083, respectively). No differences of CSF S100A8/A9 concentrations were observed between NPSLE and non-NPSLE patients. SLE patients with depression or cognitive dysfunction as an ACR NPSLE manifestation had higher serum S100A8/A9 concentrations than non-NPSLE patients (median 1460 ng/ml, p = 0.007 and 1380 ng/ml, p = 0.013, respectively). Higher serum S100A8/A9 correlated with higher VAS fatigue (r = 0.31; p = 0.008) and VAS pain (r = 0.27, p = 0.021) in SLE patients. Serum S100A8/A9 was not independently associated with NPSLE when adjusting for scores of fatigue (FSS) and pain (VAS) (OR 1.86, 95% CI 0.93–3.73, p = 0.08). Conclusions Serum S100A8/A9 concentrations may be associated with NPSLE and fatigue. S100A8/A9 may be of interest in evaluating NPSLE, although further investigations are needed.
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- 2022
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5. Synovial fluid neutrophils in oligoarticular juvenile idiopathic arthritis have an altered phenotype and impaired effector functions
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Sabine Arve-Butler, Tobias Schmidt, Anki Mossberg, Elisabet Berthold, Birgitta Gullstrand, Anders A. Bengtsson, Fredrik Kahn, and Robin Kahn
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Juvenile idiopathic arthritis ,Neutrophil ,Synovial fluid ,Phenotype ,Phagocytosis ,Oxidative burst ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Abstract 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 CD16hi CD62Llowaged 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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- 2021
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6. Children with oligoarticular juvenile idiopathic arthritis have skewed synovial monocyte polarization pattern with functional impairment—a distinct inflammatory pattern for oligoarticular juvenile arthritis
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Tobias Schmidt, Elisabet Berthold, Sabine Arve-Butler, Birgitta Gullstrand, Anki Mossberg, Fredrik Kahn, Anders A. Bengtsson, Bengt Månsson, and Robin Kahn
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Juvenile idiopathic arthritis ,Monocytes ,Polarization ,Inflammation ,Synovitis ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Abstract 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
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- 2020
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7. Comparison of Surrogate Markers of the Type I Interferon Response and Their Ability to Mirror Disease Activity in Systemic Lupus Erythematosus
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Helena Enocsson, Jonas Wetterö, Maija-Leena Eloranta, Birgitta Gullstrand, Cecilia Svanberg, Marie Larsson, Anders A. Bengtsson, Lars Rönnblom, and Christopher Sjöwall
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SLE ,lupus ,biomarker ,disease activity ,interferon ,chemokine ,Immunologic diseases. Allergy ,RC581-607 - Abstract
ObjectivesType I interferons (IFNs) are central and reflective of disease activity in systemic lupus erythematosus (SLE). However, IFN-α levels are notoriously difficult to measure and the type I IFN gene signature (IGS) is not yet available in clinical routine. This study evaluates galectin-9 and an array of chemokines/cytokines in their potential as surrogate markers of type I IFN and/or SLE disease activity.MethodsHealthy controls and well-characterized Swedish SLE patients from two cross-sectional cohorts (n=181; n=59) were included, and a subgroup (n=21) was longitudinally followed. Chemokine/cytokine responses in immune complex triggered IFN-α activity was studied in healthy donor peripheral blood mononuclear cells (PBMC). Levels of chemokines/cytokines and galectin-9 were measured by immunoassays. Gene expression was quantified by qPCR.ResultsThe IGS was significantly (p
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- 2021
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8. Low Intra-Individual Variation in Mean Platelet Volume Over Time in Systemic Lupus Erythematosus
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Lina Wirestam, Birgitta Gullstrand, Andreas Jern, Andreas Jönsen, Petrus Linge, Helena Tydén, Robin Kahn, and Anders A. Bengtsson
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mean platelet volume ,systemic lupus erythematosus ,autoimmunity ,platelets ,biomarkers ,Medicine (General) ,R5-920 - Abstract
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), p < 0.0001. Based on the reference interval, 2.4% (n = 5) of patients had large-sized platelets, 84.4% (n = 179) had normal-sized and 13.2% (n = 28) had small-sized. A larger proportion (85.7%) of patients with small-sized platelets met the anti-dsDNA criterion (ACR10b; p = 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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- 2021
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9. Low plasma concentrations of apolipoprotein M are associated with disease activity and endothelial dysfunction in systemic lupus erythematosus
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Helena Tydén, Christian Lood, Andreas Jönsen, Birgitta Gullstrand, Robin Kahn, Petrus Linge, Sunil B. Kumaraswamy, Björn Dahlbäck, and Anders A. Bengtsson
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Systemic lupus erythematosus ,Apolipoprotein M ,Disease activity ,Endothelial dysfunction ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Abstract 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
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- 2019
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10. C-Reactive Protein Levels in Systemic Lupus Erythematosus Are Modulated by the Interferon Gene Signature and CRP Gene Polymorphism rs1205
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Helena Enocsson, Birgitta Gullstrand, Maija-Leena Eloranta, Jonas Wetterö, Dag Leonard, Lars Rönnblom, Anders A. Bengtsson, and Christopher Sjöwall
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C-reactive protein ,type I interferons ,systemic lupus erythematosus ,inflammation ,biomarker ,pentraxins ,Immunologic diseases. Allergy ,RC581-607 - Abstract
ObjectivesPatients with systemic lupus erythematosus (SLE) often display modest elevations of C-reactive protein (CRP) despite raised disease activity and increased interleukin (IL-) 6. We asked to what extent IL-6 levels, the CRP polymorphism rs1205, and the type I interferon (IFN) gene signature affects the basal CRP levels in patients with SLE during a quiescent phase of the disease.MethodsCRP and IL-6 were analyzed in plasma from 57 patients meeting established classification criteria for SLE. The CRP polymorphism rs1205 was assessed and gene expression analyzed including four type I IFN-regulated genes (IGS).ResultsCRP was increased in patients with detectable IL-6 levels (p=0.001) and decreased among IGS-positive subjects (p=0.033). A multiple linear regression model revealed IL-6 to have a positive association with CRP levels, whereas both IGS-positivity and CRP genotype (rs1205) AA/GA were negatively associated with CRP-levels.ConclusionOur data offer an explanation to the modest CRP levels seen in viral infections and IFN-α driven autoimmunity and corroborate prior observations showing an IFN-α dependent downregulation of CRP. The latter observation, together with the fact that the CRP-lowering polymorphism rs1205 is overrepresented in human SLE, could explain low basal CRP and inadequate CRP-responses among patients with active SLE.
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- 2021
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11. Plasma C4d as marker for lupus nephritis in systemic lupus erythematosus
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Myriam Martin, Karolina I. Smoląg, Albin Björk, Birgitta Gullstrand, Marcin Okrój, Jonatan Leffler, Andreas Jönsen, Anders A. Bengtsson, and Anna M. Blom
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Systemic lupus erythematosus ,Complement ,C4d ,Flare ,Lupus nephritis ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Abstract Background In the present study, we sought to evaluate the complement activation product C4d as a marker for lupus nephritis in systemic lupus erythematosus (SLE). Methods C4d levels were determined by enzyme-linked immunosorbent assay in plasma samples of patients with established SLE using a novel approach based on detection of a short linear cleavage neoepitope. Cross-sectional associations were studied in 98 patients with SLE with samples taken at lower or higher respective disease activity. Temporal associations were investigated in 69 patients with SLE who were followed longitudinally for up to 5 years. Plasma samples from 77 healthy donors were included as controls. Results C4d levels were negligible in healthy control subjects and significantly increased in patients with SLE in the cross-sectional study (p < 0.0001). C4d levels discriminated between higher and lower disease activity according to ROC curve analysis (p < 0.001), exhibiting a positive predictive value of 68%. At higher disease activity, C4d levels correlated with the modified Systemic Lupus Erythematosus Disease Activity Index (p = 0.011) and predominantly with lupus nephritis (p = 0.003), exhibiting a sensitivity of 79% to identify patients with nephritis. High C4d levels together with the presence of anti-dsDNA autoantibodies preceded and thus predicted future lupus nephritis in the longitudinal study (OR 5.4, 95% CI 1.4–21.3). When we considered only patients with renal involvement (19 of 69) during the longitudinal study, we found that high C4d levels alone could forecast recurrence of future lupus nephritis (OR 3.3, 95% CI 1.2–9.6). Conclusions C4d appears to be a valuable marker for use in monitoring of patients with SLE, particularly for lupus nephritis. Importantly, C4d levels can predict impending flares of lupus nephritis and may thus be useful for informing treatment.
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- 2017
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12. RNAi as a Tool to Study Virulence in the Pathogenic Yeast Candida glabrata
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Olena P. Ishchuk, Khadija Mohamed Ahmad, Katarina Koruza, Klara Bojanovič, Marcel Sprenger, Lydia Kasper, Sascha Brunke, Bernhard Hube, Torbjörn Säll, Thomas Hellmark, Birgitta Gullstrand, Christian Brion, Kelle Freel, Joseph Schacherer, Birgitte Regenberg, Wolfgang Knecht, and Jure Piškur
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Candida glabrata ,pathogenic yeast ,RNA interference ,RNAi ,gene library ,antifungal drugs ,Microbiology ,QR1-502 - Abstract
The yeast Candida glabrata is a major opportunistic pathogen causing mucosal and systemic infections in humans. Systemic infections caused by this yeast have high mortality rates and are difficult to treat due to this yeast’s intrinsic and frequently adapting antifungal resistance. To understand and treat C. glabrata infections, it is essential to investigate the molecular basis of C. glabrata virulence and resistance. We established an RNA interference (RNAi) system in C. glabrata by expressing the Dicer and Argonaute genes from Saccharomyces castellii (a budding yeast with natural RNAi). Our experiments with reporter genes and putative virulence genes showed that the introduction of RNAi resulted in 30 and 70% gene-knockdown for the construct-types antisense and hairpin, respectively. The resulting C. glabrata RNAi strain was used for the screening of a gene library for new virulence-related genes. Phenotypic profiling with a high-resolution quantification of growth identified genes involved in the maintenance of cell integrity, antifungal drugs, and ROS resistance. The genes identified by this approach are promising targets for the treatment of C. glabrata infections.
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- 2019
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13. A Candidate Gene Approach to ANCA-Associated Vasculitis Reveals Links to the C3 and CTLA-4 Genes but not to the IL1-Ra And Fcγ-RIIa Genes
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Ulf Persson, Birgitta Gullstrand, Åsa Pettersson, Gunnar Sturfelt, Lennart Truedsson, and Mårten Segelmark
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ANCA ,Genetics ,Granulomatosis with polyangiitis ,Microscopic polyangiitis ,Wegener’s granulomatosis ,Dermatology ,RL1-803 ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Background/Aims: The aim of the study is to search for associations between Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) and polymorphisms in the genes of four key molecules possibly involved in different pathogenic pathways; complement C3, CTLA-4, Fcγ-RIIa and IL1-Ra. Patients and Methods: Patients with AAV (n=105) subgrouped as microscopic polyangiitis or granulomatosis with polyangiitis (Wegener's granulomatosis) and myeloperoxidase (MPO) or proteinase 3 (PR3) ANCA positive were compared to a control group of 200 blood donors. Polymorphisms in the genes were analysed with PCR amplification of DNA. Results: The diagnosis of AAV was confirmed in the 105 cases. The gene frequency of C3F was 0.27 in the PR3-ANCA subgroup (p=0.041) compared to 0,19 in the control group. The number of patients homozygous for the shortest 86 bp allele of CTLA-4 was significantly decreased in the whole group of patients (p=0.049). No differences were evident in the Fcγ-RIIa and IL1-Ra polymorphisms when compared to controls, neither in the whole group of patients, nor in any of the sub-groups. Conclusion: The aberrant gene frequency of the C3F allele among PR3-ANCA positive patients and the findings with the CTLA-4 polymorphism indicates that complement may be involved in pathogenesis and that T-cell activation also is of importance in these diseases.
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- 2013
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14. Type I interferon-mediated skewing of the serotonin synthesis is associated with severe disease in systemic lupus erythematosus.
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Christian Lood, Helena Tydén, Birgitta Gullstrand, Cecilia Klint, Christina Wenglén, Christoffer T Nielsen, Niels H H Heegaard, Andreas Jönsen, Robin Kahn, and Anders A Bengtsson
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Medicine ,Science - Abstract
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
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- 2015
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15. Platelet activation and anti-phospholipid antibodies collaborate in the activation of the complement system on platelets in systemic lupus erythematosus.
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Christian Lood, Helena Tydén, Birgitta Gullstrand, Gunnar Sturfelt, Andreas Jönsen, Lennart Truedsson, and Anders A Bengtsson
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Medicine ,Science - Abstract
Anti-phospholipid (aPL) antibodies are important contributors to development of thrombosis in patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE). The underlying mechanism of aPL antibody-mediated thrombosis is not fully understood but existing data suggest that platelets and the complement system are key components. Complement activation on platelets is seen in SLE patients, especially in patients with aPL antibodies, and has been related to venous thrombosis and stroke. The aim of this study was to investigate if aPL antibodies could support classical pathway activation on platelets in vitro as well as in SLE patients. Furthermore, we investigated if complement deposition on platelets was associated with vascular events, either arterial or venous, when the data had been adjusted for traditional cardiovascular risk factors. Finally, we analyzed if platelet complement deposition, both C1q and C4d, was specific for SLE. We found that aPL antibodies supported C4d deposition on platelets in vitro as well as in SLE patients (p = 0.001 and p
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- 2014
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16. Enrichment of Complement, Immunoglobulins, and Autoantibody Targets in the Proteome of Platelets from Patients with Systemic Lupus Erythematosus
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Carl Petrus, Linge, Andreas, Jern, Helena, Tydén, Birgitta, Gullstrand, Hong, Yan, Charlotte, Welinder, Robin, Kahn, Andreas, Jönsen, John W, Semple, and Anders A, Bengtsson
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Blood Platelets ,Proteome ,Tandem Mass Spectrometry ,Humans ,Immunoglobulins ,Lupus Erythematosus, Systemic ,Complement System Proteins ,Autoantibodies ,Chromatography, Liquid - Abstract
Systemic lupus erythematosus (SLE) is a complex disease characterized by autoimmunity toward apoptotic cells, excessive amounts of circulating immune complexes, and complement activation. A decreased platelet size has been observed in SLE and their nonhemostatic functions may play an active role in the disease. The main objective of this study was to find clues that could explain their decreased size and functional role, analyzing the entire platelet proteome. Platelets were isolated from 23 patients with SLE. The five individuals with the highest and lowest average platelet forward scatter were selected for further analysis. Platelet protein content was analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS) and compared with platelets from five healthy controls. Data are available via ProteomeXchange with identifier PXD031202. Out of 2,572 proteins identified, 396 had significantly different levels (ANOVA Platelets from SLE patients shared a specific protein profile, including immunoglobulins, complement proteins, and autoantigens, largely independent of the platelet size and in agreement with an integrated role for platelets in SLE.
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- 2022
17. Serum S100A8/A9 Concentrations are Associated with Neuropsychiatric Involvement and Fatigue in Systemic Lupus Erythematosus: A Cross-Sectional Study
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Kristoffer A Zervides, Andreas Jern, Jessika Nystedt, Birgitta Gullstrand, Petra C Nilsson, Pia C Sundgren, Anders A Bengtsson, and Andreas Jönsen
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Background Neuropsychiatric (NP) involvement and fatigue are major problems in systemic lupus erythematosus (SLE). S100A8/A9 is a marker of inflammation and responds to therapy in SLE patients. S100A8/A9 has an immunopathogenic role in various neurological diseases. We investigated S100A8/A9 in relation to NP-involvement and fatigue in SLE. Methods 72 consecutive SLE outpatients at a tertiary centre and 26 healthy controls were included in this cross-sectional study. NPSLE was determined by specialists in rheumatology and neurology and defined according to three attribution models: “ACR”, “SLICC A” and “SLICC B”. Cerebral MRI was assessed by a neuroradiologist and neurocognitive testing by a neuropsychologist. The individuals were assessed by scores of pain (VAS), fatigue (VAS and FSS), depression (MADRS-S), and health-related life quality (EQ5D). Concentrations of S100A8/A9 in serum and cerebrospinal fluid were measured with ELISA. Statistical calculations were performed using non-parametric methods. Results Serum concentrations of S100A8/A9 were higher in NPSLE patients compared with non-NPSLE patients when applying the ACR and SLICC A models, but not significant when applying the SLICC B model (medians 1400 ng/ml; 920 ng/ml, p=0.011; 1560 ng/ml; 1090 ng/ml, p=0.050; 1460 ng/ml; 1090 ng/ml, p=0.083, respectively). The concentrations were higher in SLE patients compared with controls (medians 1230 ng/ml; 790 ng/ml, p=0.023). No differences of CSF S100A8/A9 concentrations were observed between NPSLE and non-NPSLE patients. SLE patients with depression or cognitive dysfunction as an ACR NPSLE manifestation had higher serum S100A8/A9 concentrations than non-NPSLE patients (median 1460 ng/ml, p=0.007 and 1380 ng/ml, p=0.013, respectively). Higher serum S100A8/A9 correlated with higher VAS fatigue (r=0.31; p=0.008), VAS pain (r=0.27, p=0.021), and lower EQ5D (r=-0.29, p=0.014) in SLE patients. NPSLE was associated with higher plasma CRP concentrations, higher scores of fatigue and pain, lower EQ5D, and fewer weekly work hours. Serum S100A8/A9 was not independently associated with NPSLE when adjusting for plasma CRP, and scores of fatigue (FSS) and pain (VAS), (OR 1.70, 95% CI 0.82-3.53, p=0.15). Conclusions Serum S100A8/A9 concentrations may be associated with NPSLE and fatigue. S100A8/A9 may be of interest in evaluating NPSLE, although further investigations are needed.
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- 2021
18. Comparison of Surrogate Markers of the Type I Interferon Response and Their Ability to Mirror Disease Activity in Systemic Lupus Erythematosus
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Birgitta Gullstrand, Helena Enocsson, Cecilia Svanberg, Marie Larsson, Anders A. Bengtsson, Lars Rönnblom, Christopher Sjöwall, Maija-Leena Eloranta, and Jonas Wetterö
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0301 basic medicine ,Male ,Chemokine ,medicine.medical_treatment ,SLE ,TNF ,0302 clinical medicine ,Immunology and Allergy ,Medicine ,Lupus Erythematosus, Systemic ,Longitudinal Studies ,Cells, Cultured ,Original Research ,Aged, 80 and over ,Immunoassay ,Systemic lupus erythematosus ,galectin ,biology ,interferon ,Middle Aged ,Immune complex ,Cytokine ,Immunologi ,biomarker ,Tumor necrosis factor alpha ,Female ,Chemokines ,Adult ,Oxidoreductases Acting on CH-CH Group Donors ,Adolescent ,Galectins ,Immunology ,03 medical and health sciences ,Young Adult ,Immune system ,Predictive Value of Tests ,CXCL10 ,Humans ,CXCL11 ,Antigens ,Aged ,Rheumatology and Autoimmunity ,030203 arthritis & rheumatology ,Sweden ,Reumatologi och inflammation ,business.industry ,Gene Expression Profiling ,Tumor Suppressor Proteins ,chemokine ,Interferon-alpha ,Membrane Proteins ,Proteins ,Immunology in the medical area ,lupus ,RC581-607 ,medicine.disease ,Chemokine CXCL10 ,Cytoskeletal Proteins ,030104 developmental biology ,Cross-Sectional Studies ,Case-Control Studies ,Immunologi inom det medicinska området ,disease activity ,biology.protein ,Leukocytes, Mononuclear ,Chemokine CCL19 ,Immunologic diseases. Allergy ,business ,Transcriptome ,Biomarkers - Abstract
Objectives Type I interferons (IFNs) are central and reflective of disease activity in systemic lupus erythematosus (SLE). However, IFN-alpha levels are notoriously difficult to measure and the type I IFN gene signature (IGS) is not yet available in clinical routine. This study evaluates galectin-9 and an array of chemokines/cytokines in their potential as surrogate markers of type I IFN and/or SLE disease activity. Methods Healthy controls and well-characterized Swedish SLE patients from two cross-sectional cohorts (n=181; n=59) were included, and a subgroup (n=21) was longitudinally followed. Chemokine/cytokine responses in immune complex triggered IFN-alpha activity was studied in healthy donor peripheral blood mononuclear cells (PBMC). Levels of chemokines/cytokines and galectin-9 were measured by immunoassays. Gene expression was quantified by qPCR. Results The IGS was significantly (pFunding Agencies|Swedish Rheumatism association [R-844801]; Region Ostergotland ALF Grants [LIO-791961]; King Gustaf Vs 80-year Anniversary Foundation [FAI-2018-0504]; King Gustaf V, Queen Victorias Foundation of Freemasons; Alfred Osterlunds Foundation; Anna-Greta Crafoord Foundation; Greta and Johan Kocks Foundation; Skane University Hospital; Medical Faculty of Lund University; Swedish Research Council for Medicine and Health [2018-02399, 2018-02516, 2017-01091]
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- 2021
19. Immune responses against oxidized LDL as possible targets for prevention of atherosclerosis in systemic lupus erythematosus
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Michael Lebens, Ingrid Yao Mattisson, Gunilla Nordin Fredrikson, Anders A. Bengtsson, Sara Rattik, Jan Holmgren, Harry Björkbacka, Irena Ljungcrantz, Maria Wigren, Birgitta Gullstrand, Manuela Terrinoni, and Jan Nilsson
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0301 basic medicine ,Apolipoprotein B ,Physiology ,Autoimmunity ,030204 cardiovascular system & hematology ,medicine.disease_cause ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,immune system diseases ,medicine ,Macrophage ,Mesenteric lymph nodes ,Animals ,Humans ,Lupus Erythematosus, Systemic ,skin and connective tissue diseases ,Receptor ,Pharmacology ,Aortic atherosclerosis ,biology ,business.industry ,Atherosclerosis ,Lipoproteins, LDL ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,biology.protein ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Antibody ,business - Abstract
Patients suffering from systemic lupus erythematosus (SLE) are at increased risk of developing cardiovascular disease (CVD) and traditional therapies including statins provide insufficient protection. Impaired removal of apoptotic material is a common pathogenic mechanism in both SLE and atherosclerosis and is considered to be a key factor in the development of autoimmunity. Since oxidized LDL and apoptotic material bind to the same receptors, we aimed to investigate if targeting the oxidized LDL autoimmunity can affect atherosclerosis in SLE. To investigate the possible role of oxidized LDL autoimmunity in the accelerated atherosclerosis associated with SLE we used a hypercholesterolemic SLE mouse model (B6.lpr.ApoE-/- mice). Promoting LDL tolerance through mucosal immunization with an apolipoprotein B-100 peptide p45 (amino acids 661-680) and cholera toxin B-subunit fusion protein increased regulatory T cells and B cells in mesenteric lymph nodes and reduced plaque development in the aorta by 33%. Treatment with the oxidized LDL-specific antibody Orticumab reduced aortic atherosclerosis by 43%, subvalvular plaque area by 50% and the macrophage content by 31%. The present study provides support for oxLDL as a possible target for prevention of cardiovascular complications in SLE.
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- 2020
20. Children with oligoarticular Juvenile Idiopathic Arthritis have skewed synovial monocyte polarization pattern with functional impairment – a distinct inflammatory pattern for oligoarticular juvenile arthritis
- Author
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Birgitta Gullstrand, Sabine Arve-Butler, Anki Mossberg, Bengt Månsson, Tobias Schmidt, Elisabet Berthold, Fredrik Kahn, Robin Kahn, and Anders A. Bengtsson
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Adult ,0301 basic medicine ,musculoskeletal diseases ,lcsh:Diseases of the musculoskeletal system ,Arthritis ,CD16 ,Monocytes ,03 medical and health sciences ,0302 clinical medicine ,Synovitis ,Polarization ,Synovial Fluid ,medicine ,Humans ,Synovial fluid ,Child ,030203 arthritis & rheumatology ,Inflammation ,business.industry ,Macrophages ,Monocyte ,Synovial Membrane ,Juvenile idiopathic arthritis ,medicine.disease ,Arthritis, Juvenile ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,Oligoarticular Juvenile Idiopathic Arthritis ,Synovial membrane ,lcsh:RC925-935 ,business ,CD163 ,Research Article - Abstract
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 p p p 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.
- Published
- 2020
21. Mismatch between circulating cytokines and spontaneous cytokine production by leukocytes in hyperinflammatory COVID-19
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Karan Golestani, Robin Kahn, Anders A. Bengtsson, Tobias Schmidt, Birgitta Gullstrand, Fredrik Kahn, and Anki Mossberg
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0301 basic medicine ,Male ,medicine.medical_treatment ,Immunology ,Brief Conclusive Report ,Biology ,Peripheral blood mononuclear cell ,cytokine storm, monocytes ,Monocytes ,Flow cytometry ,Sepsis ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Immunology and Allergy ,Humans ,Aged ,Aged, 80 and over ,medicine.diagnostic_test ,Activator (genetics) ,SARS-CoV-2 ,COVID-19 ,Cell Biology ,Middle Aged ,medicine.disease ,Blockade ,030104 developmental biology ,Cytokine ,030220 oncology & carcinogenesis ,Cytokines ,Tumor necrosis factor alpha ,Female ,Cytokine storm - Abstract
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., Circulating levels of IL‐6, IL‐1b and inflammatory cytokines are mismatched with induced cytokine production by leukocytes in hyperinflammatory COVID‐19
- Published
- 2020
22. Increased serum bactericidal activity of autologous serum in C2 deficiency after vaccination against Haemophilus influenzae type b, and further support for an MBL-dependent C2 bypass mechanism
- Author
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Christina Hansson, Lisa Mellhammar, Anders A. Bengtsson, Göran Jönsson, Birgitta Gullstrand, Lillemor Skattum, and Cecilia Sahl
- Subjects
Haemophilus Infections ,030231 tropical medicine ,Serum Bactericidal Antibody Assay ,Mannose-Binding Lectin ,03 medical and health sciences ,Classical complement pathway ,0302 clinical medicine ,Haemophilus ,Medicine ,Humans ,030212 general & internal medicine ,Mannan-binding lectin ,Haemophilus Vaccines ,Antigens, Bacterial ,General Veterinary ,General Immunology and Microbiology ,biology ,business.industry ,Vaccination ,Public Health, Environmental and Occupational Health ,Haemophilus influenzae type b ,Complement C2 ,bacterial infections and mycoses ,biology.organism_classification ,Antibodies, Bacterial ,Haemophilus influenzae ,Complement system ,Antibody opsonization ,Infectious Diseases ,Immunoglobulin G ,Immunology ,Alternative complement pathway ,biology.protein ,Molecular Medicine ,Antibody ,business - Abstract
Deficiencies of C2 and other components of the classical pathway of complement are associated with increased risk of infections with encapsulated bacteria, such as Haemophilus (H.) influenzae. Defense against H. influenzae is dependent on specific antibodies and complement, which mediate serum bactericidal activity (SBA) and opsonization. Due to lack of normal classical and lectin complement pathway function in C2 deficiency (C2D), SBA would have to depend either on the alternative pathway or on C2 bypass mechanisms. Here we studied SBA against H. influenzae type b (Hib) before and after vaccination in a group of C2-deficient persons, as the bactericidal capacity of antibodies in autologous complement in relation to vaccination has not been investigated at group level in C2D. Sera from 22 persons with C2D and 26 healthy controls were available. Out of these, 18 persons with C2D and all controls had been vaccinated with Act-HIB®. SBA against Hib bacteria was analyzed with autologous serum as the only complement source. Antibodies to Hib capsular polysaccharide had been analyzed previously. Concentrations of mannose-binding lectin (MBL) and other complement components were measured in serum. SBA of both C2-deficient persons and controls was significantly more efficient after vaccination (p = 0.002 and p < 0.0001, respectively). After vaccination, all but two C2-deficient sera and one control serum showed sufficient SBA (
- Published
- 2020
23. P43 Serum S100A8/A9 concentrations are associated with neuropsychiatric involvement and fatigue in SLE
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Andreas Jern, Birgitta Gullstrand, Petra Nilsson, Jessica Nystedt, Andreas Jönsen, Kristoffer Alexander Zervides, Anders A. Bengtsson, and Pia C. Sundgren
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Cerebral atrophy ,medicine.medical_specialty ,Visual analogue scale ,business.industry ,medicine.disease ,Gastroenterology ,Hyperintensity ,Pathogenesis ,Elisa kit ,Cerebrospinal fluid ,Atrophy ,Internal medicine ,medicine ,S100a8 a9 ,business - Abstract
Background/Purpose Neuropsychiatric (NP) involvement and fatigue are both major problems in SLE. S100A8/A9 is a marker of inflammation, which responds to therapy in SLE patients. S100A8/A9 is expressed in the CNS. We investigated S100A8/A9 in relation to NPSLE and fatigue. Methods In this cross-sectional study we used ELISA (Bhulmann MRP8/14 ELISA kit, Switzerland) to measure the concentration of S100A8/A9 in serum in 72 SLE patients and 26 healthy controls and in cerebrospinal fluid (CSF) in 33 SLE patients. NP involvement was determined according to ACR case definitions for NPSLE. An MRI was performed in SLE patients and controls assessing white matter abnormalities and cerebral atrophy. Measurements of fatigue were performed using the Fatigue Severity Scale (FSS) and the Visual Analogue Scale (100 mm) (VAS). Statistical calculations were performed using non-parametric methods. Results In all, 72 female SLE patients (median age 38, range 18–52) and 26 female healthy controls (median age 40, range 23–52) were included in this study. Forty-four (61%) patients had NP involvement. NPSLE patients had higher serum S100A8/A9 concentrations (median 1.40 µg/ml) than the non-NPSLE patients (median 0.92 µg/ml; p=0.011) and the control group (median 0.79 µg/ml; p=0.004). Serum S100A8/A9 correlated with increased VAS fatigue in SLE patients (r=0.311; p=0.008), but not with FSS (r=0.184; p=0.124). Serum S100A8/A9 did not correlate with the extent of white matter lesions, atrophy of brain segments, or disease activity (SLEDAI-2K). S100A8/A9 was not detected in the CSF. Conclusions Higher serum S100A8/A9 concentrations in NPSLE patients and patients with fatigue may indicate that S100A8/A9 is involved in the pathogenesis of these manifestations, although further investigation is needed.
- Published
- 2020
24. A single nucleotide polymorphism in theNCF1gene leading to reduced oxidative burst is associated with systemic lupus erythematosus
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Iva Gunnarsson, Birgitta Gullstrand, Andreas Jönsen, Anders A. Bengtsson, Christopher Sjöwall, Åsa Johansson, Saedis Saevarsdottir, Elisabet Svenungsson, Jonas Wetterö, Rikard Holmdahl, Dag Leonard, Lars Rönnblom, and Lina Olsson
- Subjects
030203 arthritis & rheumatology ,0301 basic medicine ,chemistry.chemical_classification ,Reactive oxygen species ,Immunology ,Single-nucleotide polymorphism ,Biology ,medicine.disease_cause ,Molecular biology ,General Biochemistry, Genetics and Molecular Biology ,Autoimmunity ,Respiratory burst ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Rheumatology ,chemistry ,NADPH oxidase complex ,medicine ,Immunology and Allergy ,Ncf1 gene - Abstract
ObjectivesNcf1polymorphisms leading to low production of reactive oxygen species (ROS) are strongly associated with autoimmune diseases in animal models. The humanNCF1gene is very complex with both functional and non-functional gene copies and genotyping requires assays specific for functionalNCF1genes. We aimed at investigating association and function of the missense single nucleotide polymorphism (SNP), rs201802880 (here denoted NCF1-339) inNCF1with systemic lupus erythematosus (SLE).MethodsWe genotyped the NCF1-339 SNP in 973 Swedish patients with SLE and 1301 controls, using nested PCR and pyrosequencing. ROS production and gene expression of type 1 interferon-regulated genes were measured in isolated cells from subjects with different NCF1-339 genotypes.ResultsWe found an increased frequency of the NCF1-339 T allele in patients with SLE, 11% compared with 4% in controls, OR 3.0, 95% CI 2.4 to 3.9, p=7.0×10−20. The NCF1-339 T allele reduced extracellular ROS production in neutrophils (p=0.004) and led to an increase expression of type 1 interferon-regulated genes. In addition, the NCF1-339 T allele was associated with a younger age at diagnosis of SLE; mean age 30.3 compared with 35.9, p=2.0×1−6.ConclusionsThese results clearly demonstrate that a genetically controlled reduced production of ROS increases the risk of developing SLE and confirm the hypothesis that ROS regulate chronic autoimmune inflammatory diseases.
- Published
- 2017
25. Low plasma concentrations of apolipoprotein M are associated with disease activity and endothelial dysfunction in systemic lupus erythematosus
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Anders A. Bengtsson, Sunil B. Kumaraswamy, Birgitta Gullstrand, Christian Lood, Robin Kahn, Björn Dahlbäck, Andreas Jönsen, Helena Tydén, and Petrus Linge
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,lcsh:Diseases of the musculoskeletal system ,Apolipoprotein B ,Adolescent ,Apolipoproteins M ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Systemic lupus erythematosus ,Internal medicine ,Medicine ,Humans ,Lupus Erythematosus, Systemic ,Prospective Studies ,Disease activity ,Endothelial dysfunction ,skin and connective tissue diseases ,Reactive hyperemia ,Aged ,030203 arthritis & rheumatology ,Aged, 80 and over ,Kidney ,Leukopenia ,biology ,business.industry ,Middle Aged ,medicine.disease ,Rheumatology ,030104 developmental biology ,medicine.anatomical_structure ,APOM ,Endocrinology ,Apolipoprotein M ,biology.protein ,Disease Progression ,Female ,Endothelium, Vascular ,lcsh:RC925-935 ,medicine.symptom ,business ,Biomarkers ,Lipoprotein ,Research Article - Abstract
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
- Published
- 2019
26. Deciphering systemic lupus erythematosus-associated serum biomarkers reflecting apoptosis and disease activity
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Gunnar Sturfelt, M Kassandra, Payam Delfani, Carl A.K. Borrebaeck, Anders Carlsson, Christer Wingren, Birgitta Gullstrand, and Anders A. Bengtsson
- Subjects
Adult ,Male ,0301 basic medicine ,Antibody microarray ,Protein Array Analysis ,Apoptosis ,Pilot Projects ,Disease ,Antibodies ,Pathogenesis ,03 medical and health sciences ,Immune system ,Rheumatology ,immune system diseases ,medicine ,Humans ,Lupus Erythematosus, Systemic ,skin and connective tissue diseases ,Aged ,Retrospective Studies ,business.industry ,Autoantibody ,Blood Proteins ,Middle Aged ,medicine.disease ,Connective tissue disease ,030104 developmental biology ,Immunology ,Biomarker (medicine) ,Female ,business ,Biomarkers ,Anti-SSA/Ro autoantibodies - Abstract
Systemic lupus erythematosus (SLE) is a severe chronic inflammatory autoimmune connective tissue disease. Despite major efforts, SLE remains a poorly understood disease with unpredictable course, unknown etiology and complex pathogenesis. Apoptosis combined with deficiency in clearing apoptotic cells is an important etiopathogenic event in SLE, which could contribute to the increased load of potential autoantigen(s); however, the lack of disease-specific protein signatures deciphering SLE and the underlying biological processes is striking and represents a key limitation. In this retrospective pilot study, we explored the immune system as a specific sensor for disease, in order to advance our understanding of SLE. To this end, we determined multiplexed serum protein expression profiles of crude SLE serum samples, using antibody microarrays. The aim was to identify differential immunoprofiles, or snapshots of the immune response modulated by the disease, reflecting apoptosis, a key process in the etiology of SLE and disease activity. The results showed that multiplexed panels of SLE-associated serum biomarkers could be decoded, in particular reflecting disease activity, but potentially the apoptosis process as well. While the former biomarkers could display a potential future use for prognosis, the latter biomarkers might help shed further light on the apoptosis process taking place in SLE.
- Published
- 2016
27. Platelet-Derived S100A8/A9 and Cardiovascular Disease in Systemic Lupus Erythematosus
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Iva Gunnarsson, Andreas Jönsen, Christian Lood, Elisabet Svenungsson, Tomas Leanderson, Eva Källberg, Fredrik Ivars, Helena Tydén, Robin Kahn, Matthias Mörgelin, Birgitta Gullstrand, and Anders A. Bengtsson
- Subjects
030203 arthritis & rheumatology ,0301 basic medicine ,Lupus erythematosus ,business.industry ,Immunology ,Disease ,medicine.disease ,S100A8 ,03 medical and health sciences ,Cell and molecular biology ,030104 developmental biology ,0302 clinical medicine ,Rheumatology ,Immunology and Allergy ,Medicine ,Platelet ,Young adult ,skin and connective tissue diseases ,business ,S100a8 a9 ,Anti-SSA/Ro autoantibodies - Abstract
S100A8/A9, a pro-inflammatory and pro-thrombotic protein complex, is increased in several diseases and high levels predispose to cardiovascular disease (CVD). Recently, platelet S100A8/A9 synthesis was described in mouse and humans in relation to CVD. However, 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 has not been investigated.
- Published
- 2016
28. Pro-inflammatory S100 proteins are associated with glomerulonephritis and anti-dsDNA antibodies in systemic lupus erythematosus
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Christian Lood, Birgitta Gullstrand, Helena Tydén, Andreas Jönsen, Tomas Leanderson, Fredrik Ivars, and Anders A. Bengtsson
- Subjects
Adult ,Male ,0301 basic medicine ,Adolescent ,Neutrophils ,Phagocytosis ,Lupus nephritis ,S100A8 ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Rheumatology ,Calgranulin B ,Humans ,Lupus Erythematosus, Systemic ,Medicine ,Calgranulin A ,Aged ,Aged, 80 and over ,030203 arthritis & rheumatology ,biology ,business.industry ,Anti-dsDNA antibodies ,S100 Proteins ,S100A12 Protein ,Glomerulonephritis ,DNA ,Middle Aged ,medicine.disease ,Lupus Nephritis ,Treatment Outcome ,030104 developmental biology ,Antibodies, Antinuclear ,Immunology ,biology.protein ,Female ,Inflammation Mediators ,Antibody ,business ,Biomarkers ,Immunosuppressive Agents ,Blood sampling - Abstract
Objectives Systemic lupus erythematosus (SLE) is associated with elevated levels of S100A8/A9, pro-inflammatory proteins mainly secreted by activated polymorphonuclear neutrophils (PMNs). The underlying mechanisms for increased S100A8/A9 levels and their relation to the clinical phenotype have not been carefully investigated. We assessed S100A8/A9 and S100A12 levels in SLE patient sera in relation to disease activity, clinical phenotype, presence of anti-dsDNA antibodies and ability to promote phagocytosis of necrotic cells (NCs) by PMNs. Methods Serum levels of S100A8/A9 and S100A12 were measured by ELISA in paired samples of 100 SLE patients at time points of higher and lower disease activity. Serum-mediated phagocytosis of NCs by PMNs was analysed by flow cytometry. Clinical data were recorded at time points of blood sampling. Results Serum levels of S100A8/A9 and S100A12 were increased in SLE patients with high disease activity compared to paired samples at low disease activity ( p = 0.01 and p = 0.008, respectively). Elevated levels of S100A8/A9 were particularly seen in patients with anti-dsDNA antibodies ( p = 0.01) and glomerulonephritis before treatment ( p = 0.02). Immunosuppressive therapy was associated with a reduction of S100A8/A9 serum levels ( p = 0.002). The ability of serum to support phagocytosis of NCs by PMNs was related to increased S100A8/A9 levels ( p = 0.01). Conclusions Elevated serum levels of S100A8/A9 may be used to monitor disease activity and response to treatment in SLE patients, especially in patients with glomerulonephritis. S100A12 may be a marker of disease activity in SLE. Increased S100A8/A9 levels may reflect immune-pathological processes involving phagocytosis of immune complexes by PMNs.
- Published
- 2016
29. Stress-induced release of the S100A8/A9 alarmin is elevated in coronary artery disease patients with impaired cortisol response
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Lena Jonasson, H. Grauen Larsen, Birgitta Gullstrand, Anna Lundberg, Anders A. Bengtsson, and Alexandru Schiopu
- Subjects
Male ,0301 basic medicine ,Cortisol secretion ,Saliva ,medicine.medical_specialty ,Evening ,Hydrocortisone ,lcsh:Medicine ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Article ,S100A8 ,Cohort Studies ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Calgranulin B ,Humans ,Medicine ,Calgranulin A ,Cardiac and Cardiovascular Systems ,lcsh:Science ,Aged ,Kardiologi ,Multidisciplinary ,business.industry ,lcsh:R ,Middle Aged ,medicine.disease ,030104 developmental biology ,Endocrinology ,Glucocorticoid secretion ,Cohort ,lcsh:Q ,Female ,business ,Biomarkers ,Stress, Psychological ,Cohort study - Abstract
Psychological stress is thought to be an important trigger of cardiovascular events, yet the involved pathways and mediators are largely unknown. Elevated systemic levels of the pro-inflammatory alarmin S100A8/A9 correlate with poor prognosis in coronary artery disease (CAD) patients. Here, we investigated the links between S100A8/A9 release and parameters of anti-inflammatory glucocorticoid secretion in two different cohorts subjected to a psychological stress test. In the first cohort of 60 CAD patients, psychological stress induced a rapid increase of circulating S100A8/A9. This rapid S100A8/A9 response strongly correlated with elevated evening saliva cortisol levels, suggesting an association with a dysregulated hypothalamic–pituitary–adrenal (HPA) axis. In the second cohort of 27 CAD patients and 28 controls, elevated S100A8/A9 levels were still detectable 24 h after stress in 40% of patients and 36% of controls, with a tendency for higher levels in patients. The sustained S100A8/A9 response was associated with a poor rapid cortisol release after stress in patients, but not in the control group. Our findings reveal for the first time that acute psychological stress induces elevated levels of S100A8/A9. We also provide hypothesis-generating evidence that dysregulated cortisol secretion in CAD patients might be associated with an exaggerated pro-inflammatory S100A8/A9 response.
- Published
- 2017
30. Plasma C4d as marker for lupus nephritis in systemic lupus erythematosus
- Author
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Jonatan Leffler, Marcin Okroj, Myriam Martin, Birgitta Gullstrand, Anders A. Bengtsson, Anna M. Blom, Andreas Jönsen, Karolina I. Smoląg, and Albin Björk
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,lcsh:Diseases of the musculoskeletal system ,Immunology ,Complement ,Lupus nephritis ,Enzyme-Linked Immunosorbent Assay ,Gastroenterology ,Young Adult ,03 medical and health sciences ,Systemic lupus erythematosus ,0302 clinical medicine ,Blisibimod ,immune system diseases ,Internal medicine ,Complement C4b ,Humans ,Medicine ,Longitudinal Studies ,Young adult ,skin and connective tissue diseases ,Molecular Biology ,Aged ,Aged, 80 and over ,030203 arthritis & rheumatology ,business.industry ,Autoantibody ,Middle Aged ,medicine.disease ,Peptide Fragments ,C4d ,Rheumatology ,Complement system ,Cross-Sectional Studies ,030104 developmental biology ,Female ,lcsh:RC925-935 ,business ,Nephritis ,Biomarkers ,Flare ,Research Article ,Anti-SSA/Ro autoantibodies - Abstract
Background In the present study, we sought to evaluate the complement activation product C4d as a marker for lupus nephritis in systemic lupus erythematosus (SLE). Methods C4d levels were determined by enzyme-linked immunosorbent assay in plasma samples of patients with established SLE using a novel approach based on detection of a short linear cleavage neoepitope. Cross-sectional associations were studied in 98 patients with SLE with samples taken at lower or higher respective disease activity. Temporal associations were investigated in 69 patients with SLE who were followed longitudinally for up to 5 years. Plasma samples from 77 healthy donors were included as controls. Results C4d levels were negligible in healthy control subjects and significantly increased in patients with SLE in the cross-sectional study (p < 0.0001). C4d levels discriminated between higher and lower disease activity according to ROC curve analysis (p < 0.001), exhibiting a positive predictive value of 68%. At higher disease activity, C4d levels correlated with the modified Systemic Lupus Erythematosus Disease Activity Index (p = 0.011) and predominantly with lupus nephritis (p = 0.003), exhibiting a sensitivity of 79% to identify patients with nephritis. High C4d levels together with the presence of anti-dsDNA autoantibodies preceded and thus predicted future lupus nephritis in the longitudinal study (OR 5.4, 95% CI 1.4–21.3). When we considered only patients with renal involvement (19 of 69) during the longitudinal study, we found that high C4d levels alone could forecast recurrence of future lupus nephritis (OR 3.3, 95% CI 1.2–9.6). Conclusions C4d appears to be a valuable marker for use in monitoring of patients with SLE, particularly for lupus nephritis. Importantly, C4d levels can predict impending flares of lupus nephritis and may thus be useful for informing treatment.
- Published
- 2017
31. Cardiovascular disease in systemic lupus erythematosus is associated with increased levels of biomarkers reflecting receptor-activated apoptosis
- Author
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Johanna Gustafsson, Ingrid Yao Mattisson, Iva Gunnarsson, Gunilla Nordin Fredrikson, Maria Wigren, Anders A. Bengtsson, K Jensen-Urstad, Agneta Zickert, Kerstin Elvin, Birgitta Gullstrand, Elisabet Svenungsson, and Jan Nilsson
- Subjects
0301 basic medicine ,Adult ,Carotid Artery Diseases ,Male ,Programmed cell death ,Inflammation ,Apoptosis ,Autoimmunity ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Coronary artery disease ,03 medical and health sciences ,Peripheral Arterial Disease ,0302 clinical medicine ,Immune system ,Epidermal growth factor ,Risk Factors ,medicine ,Prevalence ,Humans ,Lupus Erythematosus, Systemic ,fas Receptor ,Cells, Cultured ,Aged ,Sweden ,Framingham Risk Score ,business.industry ,Middle Aged ,Fas receptor ,medicine.disease ,Matrix Metalloproteinases ,Up-Regulation ,Cerebrovascular Disorders ,Receptors, TNF-Related Apoptosis-Inducing Ligand ,030104 developmental biology ,Receptors, Tumor Necrosis Factor, Type I ,Case-Control Studies ,Immunology ,Leukocytes, Mononuclear ,Intercellular Signaling Peptides and Proteins ,Female ,medicine.symptom ,Inflammation Mediators ,Cardiology and Cardiovascular Medicine ,business ,Apoptosis Regulatory Proteins ,Biomarkers - Abstract
Background and aims There is convincing evidence that adaptive immune responses affect the development of atherosclerosis and thrombosis and several autoimmune diseases are associated with increased cardiovascular risk. However, our understanding of the underlying mechanisms remains limited. We investigated how biomarkers reflecting four aspects of autoimmunity: apoptosis, inflammation, tissue degradation and repair, associate with cardiovascular disease (CVD) in subjects with systemic lupus erythematosus (SLE). Methods We investigated 484 well-characterized SLE patients, 69 of whom had CVD (coronary artery disease, cerebrovascular disease or peripheral artery disease), and 253 controls. Occurrence of carotid plaques was investigated with ultrasound. Plasma levels of biomarkers reflecting apoptosis (Fas, TNF receptor 1, TRAIL receptor 2), inflammation (IL-6, IL-8, monocyte chemotactic protein-1), tissue degradation (matrix metalloproteinase (MMP)-1, MMP-3, MMP-7), and tissue repair (platelet-derived growth factor, epidermal growth factor and stem cell factor) were analyzed by Proximity Extension Assay. Results Subjects with SLE had markedly elevated plasma levels of biomarkers reflecting apoptosis, inflammation and tissue degradation as compared to controls. SLE patients with CVD had higher levels of Fas, TNF receptor 1, TRAIL receptor 2, MMP-1 and -7 than those without CVD. The same associations were found for the presence of a carotid plaque. When controlling for the factors included in the Framingham risk score, all biomarkers except MMP-1 remained associated with the presence of a carotid plaque, while only TRAIL receptor 2 levels remained significantly associated with CVD. Conclusions Our findings argue that the cardiovascular risk in SLE is associated with increased cell death by apoptosis and tissue degradation.
- Published
- 2017
32. THU0260 Low plasma concentrations of apolipoprotein m correlate to disease activity and endothelial dysfunction in sle
- Author
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Christian Lood, Björn Dahlbäck, Andreas Jönsen, Anders A. Bengtsson, Birgitta Gullstrand, and Helena Tydén
- Subjects
medicine.medical_specialty ,Apolipoprotein B ,biology ,Endothelium ,business.industry ,Inflammation ,medicine.disease ,Rheumatology ,APOM ,medicine.anatomical_structure ,Endocrinology ,Internal medicine ,Cohort ,Immunology ,medicine ,biology.protein ,medicine.symptom ,Endothelial dysfunction ,skin and connective tissue diseases ,business ,Reactive hyperemia - Abstract
Background ApoM is an antiatherogenic and vasculoprotective 25kDa apolipoprotein suggested to play a role in keeping endothelial barrier integrity. Objectives The aims of the current study were to determine the impact of SLE disease activity on apoM levels and investigate if apoM levels reflect endothelial function in SLE. Methods Plasma concentrations of apoM were measured with ELISA in two SLE cohorts, all patients fulfilling ≥4 American College of Rheumatology (ACR) classification criteria for SLE, and 100 healthy controls (HC). Patients in cohort I had active disease as evaluated with SLEDAI scores. In cohort II endothelial function was measured by EndoPAT 2000 and correlated to apoM levels. A low Reactive Hyperemia Index (RHI) value indicated endothelial dysfunction (ED). Results In cohort I, the plasma levels of apoM were found to be significantly decreased in SLE (p In cohort II, using linear regression analysis, there was a positive correlation between apoM levels and the RHI value, indicating endothelial dysfunction, in the younger SLE patients: β=0.94 CI 95% 0.22,1.65 r=0.32 p=0.011. Conclusions SLE related inflammation may have an impact on lower plasma apoM, which may affect the endothelium and the process towards cardiovascular disease. Disclosure of Interest None declared
- Published
- 2017
33. Tumour necrosis factor-α/etanercept complexes in serum predict long-term efficacy of etanercept treatment in seronegative rheumatoid arthritis
- Author
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Anders A. Bengtsson, Bengt Månsson, Birgitta Gullstrand, Elisabet Berthold, Tore Saxne, Robin Kahn, and Pierre Geborek
- Subjects
0301 basic medicine ,musculoskeletal diseases ,Adult ,Male ,medicine.medical_specialty ,Necrosis ,Immunology ,Arthritis ,Enzyme-Linked Immunosorbent Assay ,Etanercept ,Arthritis, Rheumatoid ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Internal medicine ,Immunology and Allergy ,Medicine ,Humans ,Receptor ,Seronegative rheumatoid arthritis ,030203 arthritis & rheumatology ,business.industry ,Activator (genetics) ,Tumor Necrosis Factor-alpha ,General Medicine ,Middle Aged ,medicine.disease ,030104 developmental biology ,Rheumatoid arthritis ,Antirheumatic Agents ,Female ,medicine.symptom ,business ,medicine.drug ,Follow-Up Studies - Abstract
Objective: To study whether serum levels of tumour necrosis factor-α (TNF-α), free or bound to etanercept, in biological-naïve adults with rheumatoid arthritis (RA) could predict the long-term efficacy of etanercept, measured as drug survival. Method: We identified 145 biological-naïve patients with RA starting treatment with etanercept at the Department of Rheumatology, Skåne University Hospital (1999–2008), of whom 16 had seronegative and 129 seropositive RA. TNF-α in serum was quantified using enzyme-linked immunosorbent assay in samples from the onset of treatment and at 6 week follow-up. Drug survival time was used to evaluate the long-term efficacy of etanercept. Results: Levels of TNF-α were significantly increased at follow-up compared to at the start. At the 6 week follow-up, circulating TNF-α mainly comprised TNF-α in complex with etanercept. Longer drug survival time correlated with increased TNF-α at 6 week follow-up in the patients with seronegative RA, but not in the seropositive patients. Conclusion: We demonstrated that levels of circulating TNF-α increased in almost all individuals after initiation of treatment with etanercept and that this increase mainly comprised TNF-α in complex with etanercept. More importantly, this increase may predict drug survival in adults with seronegative, but not seropositive, RA and suggests that measuring TNF-α/etanercept complexes in serum may be relevant in patients with seronegative RA.
- Published
- 2017
34. A single nucleotide polymorphism in the
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Lina M, Olsson, Åsa C, Johansson, Birgitta, Gullstrand, Andreas, Jönsen, Saedis, Saevarsdottir, Lars, Rönnblom, Dag, Leonard, Jonas, Wetterö, Christopher, Sjöwall, Elisabet, Svenungsson, Iva, Gunnarsson, Anders A, Bengtsson, and Rikard, Holmdahl
- Subjects
Adult ,Male ,Sweden ,Neutrophils ,Gene Expression ,NADPH Oxidases ,Polymorphism, Single Nucleotide ,White People ,Gene Expression Regulation ,Case-Control Studies ,Humans ,Lupus Erythematosus, Systemic ,Female ,Genetic Predisposition to Disease ,Reactive Oxygen Species ,Respiratory Burst - Abstract
We genotyped the NCF1-339 SNP in 973 Swedish patients with SLE and 1301 controls, using nested PCR and pyrosequencing. ROS production and gene expression of type 1 interferon-regulated genes were measured in isolated cells from subjects with different NCF1-339 genotypes.We found an increased frequency of the NCF1-339 T allele in patients with SLE, 11% compared with 4% in controls, OR 3.0, 95% CI 2.4 to 3.9, p=7.0×10These results clearly demonstrate that a genetically controlled reduced production of ROS increases the risk of developing SLE and confirm the hypothesis that ROS regulate chronic autoimmune inflammatory diseases.
- Published
- 2017
35. Endothelial dysfunction is associated with activation of the type I interferon system and platelets in patients with systemic lupus erythematosus
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Helena Tydén, Christoffer Tandrup Nielsen, Andreas Jönsen, Anders A. Bengtsson, Robin Kahn, Niels H. H. Heegaard, Birgitta Gullstrand, and Christian Lood
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Endothelium ,Immunology ,Lupus ,Inflammation ,Pathogenesis ,Endothelial activation ,03 medical and health sciences ,0302 clinical medicine ,systemic lupus erythematosus ,Rheumatology ,cardiovascular disease ,Interferon ,Internal medicine ,medicine ,Immunology and Allergy ,Platelet ,Platelet activation ,Endothelial dysfunction ,030203 arthritis & rheumatology ,business.industry ,medicine.disease ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,inflammation ,medicine.symptom ,business ,disease activity ,medicine.drug - Abstract
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, pConclusions: 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.
- Published
- 2017
36. A Candidate Gene Approach to ANCA-Associated Vasculitis Reveals Links to the C3 and CTLA-4 Genes but not to the IL1-Ra And Fcγ-RIIa Genes
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Gunnar Sturfelt, Birgitta Gullstrand, Mårten Segelmark, Åsa Pettersson, Lennart Truedsson, and Ulf Persson
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lcsh:Diseases of the circulatory (Cardiovascular) system ,Candidate gene ,lcsh:RC870-923 ,Proteinase 3 ,Genetics ,lcsh:Dermatology ,medicine ,cardiovascular diseases ,Allele ,Microscopic polyangiitis ,Allele frequency ,biology ,ANCA ,Wegener’s granulomatosis ,General Medicine ,lcsh:RL1-803 ,lcsh:Diseases of the genitourinary system. Urology ,medicine.disease ,lcsh:RC666-701 ,Nephrology ,Myeloperoxidase ,Immunology ,biology.protein ,Granulomatosis with polyangiitis ,Cardiology and Cardiovascular Medicine ,Vasculitis - Abstract
Background/Aims: The aim of the study is to search for associations between Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) and polymorphisms in the genes of four key molecules possibly involved in different pathogenic pathways; complement C3, CTLA-4, Fcγ-RIIa and IL1-Ra. Patients and Methods: Patients with AAV (n=105) subgrouped as microscopic polyangiitis or granulomatosis with polyangiitis (Wegener's granulomatosis) and myeloperoxidase (MPO) or proteinase 3 (PR3) ANCA positive were compared to a control group of 200 blood donors. Polymorphisms in the genes were analysed with PCR amplification of DNA. Results: The diagnosis of AAV was confirmed in the 105 cases. The gene frequency of C3F was 0.27 in the PR3-ANCA subgroup (p=0.041) compared to 0,19 in the control group. The number of patients homozygous for the shortest 86 bp allele of CTLA-4 was significantly decreased in the whole group of patients (p=0.049). No differences were evident in the Fcγ-RIIa and IL1-Ra polymorphisms when compared to controls, neither in the whole group of patients, nor in any of the sub-groups. Conclusion: The aberrant gene frequency of the C3F allele among PR3-ANCA positive patients and the findings with the CTLA-4 polymorphism indicates that complement may be involved in pathogenesis and that T-cell activation also is of importance in these diseases.
- Published
- 2013
37. The assessment of serum-mediated phagocytosis of necrotic material by polymorphonuclear leukocytes to diagnose and predict the clinical features of systemic lupus erythematosus: an observational longitudinal study
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Gro Østli Eilertsen, Anders A. Bengtsson, Christian Lood, Søren Jacobsen, Michele Compagno, Jan-Åke Nilsson, Andreas Jönsen, Gunnar Sturfelt, Birgitta Gullstrand, and Lennart Truedsson
- Subjects
Male ,Pathology ,Neutrophils ,Lupus nephritis ,Diagnostic accuracy ,Cohort Studies ,0302 clinical medicine ,immune system diseases ,Lupus Erythematosus, Systemic ,Flow cytometry ,Disease activity ,Longitudinal Studies ,skin and connective tissue diseases ,biology ,VDP::Medical disciplines: 700::Clinical medical disciplines: 750 ,VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750 ,Glomerulonephritis ,Middle Aged ,Predictive value of tests ,Cohort ,Female ,Antibody ,Research Article ,Adult ,medicine.medical_specialty ,Adolescent ,Mucocutaneous zone ,Observational Study ,03 medical and health sciences ,Necrosis ,Young Adult ,Systemic lupus erythematosus ,Phagocytosis ,Predictive Value of Tests ,Internal medicine ,Journal Article ,medicine ,Humans ,Rheumatology and Autoimmunity ,Aged ,030203 arthritis & rheumatology ,Lupus erythematosus ,business.industry ,medicine.disease ,Rheumatology ,Cross-Sectional Studies ,Immunology ,biology.protein ,business ,Biomarkers ,030215 immunology ,Follow-Up Studies - Abstract
Published version. Source at http://dx.doi.org/10.1186/s13075-016-0941-1 Background: Serum-mediated phagocytosis of antibody- and complement-opsonized necrotic cell material (NCM) by polymorphonuclear leukocytes can be quantified by using a flow cytometry–based assay. The phagocytosis of necrotic cell material (PNC) assay parallels the well-known lupus erythematosus cell test. In this study, we aimed to investigate the diagnostic accuracy of the assay and the relationship with clinical manifestations and disease activity in systemic lupus erythematosus (SLE). Methods: The diagnostic accuracy for SLE diagnosis of the PNC assay was studied by cross-sectional assessment of blood samples from 148 healthy control subjects and a multicenter rheumatic group (MRG) of 529 patients with different rheumatic symptoms. A cohort of 69 patients with an established SLE diagnosis (SLE cohort) underwent longitudinal clinical and laboratory follow-up for analysis of the temporal relationships between PNC positivity and specific clinical manifestations. Results: In 35 of 529 MRG patients, 13 of whom had SLE, the PNC assay result was positive. Combined positivity of the PNC assay and anti–double-stranded DNA antibodies increased specificity and positive predictive value for SLE diagnosis to 0.99 and 0.67, respectively. In the longitudinal study, 42 of 69 SLE cohort patients had positive results in the PNC assay at least once. PNC assay positivity was associated with current hematological manifestations and could predict mucocutaneous manifestations. When combined with hypocomplementemia, PNC positivity preceded increased Systemic Lupus Erythematosus Disease Activity Index 2000 score, glomerulonephritis, and alopecia. Conclusions: Serum-mediated PNC by polymorphonuclear leukocytes is commonly but not exclusively seen in patients with SLE. The PNC assay may be used in follow-up of patients with SLE and, especially in combination with other routinely assessed laboratory tests, may help to predict flares and different clinical manifestations, including glomerulonephritis. Our results encourage further development of the PNC assay as a complementary laboratory tool in management of patients with SLE.
- Published
- 2016
38. IgG glycan hydrolysis by endoglycosidase S diminishes the proinflammatory properties of immune complexes from patients with systemic lupus erythematosus: A possible new treatment?
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Birgitta Gullstrand, Anders A. Bengtsson, Lars Rönnblom, Christian Lood, Maria Allhorn, Mattias Collin, Lennart Truedsson, Rolf Lood, and Anders I. Olin
- Subjects
Adult ,Male ,Adolescent ,Glycoside Hydrolases ,Neutrophils ,Immunology ,Inflammation ,Antigen-Antibody Complex ,Biology ,Immunoglobulin G ,Proinflammatory cytokine ,Young Adult ,Classical complement pathway ,Immune system ,Bacterial Proteins ,Phagocytosis ,Rheumatology ,Polysaccharides ,medicine ,Humans ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,Pharmacology (medical) ,Aged ,Aged, 80 and over ,Autoimmune disease ,Lupus erythematosus ,Chemotaxis ,Hydrolysis ,Receptors, IgG ,Interferon-alpha ,Dendritic Cells ,Middle Aged ,medicine.disease ,Complement system ,biology.protein ,Female ,medicine.symptom - Abstract
Objective Systemic lupus erythematosus (SLE) is an autoimmune disease with chronic or episodic inflammation in several organ systems, related to the presence of circulating and tissue-deposited immune complexes (ICs) that stimulate leukocytes through Fc? receptors (Fc?R) with subsequent inflammation. Treatment with endoglycosidase S (EndoS), an IgG glycanhydrolyzing bacterial enzyme from Streptococcus pyogenes, has shown beneficial effects in several experimental animal models of chronic inflammatory disease. This study was undertaken to investigate whether EndoS affects the proinflammatory properties of ICs and has the potential to be developed as a therapy for SLE. Methods ICs purified from SLE patients or RNA-containing ICs formed in vitro were treated with EndoS and used in several assays reflecting different important features of SLE pathogenesis, such as phagocytosis by polymorphonuclear cells (PMNs) and plasmacytoid dendritic cells (PDCs), complement activation, and interferon-a (IFNa) production by PDCs. Results EndoS treatment abolished all proinflammatory properties of the ICs investigated. This included Fc?R-mediated phagocytosis by PDCs (P = 0.001) and subsequent production of IFNa (P = 0.002), IC-induced classical pathway of complement activation (P = 0.008), chemotaxis, and oxidative burst activity of PMNs (P = 0.002). EndoS treatment also had a direct effect on the molecular structure of ICs, causing decreased IC size and glycosylation. Conclusion Our findings indicate that EndoS treatment has prominent effects on several pathogenetically important IC-mediated events, and suggest that EndoS has the potential to be developed as a novel therapy for SLE. (Less)
- Published
- 2012
39. Neutrophil Extracellular Traps That Are Not Degraded in Systemic Lupus Erythematosus Activate Complement Exacerbating the Disease
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Birgitta Gullstrand, Christian Lood, Jonatan Leffler, Myriam Martin, Lennart Truedsson, Helena Tydén, Anders A. Bengtsson, and Anna M. Blom
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Adult ,Male ,Adolescent ,Neutrophils ,Immunology ,Inflammation ,Biology ,Severity of Illness Index ,Epitope ,Young Adult ,Antibody Specificity ,immune system diseases ,medicine ,Deoxyribonuclease I ,Humans ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,skin and connective tissue diseases ,Complement Activation ,Complement C1q ,Aged ,Autoantibodies ,Lupus erythematosus ,Autoantibody ,DNA ,Neutrophil extracellular traps ,Middle Aged ,medicine.disease ,Chromatin ,Complement (complexity) ,Complement system ,Interferon Type I ,Female ,medicine.symptom ,Extracellular Space - Abstract
Ongoing inflammation including activation of the complement system is a hallmark of systemic lupus erythematosus (SLE). Antimicrobial neutrophil extracellular traps (NETs) are composed of secreted chromatin that may act as a source of autoantigens typical for SLE. In this study, we investigated how complement interacts with NETs and how NET degradation is affected by complement in SLE patients. We found that sera from a subset of patients with active SLE had a reduced ability to degrade in vitro-generated NETs, which was mostly restored when these patients were in remission. Patients that failed to degrade NETs had a more active disease and they also displayed lower levels of complement proteins C4 and C3 in blood. We discovered that NETs activated complement in vitro and that deposited C1q inhibited NET degradation including a direct inhibition of DNase-I by C1q. Complement deposition on NETs may facilitate autoantibody production, and indeed, Abs against NETs and NET epitopes were more pronounced in patients with impaired ability to degrade NETs. NET-bound autoantibodies inhibited degradation but also further increased C1q deposition, potentially exacerbating the disease. Thus, NETs are a potent complement activator, and this interaction may play an important role in SLE. Targeting complement with inhibitors or by removing complement activators such as NETs could be beneficial for patients with SLE.
- Published
- 2012
40. Increased IgG on cell-derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation
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Birgitta Gullstrand, Line Stener, Ole Østergaard, Christoffer Tandrup Nielsen, Lennart Truedsson, Line V. Iversen, Niels Hh Heegaard, and Søren Jacobsen
- Subjects
Adult ,Male ,medicine.medical_specialty ,Immunology ,Arthritis ,Article ,Serology ,Arthritis, Rheumatoid ,Rheumatology ,Cell-Derived Microparticles ,immune system diseases ,Internal medicine ,medicine ,Humans ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,Pharmacology (medical) ,skin and connective tissue diseases ,Complement Activation ,Aged ,Autoantibodies ,Lupus erythematosus ,biology ,business.industry ,Autoantibody ,Middle Aged ,Flow Cytometry ,medicine.disease ,Complement system ,Immunoglobulin G ,Rheumatoid arthritis ,biology.protein ,Female ,Antibody ,business - Abstract
To quantify immunoglobulin and C1q on circulating cell-derived microparticles (MPs) in patients with systemic lupus erythematosus (SLE) and to determine whether immunoglobulin and C1q levels are correlated with clinical and serologic parameters.Sixty-eight clinically well-characterized SLE patients, 38 healthy controls, 6 patients with systemic sclerosis (SSc), and 6 patients with rheumatoid arthritis (RA) 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 cytometric analysis of all samples from SLE patients and healthy controls.SLE patients had significantly increased total and relative numbers of IgG-positive MPs (P = 0.0004), with a much higher average IgG load per MP (P0.0001) than healthy controls. Quantitative mass spectrometry of purified MPs verified significantly increased IgG, IgM, and C1q levels in SLE patients. In RA and SSc patients, the average IgG load per MP was significantly lower than in SLE patients (P = 0.006 and P = 0.05, respectively). Also, the IgM load and C1q load per MP were significantly higher in SLE patients than in the control groups (P0.05), except for IgM in the RA group. IgG-positive MPs were significantly associated with the presence of anti-double-stranded DNA, anti-extractable nuclear antigen, and antihistone antibodies, with total IgG, and with decreased leukocyte counts. Average IgG load per MP was associated with lower concentrations of MPs, the presence of anti-C1q antibodies, and complement consumption.Our findings indicate that circulating cell-derived MPs in SLE patients carry increased loads of IgG, IgM, and C1q and that IgG MPs are associated with autoantibodies and complement activation. The findings link immunologic reactions on MPs with the etiology of SLE.
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- 2012
41. IRF7 inhibition prevents destructive innate immunity-A target for nonantibiotic therapy of bacterial infections
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Bhairavi Swaminathan, Aftab Nadeem, Yujing Huang, Ines Ambite, Gustav Rydström, Daniel S.C. Butler, Nataliya Lutay, Caterina Cafaro, Birgitta Gullstrand, Manoj Puthia, Catharina Svanborg, and Björn Nilsson
- Subjects
0301 basic medicine ,Interferon Regulatory Factor-7 ,Inflammation ,Biology ,Kidney ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immunity ,medicine ,Animals ,Humans ,Transcription factor ,Innate immune system ,Pyelonephritis ,Kidney metabolism ,General Medicine ,Bacterial Infections ,Immunity, Innate ,Mice, Inbred C57BL ,030104 developmental biology ,Gene Expression Regulation ,Immunology ,IRF7 ,Female ,Interferon Regulatory Factor-3 ,medicine.symptom ,IRF3 ,030215 immunology ,Interferon regulatory factors ,Signal Transduction - Abstract
Boosting innate immunity represents an important therapeutic alternative to antibiotics. However, the molecular selectivity of this approach is a major concern because innate immune responses often cause collateral tissue damage. We identify the transcription factor interferon regulatory factor 7 (IRF-7), a heterodimer partner of IRF-3, as a target for non-antibiotics-based therapy of bacterial infections. We found that the efficient and self-limiting innate immune response to bacterial infection relies on a tight balance between IRF-3 and IRF-7. Deletion of Irf3 resulted in overexpression of Irf7 and led to an IRF-7-driven hyperinflammatory phenotype, which was entirely prevented if Irf7 was deleted. We then identified a network of strongly up-regulated, IRF-7-dependent genes in Irf3(-/-) mice with kidney pathology, which was absent in Irf7(-/-) mice. IRF-3 and IRF-7 from infected kidney cell nuclear extracts were shown to bind OAS1, CCL5, and IFNB1 promoter oligonucleotides. These data are consistent in children with low IRF7 expression in the blood: attenuating IRF7 promoter polymorphisms (rs3758650-T and rs10902179-G) negatively associated with recurrent pyelonephritis. Finally, we identified IRF-7 as a target for immunomodulatory therapy. Administering liposomal Irf7 siRNA to Irf3(-/-) mice suppressed mucosal IRF-7 expression, and the mice were protected against infection and renal tissue damage. These findings offer a response to the classical but unresolved question of "good versus bad inflammation" and identify IRF7 as a therapeutic target for protection against bacterial infection.
- Published
- 2015
42. Circulating complexes between tumour necrosis factor-alpha and etanercept predict long-term efficacy of etanercept in juvenile idiopathic arthritis
- Author
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Elisabet Berthold, Tobias Schmidt, Tore Saxne, Anders A. Bengtsson, Robin Kahn, Fredrik Kahn, Birgitta Gullstrand, Bengt Månsson, and Pierre Geborek
- Subjects
0301 basic medicine ,musculoskeletal diseases ,Male ,medicine.medical_specialty ,Necrosis ,genetic structures ,Adolescent ,Arthritis ,Inflammation ,Tumour necrosis factor‐alpha ,Gastroenterology ,Etanercept ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,Internal medicine ,Medicine ,Juvenile ,Humans ,Longitudinal Studies ,skin and connective tissue diseases ,Child ,030203 arthritis & rheumatology ,business.industry ,Tumor Necrosis Factor-alpha ,Infant ,Regular Article ,General Medicine ,Biomarker ,Juvenile idiopathic arthritis ,medicine.disease ,Arthritis, Juvenile ,Antirheumatic Agents ,030104 developmental biology ,Treatment Outcome ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Physical therapy ,Biomarker (medicine) ,Tumor necrosis factor alpha ,Female ,medicine.symptom ,business ,medicine.drug ,Regular Articles - Abstract
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.
- Published
- 2015
43. Autoantibodies to C1 inhibitor in SLE are associated with higher SLEDAI 2K score and with autoantibodies to cardiolipin
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Elizabeth Huynh, Lillemor Skattum, Tina Linnér, Birgitta Gullstrand, and Anders A. Bengtsson
- Subjects
biology ,business.industry ,Immunology ,Autoantibody ,Hematology ,C1-inhibitor ,chemistry.chemical_compound ,chemistry ,Cardiolipin ,biology.protein ,Immunology and Allergy ,Medicine ,business - Published
- 2016
44. Platelet transcriptional profile and protein expression in patients with systemic lupus erythematosus: up-regulation of the type I interferon system is strongly associated with vascular disease
- Author
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Maria Allhorn, Christian Lood, David Erlinge, Andreas Jönsen, Birgitta Gullstrand, Gunnar Sturfelt, Anders A. Bengtsson, Stefan Amisten, and Lennart Truedsson
- Subjects
Adult ,Antigens, Differentiation, T-Lymphocyte ,Blood Platelets ,Male ,Proteomics ,Systemic disease ,Blotting, Western ,Immunology ,Biochemistry ,Cohort Studies ,Young Adult ,Antigens, CD ,immune system diseases ,Immunopathology ,Humans ,Lupus Erythematosus, Systemic ,Medicine ,Lectins, C-Type ,Vascular Diseases ,Platelet activation ,skin and connective tissue diseases ,Aged ,Aged, 80 and over ,Autoimmune disease ,Lupus erythematosus ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Vascular disease ,Gene Expression Profiling ,Membrane Proteins ,RNA-Binding Proteins ,Cell Biology ,Hematology ,Middle Aged ,Gene signature ,medicine.disease ,Antigens, Differentiation ,Connective tissue disease ,Up-Regulation ,Interferon Type I ,Female ,business - Abstract
Patients with systemic lupus erythematosus (SLE) have a markedly increased risk to develop cardiovascular disease, and traditional cardiovascular risk factors fail to account for this increased risk. We used microarray to probe the platelet transcriptome in patients with SLE and healthy controls, and the gene and protein expression of a subset of differentially expressed genes was further investigated and correlated to platelet activation status. Real-time PCR was used to confirm a type I interferon (IFN) gene signature in patients with SLE, and the IFN-regulated proteins PRKRA, IFITM1 and CD69 (P < .0001) were found to be up-regulated in platelets from SLE patients compared with healthy volunteers. Notably, patients with a history of vascular disease had increased expression of type I IFN-regulated proteins as well as more activated platelets compared with patients without vascular disease. We suggest that interferogenic immune complexes stimulate production of IFNα that up-regulates the megakaryocytic type I IFN-regulated genes and proteins. This could affect platelet activation and contribute to development of vascular disease in SLE. In addition, platelets with type I IFN signature could be a novel marker for vascular disease in SLE.
- Published
- 2010
45. Complement classical pathway components are all important in clearance of apoptotic and secondary necrotic cells
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Gunnar Sturfelt, Birgitta Gullstrand, Ulla Mårtensson, Anders A. Bengtsson, and Lennart Truedsson
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Translational Studies ,Phagocytosis ,Immunology ,Apoptosis ,Jurkat cells ,Jurkat Cells ,Necrosis ,Classical complement pathway ,Humans ,Immunology and Allergy ,Medicine ,Complement Pathway, Classical ,Complement Activation ,Mannan-binding lectin ,biology ,business.industry ,Complement C1q ,Macrophages ,Complement C4 ,Complement C3 ,Complement C2 ,Complement system ,Antibody opsonization ,Case-Control Studies ,Alternative complement pathway ,biology.protein ,Factor D ,business - Abstract
SummaryInherited deficiencies in components of the classical complement pathway are strong disease susceptibility factors for the development of systemic lupus erythematosus (SLE) and there is a hierarchy among deficiency states, the strongest association being with C1q deficiency. We investigated the relative importance of the different complement pathways regarding clearance of apoptotic cells. Phagocytosis of labelled apoptotic Jurkat cells by monocyte-derived macrophages in the presence of sera from individuals with complement deficiencies was studied, as well as C3 deposition on apoptotic cells using flow cytometry. Sera from individuals deficient in C1q, C4, C2 or C3 all showed decreased phagocytosis. Mannose binding lectin (MBL) and the alternative pathway did not influence phagocytosis. Notably, the components of the complement classical pathway, including C1q, were equally important in clearance of apoptotic cells. This indicates that deposition of C3 fragments is of major significance; we therefore studied C3 deposition on apoptotic cells. Experiments with MBL-deficient serum depleted of C1q or factor D confirmed the predominance of the classical pathway. At low dilution, sera deficient of C1q, C4 or C2 supported C3 fragment deposition demonstrating alternative pathway activation. In conclusion, we have found that complement-mediated opsonization and phagocytosis of apoptotic cells, particularly those undergoing secondary necrosis, are dependent mainly upon an intact classical pathway. The alternative pathway is less important, but may play a role in some conditions. C1q was not more important than other classical pathway components, suggesting a role in additional pathogenetic processes in SLE other than clearance of apoptotic cells.
- Published
- 2009
46. SLE serum induces classical caspase-dependent apoptosis independent of death receptors
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Lennart Truedsson, Anders A. Bengtsson, Birgitta Gullstrand, and Gunnar Sturfelt
- Subjects
Fas-Associated Death Domain Protein ,Immunology ,Apoptosis ,Autoantigens ,Jurkat cells ,Caspase-Dependent Apoptosis ,Cell Line ,Jurkat Cells ,immune system diseases ,medicine ,Humans ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,fas Receptor ,FADD ,skin and connective tissue diseases ,Receptor ,Caspase ,Lupus erythematosus ,biology ,Receptors, Death Domain ,medicine.disease ,Caspase Inhibitors ,Mitochondria ,Proto-Oncogene Proteins c-bcl-2 ,Receptors, Tumor Necrosis Factor, Type I ,Caspases ,biology.protein ,Cancer research ,Tumor necrosis factor alpha - Abstract
The main source of autoantigens in systemic lupus erythematosus (SLE) is most likely apoptotic material. We have previously shown that sera from SLE patients can induce apoptosis in monocytes and lymphocytes, and here we characterized mechanisms of apoptosis induced by SLE serum. SLE serum seems to induce caspase-dependent classical apoptosis since cells exposed to SLE serum displayed morphology consistent with classical apoptosis as demonstrated by confocal microscopy, and pan-caspase inhibitor Z-VAD.fmk significantly reduced SLE serum-induced apoptosis. Death-receptor-independent pathways seemed to be involved since SLE serum induced apoptosis equally in FADD-mutant and wild-type Jurkat cell lines, and blocking of Fas and TNFR1 did not reduce apoptosis induction. Importantly, apoptosis was significantly reduced in a Bcl-2 overexpressing Jurkat cell line indicating involvement of mitochondrial pathways. Thus, based on morphology and caspase inhibition experiments, we have demonstrated that SLE serum induce classical caspase-dependent apoptosis, and this was independent of death receptor pathways.
- Published
- 2008
47. Association between SLE nephritis and polymorphic variants of the CRP and Fc RIIIa genes
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Iva Gunnarsson, Gunnar Sturfelt, Elisabet Svenungsson, Ola Nived, Anders A. Bengtsson, Birgitta Gullstrand, Lennart Truedsson, Andreas Jönsen, and Ingrid E. Lundberg
- Subjects
Adult ,Male ,Adolescent ,Lupus nephritis ,GPI-Linked Proteins ,Cohort Studies ,Rheumatology ,Antigens, CD ,Immunopathology ,Genotype ,medicine ,Humans ,Lupus Erythematosus, Systemic ,Genetic Predisposition to Disease ,Pharmacology (medical) ,Child ,Aged ,Aged, 80 and over ,Polymorphism, Genetic ,biology ,business.industry ,Receptors, IgG ,C-reactive protein ,Middle Aged ,medicine.disease ,Lupus Nephritis ,Genotype frequency ,Interleukin 1 Receptor Antagonist Protein ,C-Reactive Protein ,Phenotype ,Immunology ,biology.protein ,Female ,Lymphocytopenia ,business ,Serositis ,Nephritis - Abstract
Objectives. To study the relationship between clinical manifestations in systemic lupus erythematosus (SLE) with polymorphisms in suggested susceptibility genes encoding FcRIIa, FcRIIIa, FcRIIIb, CRP and IL-1Ra. Methods. Genetic polymorphisms were analysed in 323 unrelated SLE patients and 200 healthy blood donors. The genotype frequencies were compared between clinical subsets of SLE patients, as well as with healthy controls. Clinical manifestations included the ACR classification criteria. Nephritis was further classified according to WHO class on renal biopsy. Results. Presence of a CRP4 A-allele was associated with SLE nephritis (P < 0.01) and inversely correlated with arthritis (P < 0.01), when comparing within the SLE group. The FcRIIIa F/F genotype was also associated with nephritis (WHO class III and IV, P ¼ 0.04 for the SLE group) and in combination with the CRP4 A-allele a stronger association was noted (P < 0.001). Furthermore, the FcRIIIb NA2/NA2 genotype was associated with butterfly rash (P < 0.01). An association was found between seizures and the presence of both the FcRIIa R/R and the FcRIIIa F/F genotypes (P < 0.01) and an inverse correlation between serositis and the CRP4 A-allele when present together with the IL-1Ra 2-allele (P ¼ 0.01). Furthermore, a combination of the FcRIIa R/R genotype and CRP4 A-allele was associated with lymphopenia (P ¼ 0.02) and a similar result was found for the combination of FcRIIIa F/F and FcRIIIb NA2/NA2 (P ¼ 0.04). Conclusions. Polymorphic variants of the CRP and Fc� -receptor genes are associated with the clinical phenotype in SLE. Our findings suggest an immune complex-mediated pathogenesis in nephritis and seizures, while development of arthritis may depend on other pathogenetic pathways.
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- 2007
48. Platelet-Derived S100A8/A9 and Cardiovascular Disease in Systemic Lupus Erythematosus
- Author
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Christian, Lood, Helena, Tydén, Birgitta, Gullstrand, Andreas, Jönsen, Eva, Källberg, Matthias, Mörgelin, Robin, Kahn, Iva, Gunnarsson, Tomas, Leanderson, Fredrik, Ivars, Elisabet, Svenungsson, and Anders A, Bengtsson
- Subjects
Adult ,Aged, 80 and over ,Blood Platelets ,Male ,Adolescent ,Middle Aged ,Young Adult ,Cardiovascular Diseases ,Calgranulin B ,Humans ,Lupus Erythematosus, Systemic ,Calgranulin A ,Female ,Aged - Abstract
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.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.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]).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.
- Published
- 2015
49. A subset of patients with systemic lupus erythematosus fails to degrade DNA from multiple clinically relevant sources
- Author
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Jonatan Leffler, Birgitta Gullstrand, Myriam Martin, Anders A. Bengtsson, Anna M. Blom, and Katarzyna Ciacma
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Neutrophils ,Immunology ,DNA Fragmentation ,Flow cytometry ,chemistry.chemical_compound ,Young Adult ,Rheumatology ,immune system diseases ,Internal medicine ,Medicine ,Humans ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,skin and connective tissue diseases ,Aged ,Rheumatology and Autoimmunity ,medicine.diagnostic_test ,business.industry ,Neutrophil extracellular traps ,DNA ,Middle Aged ,Chromatin ,chemistry ,Apoptosis ,DNA fragmentation ,Female ,business ,Clear cell ,Research Article - Abstract
Introduction Patients with systemic lupus erythematosus (SLE) have a decreased ability to clear cell remnants and multiple deficiencies in the ability to degrade cellular chromatin have been linked to the disease. Since the discovery of neutrophil extracellular traps (NETs), a renewed interest has been sparked in this field of research with multiple studies reporting a decreased ability of patients with SLE to degrade NETs. In this study we extend these findings by investigating the ability of patients with SLE to degrade chromatin from multiple clinically relevant sources. Methods We use flow cytometry in combination with NET degradation and DNA zymogram assays to investigate the ability of sera from SLE patients to degrade chromatin from three different sources of DNA such as NETs, apoptotic and necrotic cells. This ability was further associated with clinical manifestations. Results We found that 61 % of the patients had an affected degradation of at least one chromatin source. Further, degradation of NETs correlated with degradation of chromatin from secondary necrotic cells but not with degradation of chromatin from primary necrotic cells. Patients who fail to degrade several forms of DNA more often display anti-nuclear and nephritic involvement whereas this is not observed in patients with decreased ability to degrade chromatin from primary necrotic cells. Conclusions The majority of patients with SLE has a decreased ability to degrade chromatin from clinically relevant sources. This decreased ability is further reflected in their clinical presentation.
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- 2015
50. Type I interferon-mediated skewing of the serotonin synthesis is associated with severe disease in systemic lupus erythematosus
- Author
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Christoffer Tandrup Nielsen, Birgitta Gullstrand, Andreas Jönsen, Cecilia Klint, Niels Hh Heegaard, Helena Tydén, Robin Kahn, Christian Lood, Anders A. Bengtsson, and Christina Wenglén
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Adult ,Blood Platelets ,Male ,medicine.medical_specialty ,Serotonin ,Adolescent ,lcsh:Medicine ,Endocrinology and Diabetes ,Biology ,Kidney ,Pediatrics ,Severity of Illness Index ,chemistry.chemical_compound ,Internal medicine ,medicine ,Humans ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,Lupus Erythematosus, Systemic ,Platelet ,Platelet activation ,lcsh:Science ,Kynurenine ,Rheumatology and Autoimmunity ,Aged ,Autoimmune disease ,Aged, 80 and over ,Multidisciplinary ,Lupus erythematosus ,lcsh:R ,Tryptophan ,Kidney metabolism ,Middle Aged ,medicine.disease ,Endocrinology ,Phenotype ,chemistry ,Antibodies, Antinuclear ,Case-Control Studies ,Immunology ,Interferon Type I ,lcsh:Q ,Female ,Interferon type I ,medicine.drug ,Research Article - Abstract
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
- Published
- 2014
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