| 1. |
- Björk, Mathilda, et al.
(författare)
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Quality of life and acquired organ damage are intimately related to activity limitations in patients with systemic lupus erythematosus
- 2015
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Ingår i: BMC Musculoskeletal Disorders. - : BioMed Central / Springer Verlag (Germany). - 1471-2474. ; 16:188
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Tidskriftsartikel (refereegranskat)abstract
- Background: Systemic lupus erythematosus (SLE) is an autoimmune multi-organ disease, characterized by episodes of disease flares and remissions over time, which may restrain affected patients ability to perform daily activities. The purpose of the present study was to characterize variation in activity limitations among well-defined SLE patients, and to describe disease phenotypes, acquired organ damage and their relations to activity limitation and self-reported health, respectively. Methods: The disease phenotypes were organized into 4 different clinical groups and logistic regression analyses were used to identify how an elevated health assessment questionnaire (HAQ) score was related to disease variables such as phenotypes, disease activity and damage accrual. Correlation and multiple linear regression analyses were used to examine the association between each group of variables - background variables, disease variables and self-reported measurements - and the degree of elevated HAQ. Results: We found a higher proportion of activity limitation in patients with skin and joint involvement compared to others. The presence of activity limitation, as detected by the HAQ instrument, was significantly associated with quality of life (EuroQol-5D) and accrual of organ damage using the Systemic Lupus International Collaborative Clinics/ACR damage index. Conclusions: The findings highlight the differing requirements of the multi-professional rehabilitation interventions for the various SLE phenotypes in order to optimize the clinical care of the patients.
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| 2. |
- Blomgran, Robert, et al.
(författare)
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Common Genetic Variations in the NALP3 Inflammasome Are Associated with Delayed Apoptosis of Human Neutrophils
- 2012
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Ingår i: PLOS ONE. - San Francisco, USA : Public Library of Science. - 1932-6203. ; 7:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neutrophils are key-players in the innate host defense and their programmed cell death and removal are essential for efficient resolution of inflammation. These cells recognize a variety of pathogens, and the NOD-like receptors (NLRs) have been suggested as intracellular sensors of microbial components and cell injury/stress. Some NLR will upon activation form multi-protein complexes termed inflammasomes that result in IL-1 beta production. NLR mutations are associated with auto-inflammatory syndromes, and our previous data propose NLRP3 (Q705K)/CARD-8 (C10X) polymorphisms to contribute to increased risk and severity of inflammatory disease by acting as genetic susceptibility factors. These gene products are components of the NALP3 inflammasome, and approximately 6.5% of the Swedish population are heterozygote carriers of these combined gene variants. Since patients carrying the Q705K/C10X polymorphisms display leukocytosis, the aim of the present study was to find out whether the inflammatory phenotype was related to dysfunctional apoptosis and impaired clearance of neutrophils by macrophages. less thanbrgreater than less thanbrgreater thanMethods and Findings: Patients carrying the Q705K/C10X polymorphisms displayed significantly delayed spontaneous as well as microbe-induced apoptosis compared to matched controls. Western blotting revealed increased levels and phosphorylation of Akt and Mcl-1 in the patients neutrophils. In contrast to macrophages from healthy controls, macrophages from the patients produced lower amounts of TNF; suggesting impaired macrophage clearance response. less thanbrgreater than less thanbrgreater thanConclusions: The Q705K/C10X polymorphisms are associated with delayed apoptosis of neutrophils. These findings are explained by altered involvement of different regulators of apoptosis, resulting in an anti-apoptotic profile. Moreover, the macrophage response to ingestion of microbe-induced apoptotic neutrophils is altered in the patients. Taken together, the patients display impaired turnover and clearance of apoptotic neutrophils, pointing towards a dysregulated innate immune response that influences the resolution of inflammation. The future challenge is to understand how microbes affect the activation of inflammasomes, and why this interaction will develop into severe inflammatory disease in certain individuals.
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| 3. |
- Bolin, Karin, et al.
(författare)
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Association of STAT4 Polymorphism with Severe Renal Insufficiency in Lupus Nephritis
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:12, s. 84450-
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Tidskriftsartikel (refereegranskat)abstract
- Lupus nephritis is a cause of significant morbidity in systemic lupus erythematosus (SLE) and its genetic background has not been completely clarified. The aim of this investigation was to analyze single nucleotide polymorphisms (SNPs) for association with lupus nephritis, its severe form proliferative nephritis and renal outcome, in two Swedish cohorts. Cohort I (n = 567 SLE cases, n = 512 controls) was previously genotyped for 5676 SNPs and cohort II (n = 145 SLE cases, n = 619 controls) was genotyped for SNPs in STAT4, IRF5, TNIP1 and BLK. Case-control and case-only association analyses for patients with lupus nephritis, proliferative nephritis and severe renal insufficiency were performed. In the case-control analysis of cohort I, four highly linked SNPs in STAT4 were associated with lupus nephritis with genome wide significance with p = 3.7x10(-9), OR 2.20 for the best SNP rs11889341. Strong signals of association between IRF5 and an HLA-DR3 SNP marker were also detected in the lupus nephritis case versus healthy control analysis (pless than0.0001). An additional six genes showed an association with lupus nephritis with pless than0.001 (PMS2, TNIP1, CARD11, ITGAM, BLK and IRAK1). In the case-only meta-analysis of the two cohorts, the STAT4 SNP rs7582694 was associated with severe renal insufficiency with p = 1.6x10(-3) and OR 2.22. We conclude that genetic variations in STAT4 predispose to lupus nephritis and a worse outcome with severe renal insufficiency.
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| 4. |
- Boström, E A, et al.
(författare)
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Resistin is Associated with Breach of Tolerance and Anti-nuclear Antibodies in Patients with Hepatobiliary Inflammation
- 2011
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Ingår i: Scandinavian Journal of Immunology. - : Blackwell Publishing. - 0300-9475 .- 1365-3083. ; 74:5, s. 463-470
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Tidskriftsartikel (refereegranskat)abstract
- Resistin is a cysteine-rich protein, which is abundantly expressed at the site of inflammation, and acts as a regulator of the NF-kB-dependent cytokine cascade. The aim of this study was to evaluate resistin levels in relation to inflammatory mediators, disease phenotype and autoantibody status in a spectrum of pathological conditions of the gastrointestinal tract. Resistin levels were measured with an ELISA in sera originated from 227 patients and 40 healthy controls (HC). Fifty patients diagnosed with non-alcoholic fatty liver disease (NAFLD), 53 ulcerative colitis (UC), 51 Crohns disease (CD), 46 autoimmune hepatitis (AIH) and 27 primary sclerosing cholangitis (PSC) were included. The sera were analysed with respect to biochemical parameters of systemic inflammation and liver function and to the presence of antibodies to nuclear antigens (ANA), mitochondria (AMA) and smooth muscle (SMA). Compared with HC, resistin levels were raised in AIH (P = 0.017) and PSC (P = 0.03); compared with NAFLD, levels were elevated in CD (P = 0.041), AIH (P andlt; 0.001) and PSC (P andlt; 0.001). Patients with elevated levels of resistin were more often treated with corticosteroids, but no difference was found between active disease and clinical remission. Resistin levels were significantly higher in ANA-positive individuals compared with ANA-negative (P = 0.025). Resistin levels were directly correlated with IL-6 (r = 0.30, P = 0.02) and IL-8 (r = 0.51, P andlt; 0.001). Elevated levels of resistin were prominent in patients with hepatobiliary inflammation and were associated with breach of self-tolerance, i.e. ANA positivity. Thus, we propose that resistin may be an important marker of disease severity in autoantibody-mediated gastrointestinal inflammatory diseases.
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| 5. |
- Ellegård, Rada, et al.
(författare)
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Complement Opsonization of HIV-1 Results in Decreased Antiviral and Inflammatory Responses in Immature Dendritic Cells via CR3
- 2014
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Ingår i: Journal of Immunology. - : American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 193:9, s. 4590-4601
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Tidskriftsartikel (refereegranskat)abstract
- Immature dendritic cells (iDCs) in genital and rectal mucosa may be one of the first cells to come into contact with HIV-1 during sexual transmission of virus. HIV-1 activates the host complement system, which results in opsonization of virus by inactivated complement fragments, for example, iC3b. We investigated antiviral and inflammatory responses induced in human iDCs after exposure to free HIV-1 (F-HIV), complement-opsonized HIV-1 (C-HIV), and complement and Ab-opsonized HIV-1 (CI-HIV). F-HIV gave rise to a significantly higher expression of antiviral factors such as IFN-beta, myxovirus resistance protein A, and IFN-stimulated genes, compared with C-HIV and CI-HIV. Additionally, F-HIV induced inflammatory factors such as IL-1 beta, IL-6, and TNF-alpha, whereas these responses were weakened or absent after C-HIV or CI-HIV exposure. The responses induced by F-HIV were TLR8-dependent with subsequent activation of IFN regulatory factor 1, p38, ERK, PI3K, and NF-kappa B pathways, whereas these responses were not induced by C-HIV, which instead induced activation of IFN regulatory factor 3 and Lyn. This modulation of TLR8 signaling was mediated by complement receptor 3 and led to enhanced infection. The impact that viral hijacking of the complement system has on iDC function could be an important immune evasion mechanism used by HIV-1 to establish infection in the host.
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| 6. |
- Enocsson, Helena, et al.
(författare)
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Four Anti-dsDNA Antibody Assays in Relation to Systemic Lupus Erythematosus Disease Specificity and Activity
- 2015
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Ingår i: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 42:5, s. 817-825
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Analysis of antibodies against dsDNA is an important diagnostic tool for systemic lupus erythematosus (SLE), and changes in anti-dsDNA antibody levels are also used to assess disease activity. Herein, 4 assays were compared with regard to SLE specificity, sensitivity, and association with disease activity variables. Methods. Cross-sectional sera from 178 patients with SLE, of which 11 were followed consecutively, from a regional Swedish SLE register were analyzed for immunoglobulin G (IgG) anti-dsDNA by bead-based multiplex assay (FIDIS; Theradig), fluoroenzyme-immunoassay (EliA; Phadia/Thermo Fisher Scientific), Crithidia luciliae immunofluorescence test (CLIFT; ImmunoConcepts), and line blot (EUROLINE; Euroimmun). All patients with SLE fulfilled the 1982 American College of Rheumatology and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC-12) classification criteria. Healthy individuals (n = 100), patients with rheumatoid arthritis (n = 95), and patients with primary Sjogren syndrome (n = 54) served as controls. Results. CLIFT had the highest SLE specificity (98%) whereas EliA had the highest sensitivity (35%). When cutoff levels for FIDIS, EliA, and EUROLINE were adjusted according to SLICC-12 (i.e., double the reference limit when using ELISA), the specificity and sensitivity of FIDIS was comparable to CLIFT. FIDIS and CLIFT also showed the highest concordance (84%). FIDIS performed best regarding association with disease activity in cross-sectional and consecutive samples. Fisher's exact test revealed striking differences between methods regarding associations with certain disease phenotypes. Conclusion. CLIFT remains a good choice for diagnostic purposes, but FIDIS performs equally well when the cutoff is adjusted according to SLICC-12. Based on results from cross-sectional and consecutive analyses, FIDIS can also be recommended to monitor disease activity.
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| 7. |
- Enocsson, Helena, et al.
(författare)
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Interferon-alpha Mediates Suppression of C-Reactive Protein Explanation for Muted C-Reactive Protein Response in Lupus Flares?
- 2009
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:12, s. 3755-3760
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Tidskriftsartikel (refereegranskat)abstract
- Objective. C-reactive protein (CRP) is synthesized by hepatocytes in response to interleukin-6 (IL-6) during inflammation. Despite raised IL-6 levels and extensive systemic inflammation, serum CRP levels remain low during most viral infections and disease flares of systemic lupus erythematosus (SLE). Because both viral infections and SLE are characterized by high levels of interferon-alpha (IFN alpha), the aim of this study was to determine whether this cytokine can inhibit the induction of CRP. Methods. The interference of all 12 IFN alpha subtypes with CRP promoter activity induced by IL-6 and IL-1 beta was studied in a CRP promoter- and luciferase reporter-transfected human hepatoma cell line, Hep-G2. CRIP secretion by primary human hepatocytes was analyzed by enzyme-linked immunosorbent assay. Results. CRP promoter activity was inhibited by all single IFN alpha subtypes, as well as by 2 different mixtures of biologically relevant IFN alpha subtypes. The most prominent effect was seen using a leukocyte-produced mixture of IFN alpha (56% inhibition at 1,000 IU/ml). The inhibitory effect of IFN alpha was confirmed in primary human hepatocytes. CRP promoter inhibition was dose dependent and mediated via the type I IFN receptor. Transferrin production and Hep-G2 proliferation/viability were not affected by IFN alpha. Conclusion. The current study demonstrates that IFN alpha is an inhibitor of CRP promoter activity and CRP secretion. This finding concords with previous observations of up-regulated IFN alpha and a muted CRP response during SLE disease flares. Given the fundamental role of both IFN alpha and CRP in the immune response, our results are of importance for understanding the pathogenesis of SLE and may also contribute to understanding the differences in the CRP response between viral and bacterial infections.
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| 8. |
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| 9. |
- Enocsson, Helena, et al.
(författare)
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Soluble urokinase plasminogen activator receptor : A valuable biomarker in systemic lupus erythematosus?
- 2015
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Ingår i: Clinica Chimica Acta. - : Elsevier BV. - 0009-8981 .- 1873-3492. ; 444, s. 234-241
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Forskningsöversikt (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a potentially severe autoimmune condition with an unpredictable disease course, often with fluctuations in disease activity over time. Long term inflammation and drug-related side-effects may subsequently lead to permanent organ damage, a consequence which is intimately connected to decreased quality of life and mortality. New lupus biomarkers that convey information regarding inflammation and/or organ damage are thus warranted. Today, there is no clinical biomarker that indicates the risk of damage accrual. Herein we highlight the urokinase plasminogen activator receptor (uPAR) and especially its soluble form (suPAR) that besides having biological functions in e.g. proteolysis, cell migration and tissue homeostasis, recently has emerged as a promising biomarker of inflammation and prognosis of several disorders. A strong association between suPAR and organ damage in SLE was recently demonstrated, and preliminary data (presented in this review) suggests the possibility of a predictive value of suPAR blood levels. The involvement of suPAR in the pathogenesis of SLE remains obscure, but its effects in leukocyte recruitment, phagocytic uptake of dying cells (efferocytosis) and complement regulation suggests that the central parts of the SLE pathogenesis could be regulated by suPAR, and vice versa.
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| 10. |
- Enocsson, Helena, et al.
(författare)
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Soluble urokinase plasminogen activator receptor levels reflect organ damage in systemic lupus erythematosus
- 2013
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Ingår i: Translational Research. - : Elsevier. - 1931-5244 .- 1878-1810. ; 162:5, s. 287-296
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Tidskriftsartikel (refereegranskat)abstract
- Assessments of disease activity and organ damage in systemic lupus erythematosus (SLE) remain challenging because of the lack of reliable biomarkers and disease heterogeneity. Ongoing inflammation can be difficult to distinguish from permanent organ damage caused by previous flare-ups or medication side effects. Circulating soluble urokinase plasminogen activator receptor (suPAR) has emerged as a potential marker of inflammation and disease severity, and an outcome predictor in several disparate conditions. This study was done to evaluate suPAR as a marker of disease activity and organ damage in SLE. Sera from 100 healthy donors- and 198 patients with SLE fulfilling the 1982 American College of Rheumatology classification criteria and/or the Fries criteria were analyzed for suPAR by enzyme immunoassay. Eighteen patients with varying degree of disease activity were monitored longitudinally. Disease activity was assessed by the SLE disease activity index 2000 and the physicians global assessment. Organ damage was evaluated by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI). Compared with healthy control subjects, serum suPAR levels were elevated significantly in patients with SLE. No association was recorded regarding suPAR levels and SLE disease activity in cross-sectional or consecutive samples. However, a strong association was observed between suPAR and SDI (P andlt; 0.0005). Considering distinct SDI domains, renal, neuropsychiatric, ocular, skin, and peripheral vascular damage had.a significant effect on suPAR levels. This study is the first to demonstrate an association between serum suPAR and irreversible organ damage in SLE. Further studies are warranted to evaluate suPAR and other biomarkers as predictors of evolving organ damage.
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