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  • Ge, Changrong, et al. (författare)
  • Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage
  • 2017
  • Ingår i: JCI insight. - : AMER SOC CLINICAL INVESTIGATION INC. - 2379-3708. ; 2:13
  • Tidskriftsartikel (refereegranskat)abstract
    • Today, it is known that autoimmune diseases start a long time before clinical symptoms appear. Anti-citrullinated protein antibodies (ACPAs) appear many years before the clinical onset of rheumatoid arthritis (RA). However, it is still unclear if and how ACPAs are arthritogenic. To better understand the molecular basis of pathogenicity of ACPAs, we investigated autoantibodies reactive against the C1 epitope of collagen type II (CII) and its citrullinated variants. We found that these antibodies are commonly occurring in RA. A mAb (ACC1) against citrullinated C1 was found to cross-react with several noncitrullinated epitopes on native CII, causing proteoglycan depletion of cartilage and severe arthritis in mice. Structural studies by X-ray crystallography showed that such recognition is governed by a shared structural motif "RG-TG" within all the epitopes, including electrostatic potential-controlled citrulline specificity. Overall, we have demonstrated a molecular mechanism that explains how ACPAs trigger arthritis.
  • Frodlund, M., et al. (författare)
  • Immunoglobulin A anti-phospholipid antibodies in Swedish cases of systemic lupus erythematosus : associations with disease phenotypes, vascular events and damage accrual
  • 2018
  • Ingår i: Clinical and Experimental Immunology. - : WILEY. - 0009-9104 .- 1365-2249. ; 194:1, s. 27-38
  • Tidskriftsartikel (refereegranskat)abstract
    • Immunoglobulin (Ig) G- and IgM-class anti-cardiolipin antibodies (aCL) and lupus anti-coagulant (LA) are included in the 1997 update of the American College of Rheumatology (ACR-97) systemic lupus erythematosus (SLE) criteria. Despite limited evidence, IgA-aCL and IgA anti-(2)-glycoprotein-I (anti-(2)GPI) were included in the 2012 Systemic Lupus International Collaborating Clinics criteria. The present study aimed to evaluate IgG-/IgA-/IgM-aCL and anti-(2)GPI occurrence in relation to disease phenotype, smoking habits, pharmacotherapy, anti-phospholipid syndrome (APS) and organ damage among 526 Swedish SLE patients meeting ACR-97. Patients with rheumatoid arthritis (n=100), primary Sjogren's syndrome (n=50) and blood donors (n=507) served as controls. Anti-phospholipid antibodies (aPL) were analysed by fluoroenzyme-immunoassays detecting aCL/anti-(2)GPI. Seventy-six (14%) SLE cases fulfilled the Sydney APS-criteria, and 1 aCL/anti-(2)GPI isotype (IgG/IgA/IgM) occurred in 138 SLE patients (26%). Forty-five (9%) of the SLE cases had IgA-aCL, 20 of whom (4%) lacked IgG-/IgM-aCL. Seventy-four (14%) tested positive for IgA anti-(2)GPI, 34 (6%) being seronegative regarding IgG/IgM anti-(2)GPI. Six (1%) had APS manifestations but were seropositive regarding IgA-aCL and/or IgA anti-(2)GPI in the absence of IgG/IgM-aPL and LA. Positive LA and IgG-aPL tests were associated with most APS-related events and organ damage. Exclusive IgA anti-(2)GPI occurrence associated inversely with Caucasian ethnicity [odds ratio (OR)=021, 95% confidence interval (CI)=006-072) and photosensitivity (OR=019, 95% CI=005-072). Nephritis, smoking, LA-positivity and statin/corticosteroid-medication associated strongly with organ damage, whereas hydroxychloroquine-medication was protective. In conclusion, IgA-aPL is not rare in SLE (16%) and IgA-aPL analysis may have additional value among SLE cases with suspected APS testing negative for other isotypes of aPL and LA.
  • Salomonsson, Stina, et al. (författare)
  • A population-based investigation of the autoantibody profile in mothers of children with atrioventricular block.
  • 2011
  • Ingår i: Scandinavian Journal of Immunology. - Oxford : Wiley-Blackwell. - 1365-3083 .- 0300-9475. ; 74, s. 511-517
  • Tidskriftsartikel (refereegranskat)abstract
    • The objective of the study was to investigate the antigen specificity and occurrence of individual autoantibodies in mothers of children diagnosed with atrioventricular (AV) block in a nation-wide setting. Patients with AV block detected before 15 years of age were identified using national quality registries as well as a network of pediatric and adult cardiologists and rheumatologists at the six university hospitals in Sweden. Patients with gross heart malformations, surgically or infectiously induced blocks were excluded. Blood samples were obtained from the mothers and maternal autoantibody profile, including the occurrence of antibodies against Ro52, Ro60, La, SmB, SmD, RNP-70k, RNP-A, RNP-C, CENP-C, Scl-70, Jo-1, ribosomal RNP and histones was investigated in 193 mothers of children with AV block by immunoblotting and ELISA. Autoantibody reactivity was detected in 48% (93/193) of the mothers of children with AV block. In autoantibody-positive mothers, the vast majority, 95% (88/93), had antibodies against Ro52, while 63% (59/93) had autoantibodies to Ro60 and 58% (54/93) had autoantibodies to La. In addition, 13% (12/93) of the autoantibody-positive mothers had antibodies to other investigated antigens besides Ro52, Ro60 and La, and of these anti-histone antibodies were most commonly represented, detected in 8% (7/93) of the mothers. In conclusion, this Swedish population-based study confirm that maternal autoantibodies may associate with heart block in the child. Further, our data demonstrate a dominant role of Ro52 antibodies in association with AV block.
  • Wirestam, Lina, et al. (författare)
  • Osteopontin and disease activity in patients with recent-onset systemic Lupus Erythematosus : Results from the SLICC Inception Cohort
  • 2019
  • Ingår i: Journal of Rheumatology. - : J Rheumatol Publ Co. - 0315-162X .- 1499-2752. ; 46:5, s. 492-500
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective. In cross-sectional studies, elevated osteopontin (OPN) levels have been proposed to reflect, and/or precede, progressive organ damage and disease severity in systemic lupus erythematosus (SLE). We aimed, in a cohort of patients with recent-onset SLE, to determine whether raised serum OPN levels precede damage and/or are associated with disease activity or certain disease phenotypes. Methods. We included 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who had 5 years of followup data available. All patients fulfilled the 1997 American College of Rheumatology (ACR) criteria. Baseline sera from patients and from age- and sex-matched population-based controls were analyzed for OPN using ELISA. Disease activity and damage were assessed at each annual followup visit using the SLE Disease Activity Index 2000 (SLEDAI-2K) and the SLICC/ACR damage index (SDI), respectively. Results. Compared to controls, baseline OPN was raised 4-fold in SLE cases (p < 0.0001). After relevant adjustments in a binary logistic regression model, OPN levels failed to significantly predict global damage accrual defined as SDI ≥ 1 at 5 years. However, baseline OPN correlated with SLEDAI-2K at enrollment into the cohort (r = 0.27, p < 0.0001), and patients with high disease activity (SLEDAI-2K ≥ 5) had raised serum OPN (p < 0.0001). In addition, higher OPN levels were found in patients with persistent disease activity (p = 0.0006), in cases with renal involvement (p < 0.0001) and impaired estimated glomerular filtration rate (p = 0.01). Conclusion. The performance of OPN to predict development of organ damage was not impressive. However, OPN associated significantly with lupus nephritis and with raised disease activity at enrollment, as well as over time.
  • Ambrosi, Aurelie, et al. (författare)
  • Development of heart block in children of SSA/SSB-autoantibody-positive women is associated with maternal age and displays a season-of-birth pattern
  • 2012
  • Ingår i: Annals of the Rheumatic Diseases. - London : BMJ Publishing Group. - 0003-4967 .- 1468-2060. ; 71:3, s. 334-340
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective Congenital heart block may develop in the fetuses of Ro/SSA-positive and La/SSB-positive mothers. Recurrence rates of only 10-20% despite persisting maternal antibodies indicate that additional factors are critical for the establishment of heart block. The authors investigated the influence of other maternal and fetal factors on heart block development in a Swedish population-based cohort. less thanbrgreater than less thanbrgreater thanMethods The influence of fetal gender, maternal age, parity and time of birth on heart block development was analysed in 145 families, including Ro/La-positive (n=190) and Ro/La-negative (n=165) pregnancies. less thanbrgreater than less thanbrgreater thanResults There was a recurrence rate of 12.1% in Ro/La-positive women, and no recurrence in Ro/La-negative women. Fetal gender and parity did not influence the development of heart block in either group. Maternal age in Ro/La-positive pregnancies with a child affected by heart block was, however, significantly higher than in pregnancies resulting in babies without heart block (pandlt;0.05). Seasonal timing of pregnancy influenced the outcome. Gestational susceptibility weeks 18-24 occurring during January-March correlated with a higher proportion of children with heart block and lower vitamin D levels during the same period in a representative sample of Swedish women and a corresponding higher proportion of children with heart block born in the summer (pandlt;0.02). Maternal age or seasonal timing of pregnancy did not affect the outcome in Ro/La-negative pregnancies. less thanbrgreater than less thanbrgreater thanConclusion This study identifies maternal age and seasonal timing of pregnancy as novel risk factors for heart block development in children of Ro/La-positive women. These observations may be useful for counselling when pregnancy is considered.
  • Docherty-Skogh, Ann-Charlott, et al. (författare)
  • Bone morphogenetic protein-2 delivered by hyaluronan-based hydrogel induces massive bone formation and healing of cranial defects in minipigs
  • 2010
  • Ingår i: Plastic and reconstructive surgery (1963). - : Lippincott, Williams & Wilkins. - 0032-1052 .- 1529-4242. ; 125:5, s. 1383-1392
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Reconstruction of large craniofacial bone defects is a challenge using bone transplants or alloplastic materials. The use of bone morphogenetic protein (BMP)-2 together with a suitable carrier is an attractive option that may facilitate new bone formation. The authors have developed a hydrogel that is formed in situ by the cross-linking of multifunctional hyaluronic acid and polyvinyl alcohol derivatives mixed with hydroxyapatite nanoparticles, in the presence of BMP-2. The aim of this study was to evaluate the suitability of the hydrogel as a carrier for BMP-2 in repairing critical size cranial defects in a minipig model. Methods: Cranial defects (2 × 4 cm) were created in 14 minipigs. The experimental groups were as follows: group 1, craniotomy and application of 5 ml of hydrogel with 1.25 mg of BMP-2 (n = 6); group 2, craniotomy and application of 5 ml of hydrogel without BMP-2 (n = 6); and group 3, craniotomy with no further treatment (n = 2). Results: After 3 months, computed tomographic and histologic examinations were performed. There was spontaneous ossification in the untreated group, but the healing was incomplete. The hydrogel alone demonstrated no further effects. The addition of 1.25 mg of BMP-2 to the hydrogel induced a greater than 100 percent increase in bone volume (p = 0.003) and complete healing of the defects. Histologic examination revealed compact lamellar bone in the BMP group without intertrabecular fibrous tissue, as was seen in the other groups. The hydrogel was resorbed completely within 3 months and, importantly, caused no inflammatory reaction. Conclusion: The injectable hydrogel may be favorable as a BMP-2 carrier for bone reconstruction.
  • Engstrand, Thomas, et al. (författare)
  • A novel biodegradable delivery system for bone morphogenetic protein-2.
  • 2008
  • Ingår i: Plastic and reconstructive surgery. - 1529-4242. ; 121:6, s. 1920-8
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The efficacy of recombinant growth factors in vivo is highly dependent on the delivery vehicle. The authors investigated the osteoinductive effects of recombinant human bone morphogenetic proteins (BMP)-2 implanted together with a complex of heparin and chitosan. METHODS: Sixty rats were used. Three different carriers in gel formulation (type I collagen, heparin/type I collagen, and heparin/chitosan) were mixed with either 0, 10, or 50 microg of BMP-2, making the number of groups nine. The gels were injected into the quadriceps muscles of both legs in 45 rats (n = 10 per group). Freeze-dried formulations of the carriers were also tested with the same amounts of BMP-2 using 15 rats (n = 5 per group). Four weeks after implantation, the quality and amount of newly formed bone were assessed. RESULTS: Chitosan was shown to protect the heparinase-mediated degradation of heparin in vitro. The osteoinductive effects of BMP-2 in combination with heparin/chitosan were superior as compared with BMP-2 implanted together with type I collagen. Interestingly, the heparin/chitosan complex induced a small amount of bone also without BMP-2 added. The heparin/chitosan was completely absorbed after 4 weeks as determined by histologic evaluation, and a normal active bone formation was present. The freeze-dried formulations of the carriers demonstrated similar osteoinductive effects as the gels. CONCLUSIONS: An osteoinductive formula for clinical use is needed for general bone reconstruction. Heparin in complex with chitosan has the ability to stabilize or activate the growth factor in vivo and induce the generation of new bone in good yields.
  • Engstrand, Thomas, et al. (författare)
  • Development of a bioactive implant for repair and potential healing of cranial defects
  • 2014
  • Ingår i: Journal of Neurosurgery. - 0022-3085 .- 1933-0693. ; 120:1, s. 273-277
  • Tidskriftsartikel (refereegranskat)abstract
    • The repair of complex craniofacial bone defects is challenging and a successful result is dependent on the size of the defect, quality of the soft tissue covering the defect, and choice of reconstruction method. The objective of this study was to develop a bioactive cranial implant that could provide a permanent reconstructive solution to the patient by stimulating bone healing of the defect. In this paper the authors report on the feasibility and clinical results of using such a newly developed device for the repair of a large traumatic and therapy-resistant cranial bone defect. The patient had undergone numerous attempts at repair, in which established methods had been tried without success. A mosaic-designed device was manufactured and implanted, comprising interconnected ceramic tiles with a defined calcium phosphate composition. The clinical outcome 30 months after surgery revealed a restored cranial vault without postoperative complications. Computed tomography demonstrated signs of bone ingrowth. Examination with combined 18F-fluoride PET and CT provided further evidence of bone healing of the cranial defect.
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