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  • 1.
    Aanaes, K
    et al.
    Rigshosp, Denmark .
    Rasmussen, N
    Rigshosp, Denmark Statens Serum Institute, Denmark .
    Pressler, T
    Rigshosp, Denmark Rigshosp, Denmark .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Johansen, H K
    Rigshosp, Denmark .
    Lindberg, U
    Lund University, Sweden .
    Hoiby, N
    Rigshosp, Denmark .
    Carlsson, M
    Lund University, Sweden .
    Wieslander, J
    EuroDiagnostica AB, Sweden .
    Buchwald, C
    Rigshosp, Denmark .
    Extensive Endoscopic Image-Guided Sinus Surgery Decreases BPI-ANCA in Patients with Cystic Fibrosis2012In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 76, no 6, p. 573-579Article in journal (Refereed)
    Abstract [en]

    Antineutrophil cytoplasm autoantibodies (ANCA) directed against bactericidal/permeability-increasing protein (BPI) are common in patients with cystic fibrosis (CF), and serum levels are correlated with lung colonization by Pseudomonas aeruginosa and the severity of lung damage. The production of BPI-ANCA may be due to the costimulation of BPI when mounting an immune response against P. aeruginosa. The effect of surgery aiming to eradicate bacteria and infected tissue on BPI-ANCA levels is sparsely described. A cohort of patients with CF were included: 53 patients having extensive image-guided sinus surgery (EIGSS) with topical postoperative antibiotic treatment, 131 non-operated controls and 36 who had double lung transplantation (LTX). In all 219 patients, serum samples before and after surgery or at similar intervals were analysed for IgG and IgA BPI-ANCA. The EIGSS group showed a highly significant decrease in both IgA and IgG BPI-ANCA levels compared with their own preoperative values and control group values (P andlt; 0.0010.02). The LTX patients also showed a highly significant decrease in both IgA and IgG BPI-ANCA levels (P andlt; 0.001). EIGSS and LTX decrease IgA and IgG BPI-ANCA levels in patients with CF, indicating that extensive removal of infected tissue influences the pathogenic process of autoantibody production. The results shown herein are in favour of applying EIGSS in selected patients with CF and for using BPI-ANCA as a surrogate marker for guiding further therapeutic interventions.

  • 2.
    Abdgawad, M.
    et al.
    Departments of Nephrology, Lund University, Lund, Sweden.
    Gunnarsson, L.
    Departments of Nephrology, Lund University, Lund, Sweden.
    Bengtsson, A. A.
    Departments of Rheumatology, Lund University, Lund, Sweden.
    Geborek, P.
    Departments of Rheumatology, Lund University, Lund, Sweden.
    Nilsson, L.
    Departments of Haematology, Lund University, Lund, Sweden.
    Segelmark, Mårten
    Departments of Nephrology, Lund University, Lund, Sweden.
    Hellmark, T.
    Departments of Nephrology, Lund University, Lund, Sweden.
    Elevated neutrophil membrane expression of proteinase 3 is dependent upon CD177 expression2010In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 161, no 1, p. 89-97Article in journal (Refereed)
    Abstract [en]

    Proteinase 3 (PR3) is a major autoantigen in anti-neutrophil cytoplasmic antibodies (ANCA)-associated systemic vasculitis (AASV), and the proportion of neutrophils expressing PR3 on their membrane (mPR3+) is increased in AASV. We have shown recently that mPR3 and CD177 are expressed on the same cells in healthy individuals. In this study we try to elucidate mechanisms behind the increased mPR3 expression in AASV and its relationship to CD177. All neutrophils in all individuals were either double-positive or double-negative for mPR3 and CD177. The proportion of double-positive neutrophils was increased significantly in AASV and systemic lupus erythematosus patients. The proportion of mPR3+/CD177+ cells was not correlated to general inflammation, renal function, age, sex, drug treatment and levels of circulating PR3. AASV patients had normal levels of granulocyte colony-stimulating factor and granulocyte–macrophage colony-stimulating factor. Pro-PR3 was found to constitute 10% of circulating PR3 but none of the mPR3. We found increased mRNA levels of both PR3 and CD177 in AASV, but they did not correlate with the proportion of double-positive cells. In cells sorted based on membrane expression, CD177–mRNA was several-fold higher in mPR3+ cells. When exogenous PR3 was added to CD177-transfected U937 cells, only CD177+ cells bound PR3 to their membrane. In conclusion, the increased membrane expression of PR3 found in AASV is not linked directly to circulating PR3 or PR3 gene transcription, but is dependent upon CD177 expression and correlated with the transcription of the CD177 gene.

  • 3.
    Abdgawad, Mohamed
    et al.
    Lund University.
    Pettersson, Asa
    Lund University.
    Gunnarsson, Lena
    Lund University.
    Bengtsson, Anders A
    Lund University.
    Geborek, Pierre
    Lund University.
    Nilsson, Lars
    Lund University.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Hellmark, Thomas
    Lund University.
    Decreased Neutrophil Apoptosis in Quiescent ANCA-Associated Systemic Vasculitis2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3Article in journal (Refereed)
    Abstract [en]

    Background: ANCA-Associated Systemic Vasculitis (AASV) is characterized by leukocytoclasis, accumulation of unscavenged apoptotic and necrotic neutrophils in perivascular tissues. Dysregulation of neutrophil cell death may contribute directly to the pathogenesis of AASV. less thanbrgreater than less thanbrgreater thanMethods: Neutrophils from Healthy Blood Donors (HBD), patients with AASV most in complete remission, Polycythemia Vera (PV), Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) and renal transplant recipients (TP) were incubated in vitro, and the rate of spontaneous apoptosis was measured by FACS. Plasma levels of cytokines and sFAS were measured with cytometric bead array and ELISA. Expression of pro/anti-apoptotic factors, transcription factors C/EBP-alpha, C/EBP-beta and PU.1 and inhibitors of survival/JAK2-pathway were measured by real-time-PCR. less thanbrgreater than less thanbrgreater thanResults: AASV, PV and RA neutrophils had a significantly lower rate of apoptosis compared to HBD neutrophils (AASV 50 +/- 14% vs. HBD 64 +/- 11%, p andlt; 0.0001). In RA but not in AASV and PV, low apoptosis rate correlated with increased plasma levels of GM-CSF and high mRNA levels of anti-apoptotic factors Bcl-2A1 and Mcl-1. AASV patients had normal levels of G-CSF, GM-CSF and IL-3. Both C/EBP-alpha, C/EBP-beta were significantly higher in neutrophils from AASV patients than HBD. Levels of sFAS were significantly higher in AASV compared to HBD. less thanbrgreater than less thanbrgreater thanConclusion: Neutrophil apoptosis rates in vitro are decreased in AASV, RA and PV but mechanisms seem to differ. Increased mRNA levels of granulopoiesis-associated transcription factors and increased levels of sFAS in plasma were observed in AASV. Additional studies are required to define the mechanisms behind the decreased apoptosis rates, and possible connections with accumulation of dying neutrophils in regions of vascular lesions in AASV patients.

  • 4.
    Appelgren, Daniel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology. Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Marginal-Zone B-Cells Are Main Producers of IgM in Humans, and Are Reduced in Patients With Autoimmune Vasculitis2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 2242Article in journal (Refereed)
    Abstract [en]

    In mice, B1 and marginal zone (MZ) B-cells play an important role in prevention of autoimmunity through production of regulatory cytokines and natural antibodies. There is limited knowledge about the human counterparts of these cells. We therefore investigated functions of MZ-like B-cells and the frequency of circulating MZ-like and Bl-like B-cells in healthy controls (HC), as well as in patients with autoimmune vasculitis to learn more about the role of these cells in autoimmune disease. After stimulation with CpG oligodeoxynucleotides (ODN) of class B in vitro, MZ-like B-cells were the main producers of IgM whereas switched memory B-cells primarily produced IgG and IgA. TNF and IL-10 were produced by both MZ-like and switched memory B-cells. Neither antibody nor TNF/IL-10 production by the B-cell subsets differed between patients and HC. Patients with autoimmune vasculitis, irrespective of disease activity, had lower percentage and absolute numbers of circulating MZ-like B-cells, and lower absolute numbers of B1-like B-cells. The percentage of B1-like B-cells was reduced during active disease. These findings remained significant when the analysis was confined to active treatment-naive patients (disease onset).Our results suggest that human innate-like B-cells might have a physiological role in prevention of autoimmunity.

  • 5.
    Basu, Neil
    et al.
    University of Aberdeen, Aberdeen, UK.
    Watts, Richard
    University of East Anglia, School of Medicine, Norwich, Norfolk, UK.
    Bajema, Ingeborg
    Leiden University Medical Center, Leiden, The Netherlands.
    Baslund, Bo
    Rigshospitalet, Copenhagen, Denmark .
    Bley, Thorsten
    University Hospital Freiburg, Freiburg, Germany .
    Boers, Maarten
    VU University Medical Center, Amsterdam, The Netherlands.
    Brogan, Paul
    Institute of Child Health, London, UK.
    Calabrese, Len
    Cleveland Clinic Foundation, Cleveland, Ohio, USA .
    Cid, Maria C
    Hospital Clinic, University of Barcelona IDIBAPS, Barcelona, Spain.
    Cohen-Tervaert, Jan Willem
    Maastricht UMC, Maastricht, The Netherlands.
    Flores-Suarez, Luis Felipe
    National Institute of Respiratory Disease, Mexico City, Mexico.
    Fujimoto, Shouichi
    Miyazaki University, Miyazaki, Japan.
    de Groot, Kirsten
    Klinikum Offenbach, Offenbach, Germany.
    Guillevin, Loic
    University of Paris Descartes, Paris, France.
    Hatemi, Gulen
    University of Istanbul, Istanbul, Turkey.
    Hauser, Thomas
    Immunologie-Zentrum Zürich, Zurich, Switzerland .
    Jayne, David
    Addenbrooke's Hospital, Cambridge, UK .
    Jennette, Charles
    University of North Carolina, Chapel Hill, North Carolina, USA .
    Kallenberg, Cees G M
    University Hospital Groningen, Groningen, The Netherlands.
    Kobayashi, Shigeto
    Juntendo Koshigaya Hospital, Saitama, Japan.
    Little, Mark A
    Renal Institute of Birmingham, University of Birmingham, Birmingham, UK.
    Mahr, Alfred
    University of Paris Descartes, Paris, France.
    McLaren, John
    Whytemans Brae Hospital, Kirkcaldy, Fife, UK.
    Merkel, Peter A
    Boston University School of Medicine, Boston, Massachusetts, USA .
    Ozen, Seza
    Hacettepe University, Ankara, Turkey .
    Puechal, Xavier
    Centre Hospitalier Le Mans, Le Mans, France .
    Rasmussen, Niels
    Rigshospitalet, Copenhagen, Denmark.
    Salama, Alan
    Imperial College London, London, UK.
    Salvarani, Carlo
    Arcispedale S Maria Nuova, Reggio Emilia, Italy.
    Savage, Caroline
    Renal Institute of Birmingham, University of Birmingham, Birmingham, UK .
    Scott, David G I
    Norfolk and Norwich University Hospital Trust, Norwich, Norfolk, UK .
    Segelmark, Mårten
    Lund University, Lund, Sweden.
    Specks, Ulrich
    Mayo Clinc, Minnesota, Minneapolis, USA.
    Sunderköetter, Cord
    Universitätsklinikum Münster, Münich, Germany.
    Suzuki, Kazuo
    Chiba University Graduate School of Medicine, Chiba, Japan .
    Tesar, Vladimir
    Charles University, Prague, Czech Republic.
    Wiik, Allan
    Statens Serum Institut, Copenhagen, Denmark .
    Yazici, Hasan
    University of Istanbul, Istanbul, Turkey .
    Luqmani, Raashid
    University of Oxford, Oxford, UK.
    EULAR points to consider in the development of classification and diagnostic criteria in systemic vasculitis2010In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 69, no 10, p. 1744-1750Article in journal (Refereed)
    Abstract [en]

    Objectives The systemic vasculitides are multiorgan diseases where early diagnosis and treatment can significantly improve outcomes. Robust nomenclature reduces diagnostic delay. However, key aspects of current nomenclature are widely perceived to be out of date, these include disease definitions, classification and diagnostic criteria. Therefore, the aim of the present work was to identify deficiencies and provide contemporary points to consider for the development of future definitions and criteria in systemic vasculitis.

    Methods The expert panel identified areas of concern within existing definitions/criteria. Consequently, a systematic literature review was undertaken looking to address these deficiencies and produce ‘points to consider’ in accordance with standardised European League Against Rheumatism (EULAR) operating procedures. In the absence of evidence, expert consensus was used.

    Results There was unanimous consensus for re-evaluating existing definitions and developing new criteria. A total of 17 points to consider were proposed, covering 6 main areas: biopsy, laboratory testing, diagnostic radiology, nosology, definitions and research agenda. Suggestions to improve and expand current definitions were described including the incorporation of anti-neutrophil cytoplasm antibody and aetiological factors, where known. The importance of biopsy in diagnosis and exclusion of mimics was highlighted, while equally emphasising its problems. Thus, the role of alternative diagnostic tools such as MRI, ultrasound and surrogate markers were also discussed. Finally, structures to develop future criteria were considered.

    Conclusions Limitations in current classification criteria and definitions for vasculitis have been identified and suggestions provided for improvement. Additionally it is proposed that, in combination with the updated evidence, these should form the basis of future attempts to develop and validate revised criteria and definitions of vasculitis.

  • 6.
    Carlsson, Malin
    et al.
    Lund University.
    Shukla, Swati
    Lund University.
    Petersson, Ann Cathrine
    University and Reg Labs Reg Shane.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Hellmark, Thomas
    Lund University.
    Pseudomonas aeruginosa in cystic fibrosis: Pyocyanin negative strains are associated with BPI-ANCA and progressive lung disease2011In: Journal of Cystic Fibrosis, ISSN 1569-1993, E-ISSN 1873-5010, Vol. 10, no 4, p. 265-271Article in journal (Refereed)
    Abstract [en]

    The clinical consequence of chronic Pseudomonas aeruginosa colonization in cystic fibrosis (CF) varies between individuals for unknown reasons. Auto-antibodies against bactericidal/permeability increasing protein (BPI-ANCA) are associated with poor prognosis in CF. We hypothesize that there is a correlation between the presence of BPI-ANCA, the properties of the colonizing bacteria and the clinical conditions of the host. We compared isolates of P. aeruginosa from BPI-ANCA positive CF patients who have deteriorating lung disease with BPI-ANCA negative CF patients who are in stable clinical conditions. Epithelial cells (A549) and isolated polymorphonuclear granulocytes (PMNs) were stimulated with the isolates and cell death was analyzed with flow cytometry. We found that the ANCA associated strains in most cases showed pyocyanin negative phenotypes. These strains also induced less inflammatory response than the non-ANCA associated strains as shown by apoptosis and necrosis of epithelial cells and neutrophils. Our results suggest that colonization with strains of P. aeruginosa that induce a weak inflammatory response is associated with unfavorable outcome in CF. We speculate that inadequate control of pathogen proliferation through an insufficient inflammatory response results in a slowly increasing number of bacteria and accumulation of dying PMNs in the airways, contributing to progression in CF lung disease.

  • 7.
    Carlsson, Michael C
    et al.
    Lund University.
    Bakoush, Omran
    University of Lund Hospital.
    Tengroth, Lotta
    Lund University.
    Kilsgard, Ola
    Lund University.
    Malmstrom, Johan
    Lund University.
    Hellmark, Thomas
    University of Lund Hospital.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Leffler, Hakon
    Lund University.
    Galectin-8 in IgA Nephritis: Decreased Binding of IgA by Galectin-8 Affinity Chromatography and Associated Increased Binding in Non-IgA Serum Glycoproteins2012In: Journal of Clinical Immunology, ISSN 0271-9142, E-ISSN 1573-2592, Vol. 32, no 2, p. 246-255Article in journal (Refereed)
    Abstract [en]

    Background Immunoglobulin A nephritis (IgAN) is the most common primary glomerulonephritis worldwide. It is caused by accumulation of IgA1-containing immune complexes in the kidney resulting in renal failure, which is thought to be due to altered glycosylation of IgA with a decrease of 2-3-sialylated galactosides (NeuAc alpha 2-3Gal). less thanbrgreater than less thanbrgreater thanPurpose The purpose of this study was to analyze whether altered glycosylation of IgA would lead to an altered binding to galectin-8, an endogenous lectin with strong affinity for 2-3-sialylated galactosides. Galectins are a family of beta-galactoside-binding proteins; by binding various glycoproteins, they play important roles in the regulation of cellular functions in inflammation and immunity. Hence, an altered binding of IgA to galectin-8 could lead to pathologic immune functions, such as glomerulonephritis. less thanbrgreater than less thanbrgreater thanMethods Affinity chromatography of serum glycoproteins on the human sialogalactoside-binding lectin galectin-8N permitted quantitation of bound and unbound fractions, including IgA. less thanbrgreater than less thanbrgreater thanResults Analysis of similar to 100 IgA nephritis sera showed that the galectin-8N unbound fraction of IgA increased compared to similar to 100 controls, consistent with the known loss of galactosylation. A subgroup of similar to 15% of the IgAN patients had a ratio of galectin-8 bound/unbound IgA andlt;0.09, not found for any of the controls. Unexpectedly, the galectin-8N-binding fraction of serum glycoproteins other than IgA increased in the sera of IgAN patients but not in controls, suggesting a previously unrecognized change in this disease. less thanbrgreater than less thanbrgreater thanConclusion This is the first study that relates a galectin, an endogenous lectin family, to IgA nephritis and thus should stimulate new avenues of research into the pathophysiology of the disease.

  • 8.
    Carlsson, Michael C
    et al.
    Lund University, Sweden .
    Balog, Crina I A
    Leiden University, Netherlands .
    Kilsgard, Ola
    Lund University, Sweden .
    Hellmark, Thomas
    University of Lund Hospital, Sweden .
    Bakoush, Omran
    University of Lund Hospital, Sweden .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Ferno, Marten
    University of Lund Hospital, Sweden .
    Olsson, Hakan
    University of Lund Hospital, Sweden .
    Malmstrom, Johan
    Lund University, Sweden .
    Wuhrer, Manfred
    Leiden University, Netherlands .
    Leffler, Hakon
    Lund University, Sweden Skåne University Hospital, Sweden .
    Different fractions of human serum glycoproteins bind galectin-1 or galectin-8, and their ratio may provide a refined biomarker for pathophysiological conditions in cancer and inflammatory disease2012In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1820, no 9, p. 1366-1372Article in journal (Refereed)
    Abstract [en]

    Background: Changes in glycosylation of serum proteins are common, and various glycoforms are being explored as biomarkers in cancer and inflammation. We recently showed that glycoforms detected by endogenous galectins not only provide potential biomarkers, but also have different functions when they encounter galectins in tissue cells. Now we have explored the use of a combination of two galectins with different specificities, to further increase biomarker sensitivity and specificity. less thanbrgreater than less thanbrgreater thanMethods: Sera from 14 women with metastatic breast cancer, 12 healthy controls, 14 patients with IgA-nephritis (IgAN), and 12 patients with other glomerulonephritis were fractionated by affinity chromatography on immobilized human galectin-1 or galectin-8N, and the protein amounts of the bound and unbound fractions for each galectin were determined. less thanbrgreater than less thanbrgreater thanResults: Each galectin bound largely different fractions of the serum glycoproteins, including different glycoforms of haptoglobin. In the cancer sera, the level of galectin-1 bound glycoproteins was higher and galectin-8N bound glycoproteins lower compared to the other patients groups, whereas in IgAN sera the level of galectin-8N bound glycoproteins were higher. less thanbrgreater than less thanbrgreater thanConclusion: The ratio of galectin-1 bound/galectin-8N bound glycoproteins showed high discriminatory power between cancer patients and healthy, with AUC of 0.98 in ROC analysis, and thus provides an interesting novel cancer biomarker candidate. less thanbrgreater than less thanbrgreater thanGeneral significance: The galectin-binding ability of a glycoprotein is not only a promising biomarker candidate but may also have a specific function when the glycoprotein encounters the galectin in tissue cells, and thus be related to the pathophysiological state of the patient. This article is part of a Special Issue entitled Glycoproteomics.

  • 9.
    Clavarino, Giovanna
    et al.
    Ctr Hosp Univ Grenoble Alpes, France; Univ Grenoble Alpes, France.
    Gauthier, Arnaud
    Ctr Hosp Univ Grenoble Alpes, France.
    Hellmark, Thomas
    Lund Univ, Sweden.
    Carron, Pierre-Louis
    Ctr Hosp Univ Grenoble Alpes, France.
    Giovannini, Diane
    Ctr Hosp Univ Grenoble Alpes, France.
    Colliard, Sophie
    Ctr Hosp Univ Grenoble Alpes, France.
    Dragon-Durey, Marie-Agnes
    Hop Europeen Georges Pompidou, France.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Cesbron, Jean-Yves
    Ctr Hosp Univ Grenoble Alpes, France; Univ Grenoble Alpes, France.
    Dumestre-Perard, Chantal
    Ctr Hosp Univ Grenoble Alpes, France; Univ Grenoble Alpes, France.
    Letter: Routinely used immunoassays do not detect circulating anti-GBM antibodies against native NC1 hexamer and EA epitope of the 3 chain of type IV collagen in EUROPEAN JOURNAL OF IMMUNOLOGY, vol 48, issue 6, pp 1082-10842018In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 48, no 6, p. 1082-1084Article in journal (Other academic)
    Abstract [en]

    n/a

  • 10.
    Cui, Zhao
    et al.
    Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Beijing, PR China.
    Zhao, Ming-hui
    Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Beijing, PR China.
    Segelmark, Mårten
    Department of Nephrology, Clinical Sciences in Lund, Lund University, Lund, Sweden.
    Hellmark, Thomas
    Department of Nephrology, Clinical Sciences in Lund, Lund University, Lund, Sweden.
    Natural autoantibodies to myeloperoxidase, proteinase 3, and the glomerular basement membrane are present in normal individuals2010In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 78, no 6, p. 590-597Article in journal (Refereed)
    Abstract [en]

    Anti-neutrophil cytoplasmic antibodies (ANCAs) have a pathogenic role in ANCA-associated vasculitis. The origin of ANCAs and anti-glomerular basement membrane (GBM) antibodies, however, is unknown. In this study, we determined whether natural autoantibodies against myeloperoxidase (MPO), proteinase 3 (PR3), and GBM were present in each of 10 healthy Chinese and Swedish individuals, negative for all three antigens by routine ELISA. Antibodies were purified from isolated IgG by antigen-specific affinity columns. Natural anti-GBM autoantibodies gave a linear staining pattern along the GBM of human renal sections. On ethanol-fixed granulocytes, both natural anti-MPO and anti-PR3 autoantibodies gave cytoplasmic staining. The titers of natural anti-MPO/PR3 autoantibodies were significantly lower than those from patients with vasculitis. In competition ELISA, the binding of natural anti-MPO autoantibodies could be inhibited by MPO, but not by PR3 or noncollagenous domains from type IV collagen. The same specificity results were found for natural anti-PR3 and anti-GBM autoantibodies. Overall, individuals of the Chinese origin had more natural autoantibodies than did those of the Swedish origin, but no other differences were found. Hence, our study shows that healthy individuals have masked circulating, noncross-reactive, antigen-specific natural autoantibodies against MPO, PR3, and GBM in their serum and IgG fractions. Further studies are needed to determine their role if any in the etiology of ANCA-associated vasculitis and anti-GBM disease.

  • 11.
    Englund, Martin
    et al.
    Lund University, Sweden; Boston University, MA 02215 USA.
    Merkel, Peter A.
    University of Penn, PA 19104 USA.
    Tomasson, Gunnar
    University of Iceland, Iceland.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Mohammad, Aladdin J.
    Lund University, Sweden; Addenbrookes Hospital, England.
    Comorbidities in Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis versus the General Population2016In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 43, no 8, p. 1553-1558Article in journal (Refereed)
    Abstract [en]

    Objective. To evaluate the consultation rates of selected comorbidities in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) compared with the general population in southern Sweden. Methods. We used data from a population-based cohort of patients with AAV diagnosed between 1998 and 2010 in Southern Sweden (701,000 inhabitants). For each patient we identified 4 reference subjects randomly sampled from the general population and matched for year of birth, sex, area of residence, and index year. Using the population-based Skane Healthcare Register, we identified relevant diagnostic codes, registered between 1998 and 2011, for selected comorbidities assigned after the date of diagnosis of AAV or the index date for the reference subjects. We calculated rate ratios for comorbidities (AAV: reference subjects). Results. There were 186 patients with AAV (95 women, mean age 64.5 yrs) and 744 reference persons included in the analysis. The highest rate ratios (AAV: reference) were obtained for osteoporosis (4.6, 95% CI 3.0-7.0), followed by venous thromboembolism (4.0, 95% CI 1.9-8.3), thyroid diseases (2.1, 95% CI 1.3-3.3), and diabetes mellitus (2.0, 95% CI 1.3-2.9). For ischemic heart disease, the rate ratio of 1.5 (95% CI 1.0-2.3) did not reach statistical significance. No statistically significant differences were found for cerebrovascular accidents. Conclusion. AAV is associated with increased consultation rates of several comorbidities including osteoporosis and thromboembolic and endocrine disorders. Comorbid conditions should be taken into consideration when planning and providing care for patients with AAV.

  • 12.
    Erdbrügger, Uta
    et al.
    Division of Nephrology, Department of Medicine, University of Virginia Health System, Virginia, USA.
    Kielstein, Jan T
    Department of Hypertension and Nephrology, Medical Clinic V, Klinikum Braunschweig, Braunschweig, Germany.
    Westman, Kerstin
    Department of Nephrology, Lund University, Lund, Sweden.
    Ma, Jennie Z
    Department of Biostatistics, University of Virginia Health System, Virginia, USA.
    Xin, Wenjun
    Department of Biostatistics, University of Virginia Health System, Virginia, USA.
    Bode-Böger, Stephanie M
    Otto-von-Guericke University, Institute of Clinical Pharmacology, Magdeburg, Germany.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Rasmussen, Niels
    Department of Biochemistry and Immunology, Statens Seruminstitut, Copenhagen, Denmark.
    De Groot, Kirsten
    Department of Nephrology and Rheumatology, Medical Clinic III, Sana Klinikum, Offenbach, Germany.
    Higher levels of SDMA and not ADMA are associated with poorer survival of trial patients with systemic ANCA-associated vasculitis2018In: European journal of rheumatology, ISSN 2147-9720, Vol. 5, no 3, p. 153-159Article in journal (Refereed)
    Abstract [en]

    Endothelial dysfunction, increased cardiovascular events (CVE), and accelerated atherosclerosis have been described in patients with small vessel vasculitis and collagen vascular disease. Identifying predictors of cardiovascular risk will help to optimize short- and long-term care of patients with vasculitis. The present study investigates the predictive role of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and its stereoisomer symmetric dimethylarginine (SDMA) for cardiovascular risk, all-cause mortality, and renal function in patients with anti-neutrophil-cytoplasmic antibodies-associated small vessel vasculitis (AASV) subjected to standardized treatment regimens in four European Vasculitis Study Group trials representing all stages of renal disease.

  • 13.
    Eriksson, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Hallböök, Olof
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Frequency, Diagnosis, Treatment, and Outcome of Gastrointestinal Disease in Granulomatosis with Polyangiitis and Microscopic Polyangiitis2018In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 45, no 4, p. 529-537Article in journal (Refereed)
    Abstract [en]

    Objective. Involvement of the gastrointestinal (GI) tract is a rare complication of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). The aim was to describe frequency, diagnosis, treatment, and outcome of GI disease in a large series of patients in a single center. Methods. A database that includes all patients with GPA and MPA diagnosed since 1997 in a defined area of southeastern Sweden as well as prevalent older cases and tertiary referral patients was screened for patients with GI disease. Data were retrieved from the patients medical records, and GI manifestations of vasculitis were defined as proposed by Pagnoux, et al in 2005. Results. Fourteen (6.5%) of 216 consecutive patients with GPA/MPA had GI manifestations. Abdominal pain and GI bleeding were the most common symptoms. Radiology was important for detection of GI disease, while endoscopy failed to support the diagnosis in many patients. Because of perforation, 5 patients underwent hemicolectomy or small intestine resection. Primary anastomosis was created in 2/5 and enterostomy in 3/5 patients. One patient had a hemicolectomy because of lower GI bleeding. One sigmoid abscess was treated with drainage, and 1 intraabdominal bleeding condition with arterial coiling. Two patients died from GI disease. GPA and MPA patients with and without GI disease exhibited a similar overall survival. Conclusion. GI disease was found in 6.5% among 216 patients with GPA or MPA. Surgery was judged necessary only in cases with GI perforation or severe bleeding. Multidisciplinary engagement is strongly recommended.

  • 14.
    Geetha, Duvuru
    et al.
    Johns Hopkins University, Baltimore, MD, USA.
    Hruskova, Zdenka
    Charles University, Prague, Czech Republic .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Hogan, Jonathan
    Hospital of the University of Pennsylvania, Philadelphia, USA.
    Morgan, Matthew D
    University of Birmingham, UK .
    Cavero, Teresa
    Hospital 12 de Octubre, Madrid, Spain .
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Seo, Philip
    John Hopkins University, Baltimore, USA.
    Manno, Rebecca L
    John Hopkins University, Baltimore, USA.
    Dale, Jessica
    University of Birmingham, Birmingham, UK.
    Harper, Lorraine
    University of Birmingham, UK.
    Tesar, Vladimir
    Charles University, Prague, Czech Republic .
    Jayne, David Rw
    Addenbrooke's Hospital, Cambridge, UK .
    Rituximab for treatment of severe renal disease in ANCA associated vasculitis2016In: JN. Journal of Nephrology (Milano. 1992), ISSN 1121-8428, E-ISSN 1724-6059, Vol. 29, no 2, p. 195-201Article in journal (Refereed)
    Abstract [en]

    Background

    Rituximab (RTX) is approved for remission induction in ANCA associated vasculitis (AAV). However, data on use of RTX in patients with severe renal disease is lacking.

    Methods

    We conducted a retrospective multi-center study to evaluate the efficacy and safety of RTX with glucocorticoids (GC) with and without use of concomitant cyclophosphamide (CYC) for remission induction in patients presenting with e GFR less than 20 ml/min/1.73 m2. We evaluated outcomes of remission at 6 months (6 M), renal recovery after acute dialysis at diagnosis, e-GFR rise at 6 M, patient and renal survival and adverse events.

    Results

    A total 37 patients met the inclusion criteria. The median age was 61 years. (55–73), 62 % were males, 78 % had new diagnosis and 59 % were MPO ANCA positive. The median (IQR) e-GFR at diagnosis was 13 ml/min/1.73 m2 (7–16) and 15 required acute dialysis. Eleven (30 %) had alveolar hemorrhage. Twelve (32 %) received RTX with GC, 25 (68 %) received RTX with GC and CYC and seventeen (46 %) received plasma exchange. The median (IQR) follow up was 973 (200–1656) days. Thirty two of 33 patients (97 %) achieved remission at 6 M and 10 of 15 patients (67 %) requiring dialysis recovered renal function. The median prednisone dose at 6 M was 6 mg/day. The mean (SD) increase in e-GFR at 6 months was 14.5 (22) ml/min/m2. Twelve patients developed ESRD during follow up. There were 3 deaths in the first 6 months. When stratified by use of concomitant CYC, there were no differences in baseline e GFR, use of plasmapheresis, RTX dosing regimen or median follow up days between the groups. No differences in remission, renal recovery ESRD or death were observed.

    Conclusions

    This study of AAV patients with severe renal disease demonstrates that the outcomes appear equivalent when treated with RTX and GC with or without concomitant CYC.

  • 15.
    Grundstrom, Gunilla
    et al.
    Gambro Lundia AB, Sweden .
    Christensson, Anders
    Skåne University Hospital, Sweden .
    Alquist, Maria
    Gambro Lundia AB, Sweden .
    Nilsson, Lars-Goran
    Gambro Lundia AB, Sweden .
    Segelmark, Marten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology. Skåne University Hospital, Sweden .
    Replacement of acetate with citrate in dialysis fluid: a randomized clinical trial of short term safety and fluid biocompatibility2013In: BMC Nephrology, ISSN 1471-2369, E-ISSN 1471-2369, Vol. 14, no 216Article in journal (Refereed)
    Abstract [en]

    Background

    The majority of bicarbonate based dialysis fluids are acidified with acetate. Citrate, a well known anticoagulant and antioxidant, has been suggested as a biocompatible alternative. The objective of this study was to evaluate short term safety and biocompatibility of a citrate containing acetate-free dialysis fluid.

    Methods

    Twenty four (24) patients on maintenance dialysis three times per week, 13 on on-line hemodiafiltration (HDF) and 11 on hemodialysis (HD), were randomly assigned to start with either citrate dialysis fluid (1 mM citrate, 1.5 mM calcium) or control fluid (3 mM acetate, 1.5 mM calcium) in an open-labeled cross-over trial (6 + 6 weeks with 8 treatments wash-out in between). Twenty (20) patients, 11 on HDF and 9 on HD were included in the analyses. Main objective was short term safety assessed by acid–base status, plasma ionized calcium and parathyroid hormone (PTH). In addition, biocompatibility was assessed by markers of inflammation (pentraxin 3 (PTX-3), CRP, IL-6, TNF-α and IL-1β) and thrombogenicity (activated partial thromboplastin time (APTT) and visual clotting scores).

    Results

    No differences dependent on randomization order or treatment mode (HD vs. HDF) were detected. Citrate in the dialysis fluid reduced the intra-dialytic shift in pH (+0.04 week 6 vs. +0.06 week 0, p = 0.046) and base excess (+3.9 mM week 6 vs. +5.6 mM week 0, p = 0.006) over the study period. Using the same calcium concentration (1.5 mM), citrate dialysis fluid resulted in lower post-dialysis plasma ionized calcium level (1.10 mM vs. 1.27 mM for control, p < 0.0001) and higher post-dialysis PTH level (28.8 pM vs. 14.7 pM for control, p < 0.0001) while pre-dialysis levels were unaffected. Citrate reduced intra-dialytic induction of PTX-3 (+1.1 ng/ml vs. +1.4 ng/ml for control, p = 0.04) but had no effect on other markers of inflammation or oxidative stress. Citrate reduced visual clotting in the arterial air chamber during HDF (1.0 vs. 1.8 for control, p = 0.03) and caused an intra-dialytic increase in APTT (+6.8 s, p = 0.003) without affecting post-dialysis values compared to control.

    Conclusions

    During this small short term study citrate dialysis fluid was apparently safe to use in HD and on-line HDF treatments. Indications of reduced treatment-induced inflammation and thrombogenicity suggest citrate as a biocompatible alternative to acetate in dialysis fluid. However, the results need to be confirmed in long term studies.

  • 16.
    Hellmark, Thomas
    et al.
    Lund University, Sweden .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Diagnosis and classification of Goodpastures disease (anti-GBM)2014In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 48-49, p. 108-112Article in journal (Refereed)
    Abstract [en]

    Goodpastures disease or anti-glomerular basement membrane disease (anti-GBM-disease) is included among immune complex small vessel vasculitides. The definition of anti-GBM disease is a vasculitis affecting glomerular capillaries, pulmonary capillaries, or both, with GBM deposition of anti-GBM auto-antibodies. The disease is a prototype of autoimmune disease, where the patients develop auto-antibodies that bind to the basement membranes and activate the classical pathway of the complement system, which start a neutrophil dependent inflammation. The diagnosis of anti-GBM disease relies on the detection of anti-GBM antibodies in conjunction with glomerulonephritis and/or alveolitis. Overt clinical symptoms are most prominent in the glomeruli where the inflammation usually results in a severe rapidly progressive glomerulonephritis. Despite modern treatment less than one third of the patients survive with a preserved kidney function after 6 months follow-up. Frequencies vary from 0.5 to 1 cases per million inhabitants per year and there is a strong genetic linkage to HLA-DRB1*1501 and DRB1*1502. Essentially, anti-GBM disease is now a preferred term for what was earlier called Goodpastures syndrome or Goodpastures disease; anti-GBM disease is now classified as small vessel vasculitis caused by in situ immune complex formation; the diagnosis relies on the detection of anti-GBM in tissues or circulation in conjunction with alveolar or glomerular disease; therapy is effective only when detected at an early stage, making a high degree of awareness necessary to find these rare cases; 20-35% have anti-GBM and MPO-ANCA simultaneously, which necessitates testing for anti-GBM whenever acute test for ANCA is ordered in patients with renal disease.

  • 17.
    Hruskova, Zdenka
    et al.
    Charles Univ Prague, Czech Republic; Gen Univ Hosp, Czech Republic.
    Pippias, Maria
    Univ Amsterdam, Netherlands.
    Stel, Vianda S.
    Univ Amsterdam, Netherlands.
    Abad-Diez, Jose M.
    Aragon Hlth Serv, Spain.
    Sanchez, Manuel Benitez
    Hosp Juan Ramon Jimenez, Spain.
    Caskey, Fergus J.
    Southmead Hosp, England; Univ Bristol, England.
    Collart, Frederic
    French Belgian ESRD Registry, Belgium.
    De Meester, Johan
    Dutch Speaking Belgian Renal Registry NBVN, Belgium.
    Finne, Patrik
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland; Finnish Registry Kidney Dis, Finland.
    Heaf, James G.
    Zealand Univ Hosp, Denmark.
    Magaz, Angela
    Unidad Informac Pacientes Renales Comunidad Auton, Spain.
    Palsson, Runolfur
    Landspitali Natl Univ Hosp Iceland, Iceland; Univ Iceland, Iceland.
    Varberg Reisaeter, Anna
    Oslo Univ Hosp, Norway.
    Salama, Alan D.
    UCL, England.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Traynor, Jamie P.
    ISD Scotland, Scotland.
    Massy, Ziad A.
    Ambroise Pare Univ Hosp, France; INSERM, France; Univ Paris Saclay, France.
    Jager, Kitty J.
    Univ Amsterdam, Netherlands.
    Tesar, Vladimir
    Charles Univ Prague, Czech Republic; Gen Univ Hosp, Czech Republic.
    Characteristics and Outcomes of Patients With Systemic Sclerosis (Scleroderma) Requiring Renal Replacement Therapy in Europe: Results From the ERA-EDTA Registry2019In: American Journal of Kidney Diseases, ISSN 0272-6386, E-ISSN 1523-6838, Vol. 73, no 2, p. 184-193Article in journal (Refereed)
    Abstract [en]

    Rationale amp; Objective: Data for outcomes of patients with end-stage renal disease (ESRD) secondary to systemic sclerosis (scleroderma) requiring renal replacement therapy (RRT) are limited. We examined the incidence and prevalence of ESRD due to scleroderma in Europe and the outcomes among these patients following initiation of RRT. Study Design: Registry study of incidence and prevalence and a matched cohort study of clinical outcomes. Setting amp; Participants: Patients represented in any of 19 renal registries that provided data to the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry between 2002 and 2013. Predictor: Scleroderma as the identified cause of ESRD. Outcomes: Incidence and prevalence of ESRD from scleroderma. Recovery from RRT dependence, patient survival after ESRD, and graft survival after kidney transplantation. Analytical Approach: Incidence and prevalence were calculated using population data from the European Union and standardized to population characteristics in 2005. Patient and graft survival were compared with 2 age- and sex-matched control groups without scleroderma: (1) diabetes mellitus as the cause of ESRD and (2) conditions other than diabetes mellitus as the cause of ESRD. Survival analyses were performed using Kaplan-Meier analysis and Cox regression. Results: 342 patients with scleroderma (0.14% of all incident RRT patients) were included. Between 2002 and 2013, the range of adjusted annual incidence and prevalence rates of RRT for ESRD due to scleroderma were 0.11 to 0.26 and 0.73 to 0.95 per million population, respectively. Recovery of independent kidney function was greatest in the scleroderma group (7.6% vs 0.7% in diabetes mellitus and 2.0% in other primary kidney diseases control group patients, both Pamp;lt;0.001), though time required to achieve recovery was longer. The 5-year survival probability from day 91 of RRT among patients with scleroderma was 38.9% (95% CI, 32.0%-45.8%), whereas 5-year posttransplantation patient survival and 5-year allograft survival were 88.2% (95% CI, 75.3%-94.6%) and 72.4% (95% CI, 55.0%-84.0%), respectively. Adjusted mortality from day 91 on RRT was higher among patients with scleroderma than observed in both control groups (HRs of 1.25 [95% CI, 1.05-1.48] and 2.00 [95% CI, 1.69-2.39]). In contrast, patient and graft survival after kidney transplantation did not differ between patients with scleroderma and control groups. Limitations: No data for extrarenal manifestations, treatment, or recurrence. Conclusions: Survival of patients with scleroderma who receive dialysis for more than 90 days was worse than for those with other causes of ESRD. Patient survival after transplantation was similar to that observed among patients with ESRD due to other conditions. Patients with scleroderma had a higher rate of recovery from RRT dependence than controls.

  • 18.
    Ingelsson, Björn
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderberg, Daniel
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Strid, Tobias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Söderberg, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Bergh, Ann-Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Loitto, Vesa-Matti
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Spyrou, Giannis
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Rosén, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 3, p. E478-E487Article in journal (Refereed)
    Abstract [en]

    Circulating mitochondrial DNA (mtDNA) is receiving increasing attention as a danger-associated molecular pattern in conditions such as autoimmunity, cancer, and trauma. We report here that human lymphocytes [B cells, T cells, natural killer (NK) cells], monocytes, and neutrophils derived from healthy blood donors, as well as B cells from chronic lymphocytic leukemia patients, rapidly eject mtDNA as web filament structures upon recognition of CpG and non-CpG oligodeoxynucleotides of class C. The release was quenched by ZnCl2, independent of cell death (apoptosis, necrosis, necroptosis, autophagy), and continued in the presence of TLR9 signaling inhibitors. B-cell mtDNA webs were distinct from neutrophil extracellular traps concerning structure, reactive oxygen species (ROS) dependence, and were devoid of antibacterial proteins. mtDNA webs acted as rapid (within minutes) messengers, priming antiviral type I IFN production. In summary, our findings point at a previously unrecognized role for lymphocytes in antimicrobial defense, utilizing mtDNA webs as signals in synergy with cytokines and natural antibodies, and cast light on the interplay between mitochondria and the immune system.

  • 19.
    Jayne, David R. W.
    et al.
    Addenbrookes Hospital, England.
    Bruchfeld, Annette N.
    Karolinska University Hospital, Sweden.
    Harper, Lorraine
    University of Birmingham, England.
    Schaier, Matthias
    Heidelberg University, Germany.
    Venning, Michael C.
    Manchester Royal Infirm, England.
    Hamilton, Patrick
    Manchester Royal Infirm, England.
    Burst, Volker
    Uniklin Cologne, Germany.
    Grundmann, Franziska
    Uniklin Cologne, Germany.
    Jadoul, Michel
    Clin University of St Luc, Belgium.
    Szombati, Istvan
    Budai Irgalmasrendi Korhaz, Hungary.
    Tesar, Vladimir
    Charles University of Prague, Czech Republic.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Potarca, Antonia
    ChemoCentryx Inc, CA USA.
    Schall, Thomas J.
    ChemoCentryx Inc, CA USA.
    Bekker, Pirow
    ChemoCentryx Inc, CA USA.
    Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis2017In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 28, no 9, p. 2756-2767Article in journal (Refereed)
    Abstract [en]

    Alternative C activation is involved in the pathogenesis of ANCA-associated vasculitis. However, glucocorticoids used as treatment contribute to the morbidity and mortality of vasculitis. We determined whether avacopan (CCX168), an orally administered, selective C5a receptor inhibitor, could replace oral glucocorticoids without compromising efficacy. In this randomized, placebo-controlled trial, adults with newly diagnosed or relapsing vasculitis received placebo plus prednisone starting at 60 mg daily (control group), avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily), or avacopan (30 mg, twice daily) without prednisone. All patients received cyclophosphamide or rituximab. The primary efficacy measure was the proportion of patients achieving a amp;gt;= 50% reduction in Birmingham Vasculitis Activity Score by week 12 and no worsening in any body system. We enrolled 67 patients, 23 in the control and 22 in each of the avacopan groups. Clinical response at week 12 was achieved in 14 of 20 (70.0%) control patients, 19 of 22 (86.4%) patients in the avacopan plus reduced-dose prednisone group (difference from control 16.4%; two-sided 90% confidence limit, -4.3% to 37.1%; P=0.002 for noninferiority), and 17 of 21 (81.0%) patients in the avacopan without prednisone group (difference from control 11.0%; two-sided 90% confidence limit, -11.0% to 32.9%; P=0.01 for noninferiority). Adverse events occurred in 21 of 23 (91%) control patients, 19 of 22 (86%) patients in the avacopan plus reduced-dose prednisone group, and 21 of 22 (96%) patients in the avacopan without prednisone group. In conclusion, C5a receptor inhibition with avacopan was effective in replacing high-dose glucocorticoids in treating vasculitis.

  • 20.
    Jones, Rachel B.
    et al.
    Addenbrookes Hospital, England.
    Furuta, Shunsuke
    Addenbrookes Hospital, England.
    Cohen Tervaert, Jan Willem
    Maastricht University, Netherlands.
    Hauser, Thomas
    IZZ Immunol Zentrum, Switzerland.
    Luqmani, Raashid
    Nuffield Orthopaed Centre, England.
    Morgan, Matthew D.
    University of Birmingham, England.
    Au Peh, Chen
    Royal Adelaide Hospital, Australia; University of Adelaide, Australia.
    Savage, Caroline O.
    University of Birmingham, England.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Tesar, Vladimir
    Charles University of Prague, Czech Republic.
    van Paassen, Pieter
    Maastricht University, Netherlands.
    Walsh, Michael
    McMaster University, Canada; McMaster University, Canada.
    Westman, Kerstin
    University Hospital Skåne, Sweden; Lund University, Sweden.
    Jayne, David R. W.
    Addenbrookes Hospital, England.
    Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2-year results of a randomised trial2015In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 74, no 6, p. 1178-1182Article in journal (Refereed)
    Abstract [en]

    Objectives The RITUXVAS trial reported similar remission induction rates and safety between rituximab and cyclophosphamide based regimens for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 12months; however, immunosuppression maintenance requirements and longer-term outcomes after rituximab in ANCA-associated renal vasculitis are unknown. Methods Forty-four patients with newly diagnosed ANCA-associated vasculitis and renal involvement were randomised, 3:1, to glucocorticoids plus either rituximab (375mg/m(2)/weekx4) with two intravenous cyclophosphamide pulses (n=33, rituximab group), or intravenous cyclophosphamide for 3-6months followed by azathioprine (n=11, control group). Results The primary end point at 24months was a composite of death, end-stage renal disease and relapse, which occurred in 14/33 in the rituximab group (42%) and 4/11 in the control group (36%) (p=1.00). After remission induction treatment all patients in the rituximab group achieved complete B cell depletion and during subsequent follow-up, 23/33 (70%) had B cell return. Relapses occurred in seven in the rituximab group (21%) and two in the control group (18%) (p=1.00). All relapses in the rituximab group occurred after B cell return. Conclusions At 24months, rates of the composite outcome of death, end-stage renal disease and relapse did not differ between groups. In the rituximab group, B cell return was associated with relapse. Trial registration number ISRCTN28528813.

  • 21.
    Jones, Rachel B.
    et al.
    Vasculitis and Lupus Clinic, Renal Unit, Addenbrooke’s Hospital, Cambridge, UK.
    Tervaer, Jan Willem Cohen
    Division of Clinical and Experimental Immunology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands .
    Hauser, Thomas
    ImmunologieZentrum Zürich and University Hospital, Zurich, Switzerland .
    Luqmani, Raashid
    Department of Rheumatology, Nuffield Orthopaedic Centre, Oxford , UK.
    Morgan, Matthew D.
    Department of Renal Immunobiolo - gy, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
    Peh, Chen Au
    Renal Unit, Royal Adelaide Hospital, Adelaide, Australia .
    Savage, Caroline O.
    Department of Renal Immunobiolo - gy, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology. Department of Nephrology in Lund, University Hospital of Skane and Lund University, Lund, Sweden.
    Tesar, Vladimir
    First Faculty of Medicine, Charles University, Prague, Czech Republic.
    Paassen, Pieter van
    Division of Clinical and Experimental Immunology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
    Wals, Dorothy
    Vasculitis and Lupus Clinic, Renal Unit, Addenbrooke’s Hospital, Cambridge, UK.
    Walsh, Michael
    Vasculitis and Lupus Clinic, Renal Unit, Addenbrooke’s Hospital, Cambridge, UK.
    Westman, Kerstin
    Department of Nephrology and Transplantation in Malmö, University Hospital of Skane and Lund University, Malmö, Sweden.
    Jayne, David R.W.
    Vasculitis and Lupus Clinic, Renal Unit, Addenbrooke’s Hospital, Cambridge, UK.
    Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis2010In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 363, no 3, p. 211-220Article in journal (Refereed)
    Abstract [en]

    Background

    Cyclophosphamide induction regimens for antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis are effective in 70 to 90% of patients, but they are associated with high rates of death and adverse events. Treatment with rituximab has led to remission rates of 80 to 90% among patients with refractory ANCA-associated vasculitis and may be safer than cyclophosphamide regimens.

    Methods

    We compared rituximab with cyclophosphamide as induction therapy in ANCA-associated vasculitis. We randomly assigned, in a 3:1 ratio, 44 patients with newly diagnosed ANCA-associated vasculitis and renal involvement to a standard glucocorticoid regimen plus either rituximab at a dose of 375 mg per square meter of body-surface area per week for 4 weeks, with two intravenous cyclophosphamide pulses (33 patients, the rituximab group), or intravenous cyclophosphamide for 3 to 6 months followed by azathioprine (11 patients, the control group). Primary end points were sustained remission rates at 12 months and severe adverse events.

    Results

    The median age was 68 years, and the glomerular filtration rate (GFR) was 18 ml per minute per 1.73 m2 of body-surface area. A total of 25 patients in the rituximab group (76%) and 9 patients in the control group (82%) had a sustained remission (P=0.68). Severe adverse events occurred in 14 patients in the rituximab group (42%) and 4 patients in the control group (36%) (P=0.77). Six of the 33 patients in the rituximab group (18%) and 2 of the 11 patients in the control group (18%) died (P=1.00). The median increase in the GFR between 0 and 12 months was 19 ml per minute in the rituximab group and 15 ml per minute in the control group (P=0.14).

    Conclusions

    A rituximab-based regimen was not superior to standard intravenous cyclophosphamide for severe ANCA-associated vasculitis. Sustained-remission rates were high in both groups, and the rituximab-based regimen was not associated with reductions in early severe adverse events.

  • 22.
    Kahn, Fredrik
    et al.
    University of Lund Hospital, Sweden.
    Fagerström, Anna
    University of Lund Hospital, Sweden.
    Segelmark, Mårten
    University of Lund Hospital, Sweden.
    Bakoush, Omran
    University of Lund Hospital, Sweden.
    Irreversible Kidney Damage due to Multicentric Castlemans Disease2008In: Libyan Journal of Medicine, ISSN 1993-2820, Vol. 3, no 2, p. 101-103Article in journal (Refereed)
    Abstract [en]

    Castlemans Disease (CD) is a rare lymphoproliferative disorder accompanied by marked systemic inflammatory response. Morphological diagnosis of CD requires biopsy of the whole of the involved lymph node tissue. Three histologic variants have already been described in CD morphology (hyaline vascular, plasma-cell, and mixed). In this study, we report a case of a multicentric Castlemans disease of the plasma cell variant type with negative Herpes Virus 8. The clinical presentation of this patient was of systemic amyloidosis as a result of both a delayed diagnosis and medical management. Previously described cases of CD with secondary amyloidosis have been of the localized type. Regardless, long-standing clinical remission of CD by cytotoxic drugs and anti-CD20 antibody therapy was achieved, but the nephrotic syndrome remained irreversible.

  • 23.
    Kahn, Robin
    et al.
    Lund University, Sweden.
    Mossberg, Maria
    Lund University, Sweden.
    Stahl, Anne-lie
    Lund University, Sweden.
    Johansson, Karl
    Lund University, Sweden.
    Lopatko Lindman, Ingrid
    Lund University, Sweden.
    Heijl, Caroline
    Lund University, Sweden.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Morgelin, Matthias
    Lund University, Sweden.
    Fredrik Leeb-Lundberg, L. M.
    Lund University, Sweden.
    Karpman, Diana
    Lund University, Sweden.
    Microvesicle transfer of kinin B1-receptors is a novel inflammatory mechanism in vasculitis2017In: KIDNEY INTERNATIONAL, ISSN 0085-2538, Vol. 91, no 1, p. 96-105Article in journal (Refereed)
    Abstract [en]

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

  • 24.
    Karras, Alexandre
    et al.
    Hop Europeen Georges Pompidou, France; University of Paris 05, France.
    Pagnoux, Christian
    Mt Sinai Hospital, Canada.
    Haubitz, Marion
    Klinikum Fulda, Germany; Klinikum Fulda, Germany.
    de Groot, Kirsten
    Klinikum Offenbach, Germany.
    Puechal, Xavier
    Hop Cochin, France.
    Cohen Tervaert, Jan Willem
    Maastricht University, Netherlands.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Guillevin, Loic
    University of Paris 05, France; Hop Cochin, France.
    Jayne, David
    University of Cambridge, England.
    Randomised controlled trial of prolonged treatment in the remission phase of ANCA-associated vasculitis2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, no 10, p. 1662-1668Article in journal (Refereed)
    Abstract [en]

    Objectives A prospective randomised trial to compare two different durations of maintenance immunosuppressive therapy for the prevention of relapse in anti-neutrophil cytoplasmic antibodies (ANCA)associated vasculitis (AAV). Methods Patients with AAV were recruited 18-24 months after diagnosis if they were in stable remission after cyclophosphamide/prednisolone-based induction followed by azathioprine/prednisolone maintenance therapy. They were randomised (1: 1) to receive continued azathioprine/prednisolone to 48 months from diagnosis (continuation group) or to withdraw azathioprine/prednisolone by 24 months (withdrawal group). The primary endpoint was the relapse risk, from randomisation to 48 months from diagnosis. Results One hundred and seventeen patients were randomised and 110 remained to the trial end. At entry, median serum creatinine was 116 mu mol/L (range 58-372), 53% were ANCA positive. The percentage of patients presenting with relapse was higher in the withdrawal than in the continuation treatment group (63% vs 22%, pamp;lt;0.0001, OR 5.96, 95% CI 2.58 to 13.77). ANCA positivity at randomisation was associated with relapse risk (51% vs 29%, p=0.017, OR 2.57, 95% CI 1.16 to 5.68). Renal function, ANCA specificity, vasculitis type and age were not predictive of relapse. Severe adverse events were more frequent in the continuation than withdrawal groups (nine vs three events), but the continuation group had better renal outcome (0 vs 4 cases of end-stage renal disease), with no difference in patient survival. Conclusions Prolonged remission maintenance therapy with azathioprine/prednisolone, beyond 24 months after diagnosis reduces relapse risk out to 48 months and improves renal survival in AAV.

  • 25.
    Kurz, Tino
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Weiner, Maria
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Skoglund, Camilla
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Basnet, Sandeep
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    A myelopoiesis gene signature during remission in ANCA associated vasculitis does not predict relapses but seems to reflect ongoing prednisolone therapy2014In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 175, no 2, p. 215-226Article in journal (Refereed)
    Abstract [en]

    A myelopoiesis gene signature in circulating leucocytes, exemplified by increased myeloperoxidase (MPO) and proteinase 3 (PR3) mRNA levels, has been reported in patients with active anti-neutrophil cytoplasm antibody associated vasculitis (AAV) and to a lesser extent during remission. We hypothesized that this signature could predict disease relapse. mRNA levels of PR3, MPO, selected myelopoiesis transcription factors (CEBPA, CEBPB, SPIB, SPI1) and microRNAs (miRNAs) from patient and control peripheral blood mononuclear cells (PBMCs) and polymorphonuclear cells (PMNs) were analyzed and associated with clinical data. Patients in stable remission had higher mRNA levels for PR3 (PBMCs, PMNs) and MPO (PBMCs). PR3 and SPIB mRNA correlated positively in control but negatively in patient PBMCs. Statistically significant correlations existed between PR3 mRNA and several miRNAs in controls, but not in patients. PR3/MPO mRNA levels were not associated with previous or future relapses but correlated to steroid treatment. Prednisolone doses were negatively linked to SPIB and miR-155-5p, miR-339-5p (PBMCs) and to miR-221, miR-361, miR-505 (PMNs). PR3 mRNA in PBMCs correlated with time since last flare, blood leucocyte count and estimated glomerular filtration rate. Our results show that elevated leucocyte PR3 mRNA levels in AAV patients in remission do not predict relapse. The origin seems multifactorial, but to an important part explainable by prednisolone action. Gene signatures in patients with AAV undergoing steroid treatment should therefore be interpreted accordingly.

  • 26.
    Lindberg, Ulrika
    et al.
    Lund University, Sweden; Skåne University Hospital, Sweden.
    Carlsson, Malin
    Lund University, Sweden.
    Hellmark, Thomas
    Lund University, Sweden.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    BPI-ANCA Provides Additional Clinical Information to Anti-Pseudomonas Serology: Results from a Cohort of 117 Swedish Cystic Fibrosis Patients2015In: JOURNAL OF IMMUNOLOGY RESEARCH, ISSN 2314-8861, Vol. 2015, p. 8-, article id 947934Article in journal (Refereed)
    Abstract [en]

    Patients with cystic fibrosis (CF) colonized with Pseudomonas aeruginosa (P. aeruginosa) have worse prognosis compared with patients who are not. BPI-ANCA is an anti-neutrophil cytoplasmic antibody against BPI (bactericidal/permeability increasing protein) correlating with P. aeruginosa colonization and adverse long time prognosis. Whether it provides additional information as compared to standard anti-P. aeruginosa serology tests is not known. 117 nontransplanted CF patients at the CF centre in Lund, Sweden, were followed prospectively for ten years. Bacterial colonisation was classified according to the Leeds criteria. IgA BPI-ANCA was compared with assays for antibodies against alkaline protease (AP), Elastase (ELA), and Exotoxin A (ExoA). Lung function and patient outcome, alive, lung transplanted, or dead, were registered. BPI-ANCA showed the highest correlation with lung function impairment with an r-value of 0.44. Forty-eight of the 117 patients were chronically colonized with P. aeruginosa. Twenty of these patients experienced an adverse outcome. Receiver operator curve (ROC) analysis revealed that this could be predicted by BPI-ANCA (AUC = 0.77), (p = 0.002) to a better degree compared with serology tests. BPI-ANCA correlates better with lung function impairment and long time prognosis than anti-P. aeruginosa serology and has similar ability to identify patients with chronic P. aeruginosa.

  • 27.
    Lindberg, Ulrika
    et al.
    Lund University and Skåne University Hospital, Lund, Sweden.
    Carlsson, Malin
    Lund University, Sweden.
    Löfdahl, Claes-Göran
    Lund University and Skåne University Hospital, Lund, Sweden.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Nephrology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    BPI-ANCA and long-term prognosis among 46 adult CF patients: a prospective 10-year follow-up study2012In: Clinical & Developmental Immunology, ISSN 1740-2522, E-ISSN 1740-2530, no 370107Article in journal (Refereed)
    Abstract [en]

    Introduction

    Anti-neutrophil cytoplasmic antibodies specific for bactericidal/permeability-increasing protein (BPI-ANCA) are frequent in CF patients and mainly develop in response to infection with Pseudomonas aeruginosa. It is not known to what extent BPI-ANCA correlates to prognosis.

    Objectives.

    To evaluate the prognostic value of IgA-BPI-ANCA, measured at the beginning of the study, for transplantation-free survival.

    Methods.

    A cohort of 46 adult, nontransplanted CF patients was generated, 1995–1998, and characterized using Leeds criteria, lung function, and IgA-BPI-ANCA levels measured by ELISA. The cohort was followed until December 2009, using the combined endpoint of death or lung transplantation.

    Results.

    Lung function and IgA-BPI-ANCA, but not Leeds criteria, were significantly associated with adverse outcome. No patient with normal lung function at baseline reached endpoint. Within 10 years 8/11 with high BPI-ANCA reached an endpoint compared to 3/17 ANCA-negative patients. A similar result was seen within the Leeds I group where 7 out of 9 BPI-ANCA-positive patients reached endpoint, compared to none of the 5 patients without BPI-ANCA.

    Conclusions.

    IgA-BPI-ANCA is associated with adverse outcome among Pseudomonas aeruginosa infected CF patients, suggesting that BPI-ANCA is a biomarker of an unfavourable host-pathogen interaction

  • 28.
    Lindberg, Ulrika
    et al.
    Lund Univ, Sweden.
    Svensson, Lisbeth
    Lund Univ, Sweden.
    Hellmark, Thomas
    Lund Univ, Sweden.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Shannon, Oonagh
    Lund Univ, Sweden.
    Increased platelet activation occurs in cystic fibrosis patients and correlates to clinical status2018In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 162, p. 32-37Article in journal (Refereed)
    Abstract [en]

    Cystic fibrosis (CF) is an inflammatory lung disease. Platelets have an emerging role in inflammation, however previous studies of platelet activation in CF have generated conflicting results. In this study, we determined platelet function in CF patients and correlated platelet activation to establish clinical and laboratory parameters. Twenty-two patients, aged 20.7 to 54.4 (mean 34.0, SD 9.45) years and with a mean FEV1% pred (forced expiratory volume in one second, % of predicted) of 72 (SD 21.4, range 32-110) were recruited. A combination of platelet assays was used: platelet aggregation, platelet activation and platelet-leukocyte complex formation. Platelets from CF patients exhibited significantly increased aggregation when stimulated ex-vivo, a tendency towards increased platelet upregulation of CD62P, but no increase of GPIIb/IIIa activation (PAC-1). Platelet-monocyte complex (PMC) formation was significantly increased in CF patients compared to controls, while platelet-neutrophil complex formation was not. In the CF group, platelet aggregation correlates with levels of anti-neutrophil cytoplasmic antibodies (ANCA) with specificity for bactericidal/permeability-increasing protein (BPI), BPI-ANCA (r = 0.56). The formation of PMCs correlates with lung function decline (1-FEV1%), CRP and BPI-ANCA (r = 0.61, 0.55, 0.5). We therefore confirm the presence of increased platelet activation in CF patients, and determine that further evaluation of platelet activation in relation to prognostic factors in CF is warranted.

  • 29.
    Liu Carlsen, Anting
    et al.
    Statens Serum Institute, Denmark .
    Schetter, Aaron J.
    NCI, MD USA .
    Nielsen, Christoffer T.
    Statens Serum Institute, Denmark .
    Lood, Christian
    Lund University, Sweden .
    Knudsen, Steen
    Medical Prognosis Institute, Denmark .
    Voss, Anne
    Odense University Hospital, Denmark .
    Harris, Curtis C
    NCI, MD USA .
    Hellmark, Thomas
    Lund University, Sweden .
    Segelmark, Mårten
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology. Cty Council Ostergotland, Linkoping, Sweden .
    Jacobsen, Soren
    Copenhagen University Hospital, Denmark .
    Bengtsson, Anders A.
    Lund University, Sweden .
    Heegaard, Niels H H.
    Statens Serum Institute, Denmark .
    Circulating MicroRNA Expression Profiles Associated With Systemic Lupus Erythematosus2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no 5, p. 1324-1334Article in journal (Refereed)
    Abstract [en]

    Objective To evaluate the specificity of expression patterns of cell-free circulating microRNAs (miRNAs) in systemic lupus erythematosus (SLE). Methods Total RNA was purified from plasma, and 45 different specific, mature miRNAs were determined using quantitative reverse transcriptionpolymerase chain reaction assays. A total of 409 plasma samples were obtained from 364 different patients with SLE, healthy control subjects, and control subjects with other autoimmune diseases. The results in the primary cohort of 62 patients with SLE and 29 healthy control subjects were validated in 2 independent cohorts: a validation cohort comprising 68 patients with SLE and 68 healthy control subjects, and a disease control cohort comprising 20 patients with SLE (19 of whom were from the other validation cohort), 46 healthy control subjects, 38 patients with vasculitis, 18 patients with rheumatoid arthritis, and 20 immunosuppressed patients. Results Seven miRNAs were statistically significantly differentially expressed in plasma from patients with SLE. The expression of miRNA-142-3p (miR-142-3p) and miR-181a was increased, and the expression of miR-106a, miR-17, miR-20a, miR-203, and miR-92a was decreased. In addition, the expression of miR-342-3p, miR-223, and miR-20a was significantly decreased in SLE patients with active nephritis. A predictive model for SLE based on 2 or 4 miRNAs differentiated patients with SLE from control subjects (76% accuracy) when validated independently (P andlt; 2 x 109). Use of the 4-miRNA model provided highly significant differentiation between the SLE group and disease controls, except for those with vasculitis. Conclusion Circulating miRNAs are systematically altered in SLE. A 4-miRNA signature was diagnostic of SLE, and a specific subset of miRNA profiles was associated with nephritis. All of the signature miRNAs target genes in the transforming growth factor signaling pathways. Other targets include regulation of apoptosis, cytokinecytokine receptors, T cell development, and cytoskeletal organization. These findings highlight possible dysregulated pathways in SLE and suggest that circulating miRNA patterns distinguish SLE from other immunoinflammatory phenotypes.

  • 30.
    Lyons, Paul A
    et al.
    Addenbrookes Hospital, England.
    Rayner, Tim F
    Addenbrookes Hospital, England.
    Trivedi, Sapna
    Addenbrookes Hospital, England.
    Holle, Julia U
    University Hospital Schleswig Holstein, Germany.
    Watts, Richard A
    Ipswich Hospital National Health Serv Trust, England University of E Anglia, England .
    Jayne, David R W
    Addenbrookes Hospital, England University of Cambridge, England .
    Baslund, Bo
    Copenhagen University Hospital, Denmark .
    Brenchley, Paul
    University of Manchester, England .
    Bruchfeld, Annette
    Karolinska University Hospital, Sweden .
    Chaudhry, Afzal N
    Addenbrookes Hospital, England University of Cambridge, England .
    Tervaert, Jan Willem Cohen
    Maastricht University, Netherlands .
    Deloukas, Panos
    Wellcome Trust Sanger Institute, England .
    Feighery, Conleth
    Trinity Coll Dublin, Ireland St James Hospital, Ireland .
    Gross, Wolfgang L
    University Hospital Schleswig Holstein, Germany Klinikum Bad Bramstedt, Germany .
    Guillevin, Loic
    University of Paris, France .
    Gunnarsson, Iva
    Karolinska University Hospital, Sweden .
    Harper, Lorraine
    University of Birmingham, England .
    Hruskova, Zdenka
    Charles University of Prague, Czech Republic Gen University Hospital, Czech Republic .
    Little, Mark A
    UCL, England .
    Martorana, Davide
    University Hospital, Italy .
    Neumann, Thomas
    University Hospital, Germany .
    Ohlsson, Sophie
    Karolinska Institute, Sweden Lund University, Sweden .
    Padmanabhan, Sandosh
    University of Glasgow, Scotland .
    Pusey, Charles D
    University of London Imperial Coll Science Technology and Med, England .
    Salama, Alan D
    UCL, England University of London Imperial Coll Science Technology and Med, England .
    Sanders, Jan-Stephan F
    University of Groningen, Netherlands .
    Savage, Caroline O
    GlaxoSmithKline, England .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Stegeman, Coen A
    University of Birmingham, England University of Groningen, Netherlands .
    Tesar, Vladimir
    Charles University of Prague, Czech Republic Gen University Hospital, Czech Republic .
    Vaglio, Augusto
    University Hospital, Italy .
    Wieczorek, Stefan
    Ruhr University of Bochum, Germany .
    Wilde, Benjamin
    Maastricht University, Netherlands .
    Zwerina, Jochen
    University of Erlangen Nurnberg, Germany Medical University of Vienna, Austria Medical University of Vienna, Austria .
    Rees, Andrew J
    Medical University of Vienna, Austria .
    Clayton, David G
    Addenbrookes Hospital, England.
    Smith, Kenneth G C
    Addenbrookes Hospital, England.
    Genetically Distinct Subsets within ANCA-Associated Vasculitis2012In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, no 3, p. 214-223Article in journal (Refereed)
    Abstract [en]

    BACKGROUND less thanbrgreater than less thanbrgreater thanAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegeners granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. less thanbrgreater than less thanbrgreater thanMETHODS less thanbrgreater than less thanbrgreater thanA genomewide association study was performed in a discovery cohort of 1233 U. K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. less thanbrgreater than less thanbrgreater thanRESULTS less thanbrgreater than less thanbrgreater thanWe found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding alpha(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P = 6.2x10(-89), P = 5.6x10(-12), and P = 2.6x10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P = 2.1x10(-8)). less thanbrgreater than less thanbrgreater thanCONCLUSIONS less thanbrgreater than less thanbrgreater thanThis study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.)

  • 31.
    Maritati, Federica
    et al.
    Parma University Hospital, Italy.
    Fenoglio, Roberta
    G Bosco Hospital, Italy; University of Turin, Italy.
    Pillebout, Evangeline
    St Louis Hospital, France.
    Emmi, Giacomo
    University of Florence, Italy.
    Urban, Maria L.
    Parma University Hospital, Italy.
    Rocco, Rossana
    Parma University Hospital, Italy.
    Nicastro, Maria
    Parma University Hospital, Italy.
    Incerti, Monia
    Parma University Hospital, Italy.
    Goldoni, Matteo
    University of Parma, Italy.
    Trivioli, Giorgio
    Parma University Hospital, Italy.
    Silvestri, Elena
    University of Florence, Italy.
    Mohammad, Aladdin J.
    Lund University, Sweden; University of Cambridge, England.
    Jayne, David
    University of Cambridge, England.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Novikov, Pavel
    Sechenov First Moscow State Medical University, Russia.
    Harris, Helen
    Whytemans Brae Hospital, Scotland.
    Roccatello, Dario
    G Bosco Hospital, Italy; University of Turin, Italy.
    Vaglio, Augusto
    Parma University Hospital, Italy.
    Brief Report: Rituximab for the Treatment of Adult-Onset IgA Vasculitis (Henoch-Schonlein)2018In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 70, no 1, p. 109-114Article in journal (Refereed)
    Abstract [en]

    ObjectiveAdult-onset IgA vasculitis (Henoch-Schonlein) (IgAV) is a rare systemic vasculitis characterized by IgA1-dominant deposits. The treatment of adult-onset IgAV is controversial and is based on the combination of glucocorticoids and immunosuppressive agents, but many patients have refractory or relapsing disease despite treatment. Rituximab (RTX) is a B cell-depleting antibody of proven efficacy in antineutrophil cytoplasmic antibody-associated vasculitis. We undertook this study to test the efficacy and safety of RTX in a multicenter cohort of patients with adult-onset IgAV. MethodsIn this multicenter observational study, we included patients with adult-onset IgAV who had received RTX either for refractory/relapsing disease or because they had contraindications to conventional glucocorticoid/immunosuppressive therapy. We analyzed the rates of remission (defined on the basis of the Birmingham Vasculitis Activity Score [BVAS]) and relapse as well as the variations over time in estimated glomerular filtration rate (GFR), proteinuria, C-reactive protein (CRP) level, BVAS, and prednisone dose. ResultsTwenty-two patients were included; their median duration of follow-up was 24 months (interquartile range 18-48 months). Sixteen patients received RTX as add-on therapy and 6 as monotherapy. Twenty patients (90.9%) achieved remission, and 7 of those 20 patients (35%) had subsequent relapse of disease. There were significant reductions in 24-hour proteinuria (P amp;lt; 0.0001), CRP level (P = 0.0005), BVAS (P amp;lt; 0.0001), and prednisone dose (P amp;lt; 0.0001) from RTX initiation through the last follow-up visit; estimated GFR remained stable. RTX was generally well tolerated. One patient died after 60 months of follow-up. ConclusionOur data suggest that RTX is an effective and safe therapeutic option for adult-onset IgAV.

  • 32.
    McAdoo, Stephen P.
    et al.
    Imperial Coll London, England.
    Tanna, Anisha
    Imperial Coll London, England.
    Hruskova, Zdenka
    Gen University Hospital, Czech Republic; Charles University of Prague, Czech Republic.
    Holm, Lisa
    Skånes University Hospital, Sweden.
    Weiner, Maria
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Arulkumaran, Nishkantha
    Imperial Coll London, England.
    Kang, Amy
    Imperial Coll London, England.
    Satrapova, Veronika
    Gen University Hospital, Czech Republic; Charles University of Prague, Czech Republic.
    Levy, Jeremy
    Imperial Coll London, England.
    Ohlsson, Sophie
    Skånes University Hospital, Sweden.
    Tesar, Vladimir
    Gen University Hospital, Czech Republic; Charles University of Prague, Czech Republic.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Pusey, Charles D.
    Imperial Coll London, England.
    Patients double-seropositive for ANCA and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients2017In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 92, no 3, p. 693-702Article in journal (Refereed)
    Abstract [en]

    Co-presentation with both ANCA and anti-GBM antibodies is thought to be relatively rare. Current studies of such double-positive cases report small numbers and variable outcomes. To study this further we retrospectively analyzed clinical features and long-term outcomes of a large cohort of 568 contemporary patients with ANCA-associated vasculitis, 41 patients with anti-GBM disease, and 37 double-positive patients with ANCA and anti-GBM disease from four European centers. Double-positive patients shared characteristics of ANCA-associated vasculitis (AAV), such as older age distribution and longer symptom duration before diagnosis, and features of anti-GBM disease, such as severe renal disease and high frequency of lung hemorrhage at presentation. Despite having more evidence of chronic injury on renal biopsy compared to patients with anti-GBM disease, double-positive patients had a greater tendency to recover from being dialysis-dependent after treatment and had intermediate long-term renal survival compared to the single-positive patients. However, overall patient survival was similar in all three groups. Predictors of poor patient survival included advanced age, severe renal failure, and lung hemorrhage at presentation. No single-positive anti-GBM patients experienced disease relapse, whereas approximately half of surviving patients with AAV and double-positive patients had recurrent disease during a median follow-up of 4.8 years. Thus, double-positive patients have a truly hybrid disease phenotype, requiring aggressive early treatment for anti-GBM disease, and careful long-term follow-up and consideration for maintenance immunosuppression for AAV. Since double-positivity appears common, further work is required to define the underlying mechanisms of this association and define optimum treatment strategies.

  • 33.
    Mohammad, A. J.
    et al.
    Department of Medicine, Section of Rheumatology, Helsingborg Hospital, Helsingborg and Departments of Nephrology, Lund University Hospital, Lund, Sweden .
    Bakoush, O.
    Departments of Nephrology, Lund University Hospital, Lund, Sweden .
    Sturfelt, G.
    Departments of Rheumatology, Lund University Hospital, Lund, Sweden .
    Segelmark, Mårten
    Departments of Nephrology, Lund University Hospital, Lund, Sweden .
    The extent and pattern of organ damage in small vessel vasculitis measured by the Vasculitis Damage Index (VDI)2009In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 38, no 4, p. 268-265Article in journal (Refereed)
    Abstract [en]

    Objectives: To assess the extent and pattern of irreversible organ damage in patients with Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), and Churg–Strauss syndrome (CSS) by a cross‐sectional point prevalence study within a defined geographical area.

    Methods: The Vasculitis Damage Index (VDI) was recorded for 86 prevalent cases, classified as 46 patients with WG, 27 with MPA, nine with PAN, and four with CSS from a defined population in southern Sweden, with a median age of 64.8 years and a median disease duration of 9 years. The VDI was determined for all patients at the day of point prevalence (pp), 1 January 2003.

    Results: The median VDI score was 3 [interquartile range (IQR) 2–5] for all patients: 3 (2–4) for WG, 3 (1.5–4.5) for MPA, 5 (2–6) for PAN, and 1.5 (0.75–2.75) for CSS. Only 9% of patients had not been assigned a single item of damage. The most common damage was cardiovascular, followed by renal, neuropsychiatric, ear nose and throat (ENT), and musculoskeletal. Major vascular and treatment‐related damage was associated with advanced age whereas ENT damage was more prevalent in younger patients. There was an almost complete separation between ENT damage and cardiac and renal damage with only two out of the 22 patients assigned ENT damage having experienced renal damage; none had been assigned cardiac damage. Patients with cardiac damage had significantly higher damage rates.

    Conclusions: Damage remains an important problem for patients with systemic vasculitis despite effective remission‐inducing drugs. Only a small fraction of patients are unmarked by their disease.

  • 34.
    Mohammad, A.
    et al.
    Lund University, Sweden Skåne University Hospital, Sweden .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Primary systemic vasculitis with severe alpha(1)-antitrypsin deficiency revisited2014In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 43, no 3, p. 242-245Article in journal (Refereed)
    Abstract [en]

    Objectives: To study the clinical characteristics and epidemiology of the combination of primary systemic vasculitis (PSV) and severe alpha-1 antitrypsin (alpha(1)-AT) deficiency. Method: Patients with PSV [granulomatosis with polyangiitis (GPA) (Wegeners), microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss), and polyarteritis nodosa] were identified through diagnosis registries and serological databases. Clinical and laboratory data, including the presence of severe alpha(1)-AT deficiency, were collected from the time of diagnosis. During follow-up, data on relapses and permanent organ damage were collected. Using the county of Skane as the denominator population, we estimated the annual incidence rate and point prevalence of PSV in people with severe alpha(1)-AT deficiency. Results: Five patients (three women, median age 49 years) with PSV diagnosed between 1996 and 2008 were found to have alpha(1)-AT deficiency, all of them carrying the protease inhibitor ZZ (PiZZ) phenotype. During follow-up (median time 166 months, range 53-208), four patients experienced a total of 13 relapses. The median Vasculitis Damage Index (VDI) score for all patients was 3 (range 1-4) at year 1, and 7 (range 3-9) at the last follow-up. The incidence rate of PSV among PiZZ carriers was estimated to be 397/million [95% confidence interval (CI) 8-787]. The point prevalence on 1 January 2013 was estimated to be 4689/million (95% CI 94-9285). Conclusions: In this study both the incidence and prevalence of PSV were elevated nearly 10-fold for individuals with severe alpha(1)-AT deficiency compared with the general population. Combined with previous publications, this indicates a dose-response relationship for the genetic risk and suggests a causal relationship between the PiZ allele and vasculitis.

  • 35.
    Mohammad, Aladdin J.
    et al.
    Lund University; Skåne University Hospital, Lund, Sweden .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    A population-based study showing better renal prognosis for proteinase 3 antineutrophil cytoplasmic antibody (ANCA)-associated nephritis versus myeloperoxidase ANCA-associated nephritis2014In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 41, no 7, p. 1366-1373Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is usually differentiated based on clinical phenotypes, but recent data indicate that myeloperoxidase (MPO)-AAV is genetically distinct from proteinase 3 (PR3)-AAV. We reviewed a population-based cohort of AAV, focusing on differences in clinical and laboratory characteristics and to compare renal outcome between MPO-ANCA and PR3-ANCA nephritis.

    METHODS:

    All new cases of AAV diagnosed between 1997 and 2009 in a geographically defined area in southern Sweden were retrieved using a validated search algorithm. Data were collected from time of diagnosis and end of followup. Renal and patient survival were analyzed according to ANCA serotype.

    RESULTS:

    During the study period, 201 patients were diagnosed with AAV, 98 tested positive for PR3-ANCA, and 85 for MPO-ANCA. Patients with PR3-ANCA were younger, had significantly higher inflammatory activity, and had a larger number of organs involved at diagnosis, but nephritis was more prevalent among patients with MPO-associated (72/85; 85%) versus PR3-associated disease (67/98, 68%). When comparing only patients with ANCA-associated nephritis, those with MPO-ANCA were more likely to develop endstage renal disease (n = 27, 38%) than those with PR3-ANCA (n = 10, 15%), p = 0.003. The risk remained significantly elevated after adjusting for sex, age, and s-creatinine level at diagnosis (HR 2.64; 95% CI 1.25-5.58; p = 0.003). There were no significant differences in mortality rates between the 2 groups.

    CONCLUSION:

    The outcome in this population-based cohort indicates that among AAV patients with nephritis, renal prognosis is better in the PR3-ANCA group, even after adjustment for sex, age, and renal function at diagnosis.

  • 36.
    Mohammad, Aladdin J.
    et al.
    Addenbrookes Hospital, England; Lund University, Sweden.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Smith, Rona
    Addenbrookes Hospital, England.
    Englund, Martin
    Boston University, MA 02118 USA; Lund University, Sweden.
    Nilsson, Jan-Ake
    Lund University, Sweden.
    Westman, Kerstin
    Lund University, Sweden.
    Merkel, Peter A.
    University of Penn, PA 19104 USA.
    Jayne, David R. W.
    Addenbrookes Hospital, England.
    Severe Infection in Antineutrophil Cytoplasmic Antibody-associated Vasculitis2017In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 44, no 10, p. 1468-1475Article in journal (Refereed)
    Abstract [en]

    Objective. To compare the rate of severe infections after the onset of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with the rate in the background population, and to identify predictors of severe infections among patients with AAV. Methods. The study cohort was 186 patients with AAV diagnosed from 1998 to 2010, consisting of all known cases in a defined population in southern Sweden. For each patient, 4 age-and sex-matched reference subjects were randomly chosen from the background population. Using the Skane Healthcare Register, all International Classification of Diseases codes of infections assigned from 1998 to 2011 were identified. Severe infections were defined as infectious episodes requiring hospitalization. Rate ratios were calculated by dividing the rate in AAV by the rate among the reference subjects. Results. The rate ratio for all severe infections was 4.53 (95% CI 3.39-6.00). The highest rate ratios were found for upper respiratory tract: 8.88 (3.54-25.9), Clostridium difficile: 5.35 (1.54-23.8), nonspecific septicemia 4.55 (1.60-13.8), and skin 5.35 (1.69-19.8). Of the severe infections, 38.4% occurred within 6 months of diagnosis, 30.2% from 7-24 months, and 31.4% after 24 months. High serum creatinine and older age at diagnosis were associated with severe infection (p amp;lt; 0.001). Of those with severe infection, 46.5% died during followup compared to 26% of patients without severe infection (p = 0.004). Conclusion. Patients with AAV have markedly higher rates of severe infection compared with the background population, especially patients with older age and impaired renal function. The risk of severe infection is particularly high in the first 6 months following the diagnosis of vasculitis.

  • 37.
    Mohammad, Aladdin J
    et al.
    Lunds University, Addenbrooke's Hospital Cambridge UK.
    Weiner, Maria
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Johansson, Martin E
    Lund University, Malmö .
    Bengtsson, Anders A
    Lund University, Lund .
    Ståhl-Hallengren, Christina
    Helsingborg Hospital .
    Nived, Ola
    Lund University.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Sturfelt, Gunnar
    Lund University.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology. Linköping University, Faculty of Health Sciences.
    Incidence and disease severity of anti-neutrophil cytoplasmic antibody-associated nephritis are higher than in lupus nephritis in Sweden.2015In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 30, p. i23-i30Article in journal (Refereed)
    Abstract [en]

    Objectives :The objectives of this study were to compare incidence rates, renal and patient survival between lupus nephritis (LN) and anti-neutrophil cytoplasmic antibody-associated nephritis (AAN) during a 12-year period in two geographically defined populations in Sweden.

    METHODS: In the health care districts surrounding the Skåne University Hospital in Lund [mean population ≥18 years (1997-2008), 188 400] and the University Hospital in Linköping [mean population ≥18 years (1997-2008), 328 900] all patients with biopsy-proven LN and AAN during the period 1997-2008 were included in the study if they (i) were residing within the study areas at the time of onset of nephritis, (ii) had a clinical diagnosis of either SLE or ANCA-associated vasculitis (AAV) and (iii) experienced a first flare of biopsy-proven nephritis during the study period.

    RESULTS: Eighty-two patients (Lund 44 + Linköping 38) with biopsy-proven AAN were identified and 27 patients with LN (Lund 13 + Linköping 14). The annual incidence rate per million inhabitants aged ≥18 years in both study areas was estimated to be 13.2 (95% CI 10.4-16.1) for AAN and 4.3 (95% CI 2.7-6.0) for LN, P < 0.001. The patients were followed until January 2013. During the follow-up time 38 patients died (AAN 36, LN 2; P = 0.001), and 20 patients went into end-stage renal disease (AAN 19 and LN 1), P = 0.020.

    CONCLUSIONS: In Sweden, AAN was three times more common than LN, and the outcome was considerably worse. SLE is often diagnosed before the onset of nephritis leading to earlier treatment, while AAN is still often diagnosed at a later stage.

  • 38.
    Mohammad, Aladdin
    et al.
    Lund University, Sweden .
    Mandl, Thomas
    Lund University, Sweden .
    Sturfelt, Gunnar
    Lund University, Sweden .
    Segelmark, Mårten
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Incidence, prevalence and clinical characteristics of Behcets disease in southern Sweden2013In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 52, no 2, p. 304-310Article in journal (Refereed)
    Abstract [en]

    Objective. To study the incidence, prevalence and clinical characteristics of Behc, ets disease (BD) in a defined population in southern Sweden. less thanbrgreater than less thanbrgreater thanMethods. The study area consists of three health-care districts with an adult population (andgt;= 15 years) of 809 317 on 1 January 2011 (25% of non-Swedish ancestry), situated in Skane, the southernmost county in Sweden. Patients were identified using clinical registries in all the five hospitals within the study area. Only patients fulfilling the International Study Group criteria for diagnosis of BD were included. less thanbrgreater than less thanbrgreater thanResults. Forty patients (13 women) fulfilling the diagnosis criteria for BD (70% of non-Swedish ancestry) were identified. The point prevalence of BD on 1 January 2011 was 4.9/100 000 adults (95% CI 3.4, 6.5) and was higher among the population of non-Swedish ancestry (13.6 vs 2.0/100 000, Pandlt;0.001), and higher among men (6.8 vs 3.2/100 000, P=0.019). There were 20 incident cases (diagnosed in Sweden between 1997 and 2010). The annual incidence rate was 0.2/100 000 adults (95% CI 0.1, 0.3) and was higher among the population of non-Swedish ancestry (0.6 vs 0.1/100 000, Pandlt;0.001). The incidence was 0.3/100 000 adults in men and 0.1/100 000 in women, P = 0.143. During the course of the disease, 100% of the patients developed oral ulceration, 80% genital ulcers, 88% skin lesions, 53% eye disease, 40% arthritis/arthralgia and 20% venous thrombosis. less thanbrgreater than less thanbrgreater thanConclusion. The prevalence of BD is higher in Sweden than previously reported, mainly due to immigration. The incidence of BD remains elevated for immigrants from high-prevalence regions even long after settling in Sweden.

  • 39.
    Mohammad, Aladdin
    et al.
    Sektionen för reumatologi, Internmedicin, Helsingborgs Lasarett och Avdelningen för Njurmedicin, Lunds universitet, och Njurmedicin, Skånes universitetssjukhus, Lund, Sverige.
    Segelmark, Mårten
    Avdelningen för Njurmedicin, Lunds universitet, Lund, Sverige.
    ANCA associerade systemiska vaskuliter och polyarteritis nodosa – epidemiologi2010In: Best practice Reumatologi, ISSN 1903-6590, no 2, p. 5-8Article in journal (Other academic)
  • 40.
    Mohammad, Aladdin
    et al.
    Lund University and Skåne University Hospital, Lund.
    Segelmark, Mårten
    Department of Internal Medicine, Division of Rheumatology, Helsingborg Hospital, Helsingborg, Sweden.
    Association of cigarette smoking with organ damage in primary systemic vasculities2011In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 40, no 1, p. 51-56Article in journal (Refereed)
    Abstract [en]

    Objectives: To study the association between late organ damage in patients with primary systemic vasculitis (PSV) and cigarette smoking. PSV included Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS), and polyarteritis nodosa (PAN). Methods: The pattern and extent of organ damage according to the Vasculitis Damage Index (VDI) were analysed for 86 prevalent cases with PSV retrieved from a geographically defined population in southern Sweden (46 WG, 27 MPA, four CSS, and nine PAN). Data on clinical findings, laboratory tests, and smoking habits were collected from case records from the time of diagnosis. The patients were stratified into two main groups according to their smoking habits: smokers (subdivided into active and ex-smokers) and non-smokers (patients who had never smoked). Results: Data on smoking habits were available for 77 patients (90%). Thirty-three (38%) patients were categorized as smokers and 44 (51%) were non-smokers. Smoking was more common in men (61.5% vs. 23.6% in women, p = 0.001). There were no differences in smoking habits between the main diagnostic groups (WG 40% smokers, MPA 45%). Ear, nose, and throat (ENT) damage was significantly more prevalent in non-smokers (p = 0.001). Myocardial infarction (MI) and end-stage renal disease (ESRD) were more common in the current smokers (p = 0.04) than in the non-smokers. Conclusions: We found ENT damage to be significantly less prevalent in smokers. This is the first report of a possible modifying effect of cigarette smoking on the development of organ damage in PSV, but more studies are needed before any firm conclusions can be made.

  • 41.
    Mohammad, Aladdin
    et al.
    Skåne University Hospital.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Prevalence of ANCA Associated Vasculitis and Polyarteritis Nodosa in Southern Sweden-Revisited 2010 in ARTHRITIS AND RHEUMATISM, vol 63, issue 10, pp S727-S7282011In: ARTHRITIS AND RHEUMATISM, Wiley-Blackwell , 2011, Vol. 63, no 10, p. S727-S728Conference paper (Refereed)
    Abstract [en]

    n/a

  • 42.
    Mossberg, M.
    et al.
    Lund Univ, Sweden.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Kahn, R.
    Lund Univ, Sweden.
    Englund, M.
    Lund Univ, Sweden.
    Mohammad, A. J.
    Lund Univ, Sweden; Addenbrookes Hosp, England.
    Epidemiology of primary systemic vasculitis in children: a population-based study from southern Sweden2018In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 47, no 4, p. 295-302Article in journal (Refereed)
    Abstract [en]

    Objectives: To estimate the annual incidence rate of paediatric primary systemic vasculitis (PSV) in a defined geographical area in southern Sweden.Methods: Potential cases of PSV [IgA vasculitis (IgAV, Henoch-Schonlein purpura), Kawasaki disease (KD), granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), polyarteritis nodosa (PAN), and Takayasus arteritis (TAK)] were identified in a comprehensive regional healthcare register. The study area is Skane, the southernmost county of Sweden (population 1.29 million; 21.4% aged amp;lt;18years). Case records for children (0-17years) assigned a diagnosis code between M300 and M319 and/or D690 were reviewed to ascertain diagnosis. Only patients diagnosed between 2004 and 2014 were included.Results: In total, 556 patients with PSV were identified. The annual incidence rate per million children (95% confidence interval) was estimated to be 200 (183-217) for all PSV, 175.5 for IgAV (160-191), 20.1 for KD (14.9-25.4), 1.4 (0-2.8) for each of GPA and MPA, 0.7 (0-1.7) for PAN, and 0.4 (0-1.1) for each of EGPA and TAK. Among children aged amp;lt;10years, 99.5% of cases were either IgAV or KD, both exhibiting a seasonal pattern paralleling infections. There were no deaths, but three cases of end-stage renal disease were noted, all in MPA.Conclusions: Vasculitis is relatively common during childhood. Mild cases associated with the infection season are most common in the youngest age groups, while during adolescence a substantial proportion has more severe forms of vasculitis.

  • 43.
    Mossberg, Maria
    et al.
    Lund University, Sweden.
    Stahl, Anne-lie
    Lund University, Sweden.
    Kahn, Robin
    Lund University, Sweden.
    Kristoffersson, Ann-Charlotte
    Lund University, Sweden.
    Tati, Ramesh
    Lund University, Sweden.
    Heijl, Caroline
    Lund University, Sweden.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Leeb-Lundberg, L. M. Fredrik
    Lund University, Sweden.
    Karpman, Diana
    Lund University, Sweden.
    Cl-Inhibitor Decreases the Release of Vasculitis-Like Chemotactic Endothelial Microvesicles2017In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 28, no 8, p. 2472-2481Article in journal (Refereed)
    Abstract [en]

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

  • 44.
    Ohlsson, S M
    et al.
    Lund University, Sweden .
    Pettersson, A
    Lund University, Sweden .
    Ohlsson, S
    Lund University, Sweden .
    Selga, D
    Lund University, Sweden .
    Bengtsson, A A
    Lund University, Sweden .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Hellmark, T
    Lund University, Sweden .
    Phagocytosis of apoptotic cells by macrophages in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis2012In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 170, no 1, p. 47-56Article in journal (Refereed)
    Abstract [en]

    Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune diseases, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). It is not known why ANCA develop, but it has been shown that they participate in pathogenesis by activating polymorphonuclear neutrophils (PMNs). In this study we hypothesize that dysregulation of phagocytosis in AAV leads to the accumulation of apoptotic neutrophils seen in association with blood vessels in AAV. These cells progress into secondary necrosis, contributing to tissue damage and autoantibody formation. Peripheral blood cells were counted, and phagocytosis was investigated using monocyte-derived macrophages (M circle divide) and PMNs from healthy blood donors (HBD), AAV patients and systemic lupus erythematosus (SLE) patients. Furthermore, the effect of serum was assessed. Phagocytosis was measured using flow cytometry. The results showed no deviation in monocyte subpopulations for AAV patients compared to HBDs, although there was a decrease in lymphocyte and pDC (plasmacytoid dendritic cell) populations (4.2 X 106 cells/l versus 10.4 X 106 cells/l, P andlt; 0.001). The number of neutrophils was increased (6.0 X 109 cells/l versus 3.8 X 109 cells/l, P andlt; 0.001). There were no differences found in the ability of M circle divide s to engulf apoptotic cells, nor when comparing apoptotic PMNs to become engulfed. However, serum from AAV donors tended to decrease the phagocytosis ability of M circle divide s (36%) compared to serum from HBDs (43%). In conclusion, there is no intrinsic dysfunction in the M circle divide s or in the PMNs that have an effect on phagocytic activity, but ANCA may play a role by decreasing phagocytic ability.

  • 45.
    Ohlsson, Sophie
    et al.
    Department of Nephrology, Lund University Hospital, Institute for Clinical Sciences, Lund, Sweden and Kidney Research Laboratory, BMC C14, Lund, Sweden.
    Bakoush, Omran
    Department of Nephrology, Lund University Hospital, Institute for Clinical Sciences, Lund, Sweden.
    Tencer, Jan
    Department of Nephrology, Lund University Hospital, Institute for Clinical Sciences, Lund, Sweden.
    Torffvit, Ole
    Department of Nephrology, Lund University Hospital, Institute for Clinical Sciences, Lund, Sweden.
    Segelmark, Mårten
    Department of Nephrology, Lund University Hospital, Institute for Clinical Sciences, Lund, Sweden.
    Monocyte Chemoattractant Protein 1 is a Prognostic Marker in ANCA-Associated Small Vessel Vasculitis2009In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, Vol. 2009, no (2009), p. Art.-ID 584916-Article in journal (Refereed)
    Abstract [en]

    Background

    The (anti neutrophil cytoplasmatic autoantibody ANCA), associated small vessel vasculitides (ASVV) are relapsing-remitting inflammatory disorders, involving various organs, such as the kidneys. (Monocyte chemoattractant protein 1 MCP-1) has been shown to be locally up regulated in glomerulonephritis and recent studies have pointed out MCP-1 as a promising marker of renal inflammation. Here we measure urinary cytokine levels in different phases of disease, exploring the possible prognostic value of MCP-1, together with (interleukin 6 IL-6), (interleukin 8 IL-8) and (immunoglobulin M IgM).

    Methods

    MCP-1, IL-6 and IL-8 were measured using commercially available ELISA kits, whereas IgM in the urine was measured by an in-house ELISA.

    Results

    The MCP-1 levels in urine were significantly higher in patients in stable phase of the disease, compared with healthy controls. Patients in stable phase, with subsequent adverse events; had significantly higher MCP-1 values than patients who did not. MCP-1 and IgM both tended to be higher in patients relapsing within three months, an observation, however, not reaching statistical significance. Urinary levels of IL-6 correlated with relapse tendency, and IL-8 was associated with disease outcome.

    Conclusions

    Patients with ASVV have raised cytokine levels in the urine compared to healthy controls, even during remission. Raised MCP-1 levels are associated with poor prognosis and possibly also with relapse tendency. The association with poor prognosis was stronger for U-MCP-1 than for conventional markers of disease like CRP, BVAS, and ANCA, as well as compared to candidate markers like U-IgM and U-IL-8. We thus consider U-MCP-1 to have promising potential as a prognostic marker in ASVV.

  • 46.
    Ohlsson, Sophie
    et al.
    Skåne University Hospital, Sweden .
    Herlitz, Hans
    Sahlgrens University Hospital, Sweden .
    Lundberg, Sigrid
    Karolinska University Hospital, Sweden .
    Selga, Daina
    Skåne University Hospital, Sweden .
    Molne, Johan
    Sahlgrens University Hospital, Sweden .
    Wieslander, Jorgen
    Eurodiagnost AB, Sweden .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Circulating Anti-Glomerular Basement Membrane Antibodies With Predominance of Subclass IgG4 and False-Negative Immunoassay Test Results in Anti-Glomerular Basement Membrane Disease2014In: American Journal of Kidney Diseases, ISSN 0272-6386, E-ISSN 1523-6838, Vol. 63, no 2, p. 289-293Article in journal (Refereed)
    Abstract [en]

    Autoantibodies against a constituent of the glomerular basement membrane (GBM), the alpha 3-chain of type IV collagen, can cause both rapidly progressive glomerulonephritis and alveolar hemorrhage, referred to as anti-GBM disease or Goodpasture disease. Anti-GBM antibodies generally are of immunoglobulin G subclass 1 (IgG1) and can in most cases readily be detected in the circulation using enzyme-linked immunosorbent assays (ELISAs). We report 4 cases in which anti-GBM ELISA yielded negative or borderline results despite life-threatening disease. All 4 patients had positive results by IgG4 anti-GBM ELISA and all had undetectable anti-neutrophil cytoplasmic antibody. All cases were confirmed with kidney biopsy. Two of the patients showed higher signal in anti-GBM ELISA when using a nondenaturing coating buffer. All 4 were young women with severe alveolar hemorrhage and favorable renal outcome, suggesting that patients with predominance of IgG4 autoantibodies may constitute a distinct subgroup of anti-GBM disease. We conclude that patients with idiopathic alveolar hemorrhage can have anti-GBM disease detected by only IgG subclass-specific tests or kidney biopsy.

  • 47.
    Ohlsson, Sophie
    et al.
    Skåne University Hospital, Sweden .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    In Reply to IgG4-Restricted Anti-Glomerular Basement Membrane Autoantibodies Targeting Quaternary Epitopes of Native alpha 345(IV) Collagen2014In: American Journal of Kidney Diseases, ISSN 0272-6386, E-ISSN 1523-6838, Vol. 64, no 1, p. 157-157Article in journal (Other academic)
  • 48.
    Ohlsson, Susanne M.
    et al.
    Lund University, Sweden .
    Ohlsson, Sophie
    Lund University, Sweden .
    Söderberg, Daniel
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Gunnarsson, Lena
    Lund University, Sweden .
    Pettersson, Åsa
    Lund University, Sweden .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Hellmark, Thomas
    Lund University, Sweden .
    Neutrophils from vasculitis patients exhibit an increased propensity for activation by anti-neutrophil cytoplasmic antibodies2014In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 176, no 3, p. 363-372Article in journal (Refereed)
    Abstract [en]

    Anti-neutrophil cytoplasmic antibodies (ANCA) are thought to be pathogenic in ANCA-associated vasculitis (AAV) by stimulating polymorphonuclear leucocytes (PMNs) to degranulate and produce reactive oxygen species (ROS). The aim of this study was to investigate if PMNs from AAV patients are stimulated more readily by ANCA compared with PMNs from healthy controls (HCs). Differences in ANCA characteristics that can account for different stimulation potential were also studied. PMNs from five AAV patients and five HCs were stimulated with 10 different immunoglobulins (Ig)Gs, purified from PR3-ANCA-positive patients, and ROS production, degranulation and neutrophil extracellular trap (NET) formation was measured. ANCA levels, affinity and clinical data of the AAV donors were recorded. The results show that PMNs from AAV patients produce more intracellular ROS (P=0 center dot 019), but degranulate to a similar extent as PMNs from HCs. ROS production correlated with NET formation. Factors that may influence the ability of ANCA to activate PMNs include affinity and specificity for N-terminal epitopes. In conclusion, our results indicate that PMNs from AAV patients in remission behave quite similarly to HC PMNs, with the exception of a greater intracellular ROS production. This could contribute to more extensive NET formation and thus an increased exposure of the ANCA autoantigens to the immune system.

  • 49.
    Peng, Xiang
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Jinan University, Guangdong, China.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Kurz, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. University of Örebro, Sweden.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    The neutrophil serine protease PR3 induces shape change of platelets via the Rho/Rho kinase and Ca2+ signaling pathways2014In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 134, no 2, p. 418-425Article in journal (Refereed)
    Abstract [en]

    Introduction: Proteinase 3 (PR3) is released from neutrophil azurophilic granules and exerts complex effects on the inflammatory process. PR3 catalyzes the degradation of a number of macromolecules, but the consequences on blood cells are less well defined. In the present study, the effect of PR3 on human platelets was thoroughly investigated. Methods: The experiments were performed on washed platelets freshly isolated from blood donated by healthy human volunteers. Platelets shape change and aggregation was measured on a Chrono-Log aggregometer. The phosphorylated form of MYPT1 was visualized by immunostaining. Platelet activation was further evaluated by flow cytometry. Results: PR3 induced platelet shape change but not aggregation. Flow cytometry analysis showed that PR3 induced no P-selectin expression or binding of fibrinogen to the platelets, and it did not change the activation in response to PAR1- or PAR4-activating peptides or to thrombin. Furthermore, Fura-2 measurement and immuno-blotting analysis, respectively, revealed that PR3 stimulated small intracellular Ca2+ mobilization and Thr696-specific phosphorylation of the myosin phosphatase target subunit 1 (MYPT1). Separate treatment of platelets with the Rho/Rho kinase inhibitor Y-27632 and the intracellular Ca2+ chelator BAPTA/AM reduced the shape change induced by PR3 whereas concurrent treatment completely inhibited it. Conclusion: The data shows that the neutrophil protease PR3 is a direct modulator of human platelets and causes shape change through activation of the Rho/Rho kinase and Ca2+ signaling pathways. This finding highlights an additional mechanism in the complex interplay between neutrophils and platelets.

  • 50.
    Persson, Ulf
    et al.
    Lund University, Sweden Lundby Hospital, Sweden .
    Gullstrand, Birgitta
    Lund University, Sweden .
    Pettersson, Asa
    Lund University, Sweden .
    Sturfelt, Gunnar
    Lund University, Sweden .
    Truedsson, Lennart
    Lund University, Sweden .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    A Candidate Gene Approach to ANCA-Associated Vasculitis Reveals Links to the C3 and CTLA-4 Genes but not to the IL1-Ra And Fc gamma-RIIa Genes2013In: Kidney and Blood Pressure Research, ISSN 1420-4096, E-ISSN 1423-0143, Vol. 37, no 6, p. 641-648Article in journal (Refereed)
    Abstract [en]

    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, Fc gamma-RIIa and IL1-Ra. Patients and Methods: Patients with AAV (n=105) subgrouped as microscopic polyangiitis or granulomatosis with polyangiitis (Wegeners 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 Fc gamma-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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