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  • 1.
    Eriksson, Oskar
    et al.
    Uppsala University, Sweden.
    Mohlin, Camilla
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Nilsson, Bo
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University, Sweden.
    The Human Platelet as an Innate Immune Cell: Interactions Between Activated Platelets and the Complement System2019Inngår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, s. 1-16, artikkel-id 1590Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Platelets play an essential role in maintaining homeostasis in the circulatory system after an injury by forming a platelet thrombus, but they also occupy a central node in the intravascular innate immune system. This concept is supported by their extensive interactions with immune cells and the cascade systems of the blood. In this review we discuss the close relationship between platelets and the complement system and the role of these interactions during thromboinflammation. Platelets are protected from complement-mediated damage by soluble and membrane-expressed complement regulators, but they bind several complement components on their surfaces and trigger complement activation in the fluid phase. Furthermore, localized complement activation may enhance the procoagulant responses of platelets through the generation of procoagulant microparticles by insertion of sublytic amounts of C5b9 into the platelet membrane. We also highlight the role of post-translational protein modifications in regulating the complement system and the critical role of platelets in driving these reactions. In particular, modification of disulfide bonds by thiol isomerases and protein phosphorylation by extracellular kinases have emerged as important mechanisms to fine-tune complement activity in the platelet microenvironment. Lastly, we describe disorders with perturbed complement activation where part of the clinical presentation includes uncontrolled platelet activation that results in thrombocytopenia, and illustrate how complement-targeting drugs are alleviating the prothrombotic phenotype in these patients. Based on these clinical observations, we discuss the role of limited complement activation in enhancing platelet activation and consider how these drugs may provide opportunities for further dissecting the complex interactions between complement and platelets.

  • 2.
    Nilsson Ekdahl, Kristina
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Persson, Barbro
    Uppsala University.
    Mohlin, Camilla
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Skattum, Lillemor
    Lund University.
    Nilsson, Bo
    Uppsala University.
    Interpretation of Serological Complement Biomarkers in Disease2018Inngår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, artikkel-id 2237Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Complement systemaberrations have been identified as pathophysiological mechanisms in a number of diseases and pathological conditions either directly or indirectly. Examples of such conditions include infections, inflammation, autoimmune disease, as well as allogeneic and xenogenic transplantation. Both prospective and retrospective studies have demonstrated significant complement-related differences between patient groups and controls. However, due to the low degree of specificity and sensitivity of some of the assays used, it is not always possible to make predictions regarding the complement status of individual patients. Today, there are three main indications for determination of a patient's complement status: (1) complement deficiencies (acquired or inherited); (2) disorders with aberrant complement activation; and (3) C1 inhibitor deficiencies (acquired or inherited). An additional indication is to monitor patients on complement-regulating drugs, an indication which may be expected to increase in the near future since there is now a number of such drugs either under development, already in clinical trials or in clinical use. Available techniques to study complement include quantification of: (1) individual components; (2) activation products, (3) function, and (4) autoantibodies to complement proteins. In this review, we summarize the appropriate indications, techniques, and interpretations of basic serological complement analyses, exemplified by a number of clinical disorders.

  • 3.
    Orrem, Hilde L.
    et al.
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Nilsson, Per H.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Natl Hosp Norway, Norway;Univ Oslo, Norway;Univ Oslo, Norway.
    Pischke, Soren E.
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Kleveland, Ola
    St Olavs Hosp, Norway;Norwegian Univ Sci & Technol, Norway.
    Yndestad, Arne
    Univ Oslo, Norway;Natl Hosp Norway, Norway;Oslo Univ Hosp, Norway.
    Ekholt, Karin
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Damas, Jan K.
    Norwegian Univ Sci & Technol, Norway.
    Espevik, Terje
    Norwegian Univ Sci & Technol, Norway.
    Bendz, Bjorn
    Natl Hosp Norway, Norway.
    Halvorsen, Bente
    Univ Oslo, Norway;Natl Hosp Norway, Norway.
    Gregersen, Ida
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Wiseth, Rune
    St Olavs Hosp, Norway;Norwegian Univ Sci & Technol, Norway.
    Andersen, Geir O.
    Oslo Univ Hosp, Norway.
    Ueland, Thor
    Univ Oslo, Norway;Natl Hosp Norway, Norway;Oslo Univ Hosp, Norway.
    Gullestad, Lars
    Univ Oslo, Norway;Oslo Univ Hosp, Norway;Natl Hosp Norway, Norway.
    Aukrust, Pal
    Univ Oslo, Norway;Natl Hosp Norway, Norway;Oslo Univ Hosp, Norway.
    Barratt-Due, Andreas
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Mollnes, Tom E.
    Natl Hosp Norway, Norway;Univ Oslo, Norway;Norwegian Univ Sci & Technol, Norway;Nordland Hosp, Norway;Univ Tromso, Norway.
    IL-6 Receptor Inhibition by Tocilizumab Attenuated Expression of C5a Receptor 1 and 2 in Non-ST-Elevation Myocardial Infarction2018Inngår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, artikkel-id 2035Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Elevated interleukin-6 (IL-6) and complement activation are associated with detrimental effects of inflammation in coronary artery disease (CAD). The complement anaphylatoxins C5a and C3a interact with their receptors; the highly inflammatory C5aR1, and the C5aR2 and C3aR. We evaluated the effect of the IL-6 receptor (IL-6R)-antagonist tocilizumab on the expression of the anaphylatoxin receptors in whole blood from non-ST-elevation myocardial infarction (NSTEMI) patients. Separately, anaphylatoxin receptor expression in peripheral blood mononuclear cells (PBMC) from patients with different entities of CAD was investigated. Materials and Methods: NSTEMI patients were randomized to one dose of tocilizumab (n = 28) or placebo (n = 32) and observed for 6 months. Whole blood samples drawn at inclusion, at day 2, 3 and after 6 months were used for mRNA isolation. Plasma was prepared for analysis of complement activation measured as sC5b-9 by ELISA. Furthermore, patients with different CAD entities comprising stable angina pectoris (SAP, n = 22), non-ST-elevation acute coronary syndrome (NSTE-ACS, n = 21) and ST-elevation myocardial infarction (STEMI, n = 20) were included. PBMC was isolated from blood samples obtained at admission to hospital and mRNA isolated. Anaphylatoxin-receptor-expression was analyzed with qPCR using mRNA from whole blood and PBMC, respectively. Results: Our main findings were (i) Tocilizumab decreased C5aR1 and C5aR2 mRNA expression significantly (p < 0.001) and substantially (> 50%) at day 2 and 3, whereas C3aR expression was unaffected. (ii) Tocilizumab did not affect complement activation. (iii) In analyzes of different CAD entities, C5aR1 expression was significantly increased in all CAD subgroups compared to controls with the highest level in the STEMI patients (p < 0.001). For C5aR2 and C3aR the expression compared to controls were more moderate with increased expression of C5aR2 in the STEMI group (p < 0.05) and C3aR in the NSTE-ACS group (p < 0.05). Conclusion: Expression of C5aR1 and C5aR2 in whole blood was significantly attenuated by IL-6R-inhibition in NSTEMI patients. These receptors were significantly upregulated in PBMC CAD patients with particularly high levels of C5aR1 in STEMI patients.

  • 4.
    Sandholm, Kerstin
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Persson, Barbro
    Uppsala University.
    Skattum, Lillemor
    Lund University.
    Eggertsen, Gösta
    Karolinska Institutet;Karolinska University Hospital.
    Nyman, Dag
    Aland Cent Hosp, Finland.
    Gunnarsson, Iva
    Karolinska Institutet;Karolinska University Hospital.
    Svenungson, Elisabet
    Karolinska Institutet;Karolinska University Hospital.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Evaluation of a Novel Immunoassay for Quantification of C1q for Clinical Diagnostic Use2019Inngår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, artikkel-id 7Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: C1q is a valuable biomarker of disease activity in systemic lupus erythematosus (SLE). The "gold standard" assay, rocket immunoelectrophoresis (RIE), is time-consuming, and thus a shift to soluble immune precipitation techniques such as nephelometry has occurred. However, quantification of C1q with these techniques has been questioned as a result of the antibody binding properties of C1q. In the present work, we have compared results using various techniques (RIE, nephelometry, and ELISA) and have developed and validated a new magnetic bead-based sandwich immunoassay (MBSI). Methods: C1q was quantified by nephelometry and the new sandwich immunoassay in 45 serum samples analyzed using RIE. C1q was also assessed in plasma using RIE and sandwich immunoassay in samples from SLE patients with nephritis (n = 69), SLE patients without nephritis (n = 310) as classified by BILAG score, and matched controls (n = 322). In addition, cerebrospinal fluid (CSF) samples from 31 patients, previously analyzed with ELISA, were also analyzed with the MBSI to test the behavior of this new assay in the lower detection range. Results: We found a strong correlation between the new MBSI, RIE, and ELISA, but not with nephelometry. The MBSI demonstrated lower levels of C1q in SLE patients than in matched controls (p < 0.0001), and patients with nephritis had lower levels than patients without nephritis (p < 0.01). Similarily, RIE showed significant differences between the patient groups (p < 0.0001). An association was also found between the levels of C1q and the SLE disease activity index (SLEDAI). Furthermore, there was good correlation between the values obtained by MBSI and ELISA, in both serum (r = 0.960) and CSF (r = 0.786), underscoring the ability of both techniques to measure low concentrations of C1q with high accuracy. Conclusion: The sandwich immunoassay correlated well with RIE, but soluble immune precipitation techniques, such as nephelometry, did not appear suitable alternatives, since C1q itself, and possibly anti-C1q antibodies, interfered with the measurements. The new sandwich immunoassay is therefore a good replacement for RIE in monitoring SLE disease activity.

  • 5.
    Zhao, Fei
    et al.
    Leibniz Inst Nat Prod Res & Infect Biol, Germany.
    Afonso, Sara
    Leibniz Inst Nat Prod Res & Infect Biol, Germany.
    Lindner, Susanne
    Leibniz Inst Nat Prod Res & Infect Biol, Germany.
    Hartmann, Andrea
    Leibniz Inst Nat Prod Res & Infect Biol, Germany.
    Loeschmann, Ina
    Leibniz Inst Nat Prod Res & Infect Biol, Germany.
    Nilsson, Bo
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Linneaus Ctr Bomat Chem, Kalmar, Sweden..
    Weber, Lutz T.
    Univ Hosp Cologne, Germany.
    Habbig, Sandra
    Univ Hosp Cologne, Germany.
    Schalk, Gesa
    Univ Hosp Cologne, Germany.
    Kirschfink, Michael
    Heidelberg Univ, Germany.
    Zipfel, Peter F.
    Leibniz Inst Nat Prod Res & Infect Biol, Germany;Friedrich Schiller Univ Jena, Germany.
    Skerka, Christine
    Leibniz Inst Nat Prod Res & Infect Biol, Germany.
    C3-Glomerulopathy Autoantibodies Mediate Distinct Effects on Complement C3-and C5-Convertases2019Inngår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, s. 1-14, artikkel-id 1030Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    C3 glomerulopathy (C3G) is a severe kidney disease, which is caused by defective regulation of the alternative complement pathway. Disease pathogenesis is heterogeneous and is caused by both autoimmune and genetic factors. Here we characterized IgG autoantibodies derived from 33 patients with autoimmune C3 glomerulopathy. Serum antibodies from all 33 patients as well as purified IgGs bound to the in vitro assembled C3-convertase. Noteworthy, two groups of antibodies were identified: group 1 with strong (12 patients) and group 2 with weak binding C3-convertase autoantibodies (22 patients). C3Nef, as evaluated in a standard C3Nef assay, was identified in serum from 19 patients, which included patients from group 1 as well as group 2. The C3-convertase binding profile was independent of C3Nef. Group 1 antibodies, but not the group 2 antibodies stabilized the C3-convertase, and protected the enzyme from dissociation by Factor H. Also, only group 1 antibodies induced C3a release. However, both group 1 and group 2 autoantibodies bound to the C5-convertase and induced C5a generation, which was inhibited by monoclonal anti-C5 antibody Eculizumab in vitro. In summary, group 1 antibodies are composed of C3Nef and C5Nef antibodies and likely over-activate the complement system, as seen in hemolytic assays. Group 2 antibodies show predominantly C5Nef like activities and stabilize the C5 but not the C3-convertase. Altogether, these different profiles not only reveal a heterogeneity of the autoimmune forms of C3G (MPGN), they also show that in diagnosis of C3G not all autoimmune forms are identified and thus more vigorous autoantibody testing should be performed.

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