lnu.sePublications
Change search
Refine search result
1 - 11 of 11
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Denk, Stephanie
    et al.
    Univ Hosp Ulm, Germany.
    Neher, Miriam D.
    Univ Hosp Ulm, Germany.
    Messerer, David A. C.
    Univ Hosp Ulm, Germany.
    Wiegner, Rebecca
    Univ Hosp Ulm, Germany.
    Nilsson, Bo
    Uppsala University.
    Rittirsch, Daniel
    Univ Hosp Zurich, Switzerland.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Weckbach, Sebastian
    Ulm Univ, Germany.
    Ignatius, Anita
    Ulm Univ, Germany.
    Kalbitz, Miriam
    Univ Hosp Ulm, Germany.
    Gebhard, Florian
    Univ Hosp Ulm, Germany.
    Weiss, Manfred E.
    Univ Hosp Ulm, Germany.
    Vogt, Josef
    Ulm Univ, Germany.
    Radermacher, Peter
    Ulm Univ, Germany.
    Koehl, Joerg
    Univ Lubeck, Germany;Cincinnati Childrens Hosp Med Ctr, USA.
    Lambris, John D.
    Univ Penn, USA.
    Huber-Lang, Markus S.
    Univ Hosp Ulm, Germany.
    Complement C5a Functions as a Master Switch for the pH Balance in Neutrophils Exerting Fundamental Immunometabolic Effects2017In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 198, no 12, p. 4846-4854Article in journal (Refereed)
    Abstract [en]

    During sepsis, excessive activation of the complement system with generation of the anaphylatoxin C5a results in profound disturbances in crucial neutrophil functions. Moreover, because neutrophil activity is highly dependent on intracellular pH (pH(i)), we propose a direct mechanistic link between complement activation and neutrophil pHi. In this article, we demonstrate that in vitro exposure of human neutrophils to C5a significantly increased pHi by selective activation of the sodium/hydrogen exchanger. Upstream signaling of C5a-mediated intracellular alkalinization was dependent on C5aR1, intracellular calcium, protein kinase C, and calmodulin, and downstream signaling regulated the release of antibacterial myeloperoxidase and lactoferrin. Notably, the pH shift caused by C5a increased the glucose uptake and activated glycolytic flux in neutrophils, resulting in a significant release of lactate. Furthermore, C5a induced acidification of the extracellular micromilieu. In experimental murine sepsis, pHi of blood neutrophils was analogously alkalinized, which could be normalized by C5aR1 inhibition. In the clinical setting of sepsis, neutrophils from patients with septic shock likewise exhibited a significantly increased pHi. These data suggest a novel role for the anaphylatoxin C5a as a master switch of the delicate pHi balance in neutrophils resulting in profound inflammatory and metabolic changes that contribute to hyperlactatemia during sepsis.

  • 2. Hamad, Osama
    et al.
    Nilsson, Per H.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Wouters, Diana
    Lambris, John
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson, Bo
    Complement Component C3 Binds to Activated Normal Platelets without Preceding Proteolytic Activation and Promotes Binding to Complement Receptor 12010In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 184, no 5, p. 2686-2692Article in journal (Refereed)
    Abstract [en]

    It has been reported that complement is activated on the surface of activated platelets, despite the presence of multiple regulators of complement activation. To reinvestigate the mechanisms by which activated platelets bind to complement components, the presence of complement proteins on the surfaces of nonactivated and thrombin receptor-activating peptide-activated platelets was analyzed by flow cytometry and Western blot analyses. C1q, C4, C3, and C9 were found to bind to thrombin receptor-activating peptide-activated platelets in lepirudin-anticoagulated platelet-rich plasma (PRP) and whole blood. However, inhibiting complement activation at the C1q or C3 level did not block the binding of C3 to activated platelets. Diluting PRP and chelating divalent cations also had no effect, further indicating that the deposition of complement components was independent of complement activation. Furthermore, washed, activated platelets bound added C1q and C3 to the same extent as platelets in PRP. The use of mAbs against different forms of C3 demonstrated that the bound C3 consisted of C3(H2O). Furthermore, exogenously added soluble complement receptor 1 was shown to bind to this form of platelet-bound C3. These observations indicate that there is no complement activation on the surface of platelets under physiological conditions. This situation is in direct contrast to a number of pathological conditions in which regulators of complement activation are lacking and thrombocytopenia and thrombotic disease are the ultimate result. However, the generation of C3(H2O) represents nonproteolytic activation of C3 and after factor I cleavage may act as a ligand for receptor binding.

  • 3.
    Huber-Lang, Markus
    et al.
    University of Ulm, Germany.
    Barratt-Due, Andreas
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Pischke, Søren E
    University of Oslo, Rikshospitalet, Norway.
    Sandanger, Øystein
    University of Oslo, Rikshospitalet, Norway.
    Nilsson, Per H.
    University of Oslo, Rikshospitalet, Norway.
    Nunn, Miles A
    Ctr Ecol & Hydrol, Oxon, UK.
    Denk, Stephanie
    University of Ulm, Germany.
    Gaus, Wilhelm
    University of Ulm, Germany.
    Espevik, Terje
    Norwegian Univ Sci & Technol, Norway.
    Mollnes, Tom E
    University of Oslo, Rikshospitalet, Norway ; Norwegian Univ Sci & Technol, Norway; University of Tromsö, Norway.
    Double blockade of CD14 and complement C5 abolishes the cytokine storm and improves morbidity and survival in polymicrobial sepsis in mice.2014In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 192, no 11, p. 5324-5331Article in journal (Refereed)
    Abstract [en]

    Sepsis and septic shock, caused by an excessive systemic host-inflammatory response, are associated with high morbidity and mortality. The complement system and TLRs provide important pattern recognition receptors initiating the cytokine storm by extensive cross-talk. We hypothesized that double blockade of complement C5 and the TLR coreceptor CD14 could improve survival of experimental polymicrobial sepsis. Mice undergoing cecal ligation and puncture (CLP)-induced sepsis were treated with neutralizing anti-CD14 Ab biG 53, complement C5 inhibitor coversin (Ornithodoros moubata C inhibitor), or a combination thereof. The inflammatory study (24-h observation) revealed statistically significant increases in 22 of 24 measured plasma biomarkers in the untreated CLP group, comprising 14 pro- and anti-inflammatory cytokines and 8 chemokines, growth factors, and granulocyte activation markers. Single CD14 or C5 blockade significantly inhibited 20 and 19 of the 22 biomarkers, respectively. Combined CD14 and C5 inhibition significantly reduced all 22 biomarkers (mean reduction 85%; range 54-95%) compared with the untreated CLP group. Double blockade was more potent than single treatment and was required to significantly inhibit IL-6 and CXCL1. Combined inhibition significantly reduced morbidity (motility and eyelid movement) and mortality measured over 10 d. In the positive control CLP group, median survival was 36 h (range 24-48 h). Combined treatment increased median survival to 96 h (range 24-240 h) (p = 0.001), whereas survival in the single-treatment groups was not significantly increased (median and range for anti-CD14 and anti-C5 treatment were 36 h [24-48 h] and 48 h [24-96 h]). Combined with standard intervention therapy, specific blockade of CD14 and C5 might represent a promising new therapeutic strategy for treatment of polymicrobial sepsis.

  • 4. Mangsbo, Sara
    et al.
    Sanchez, Javier
    Anger, Kerstin
    Lambris, John
    Nilsson Ekdahl, Kristina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Loskog, Angelica
    Nilsson, Bo
    Tötterman, Thomas
    Complement activation by CpG in a human whole blood loop system: mechanisms and immunomodulatory effects2009In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 183, no 10, p. 6724-6732Article in journal (Refereed)
    Abstract [en]

    Phosphorothioate oligodeoxynucleotides can activate complement, and experimental murine studies have revealed differential effects upon simultaneous TLR stimulation and complement activation compared with either event alone. We set out to investigate the immune stimulatory effects of CpG 2006 in fresh non-anticoagulated human blood with or without presence of active complement. We also sought to elucidate the mechanism behind complement activation upon stimulation with phosphorothioate CpG 2006. In a human blood loop system, both backbone and sequence-specific effects by CpG were counteracted by selective inhibition of C3. Furthermore, DNA backbone-mediated CD40 and CD83 expression on monocytes and sequence-specific IL-6 and TNF production were reduced by complement inhibition. CpG-induced complement activation occurred via either the classical or the alternative pathway and deposits of both IgM and properdin, two activators of complement, were detected on CpG after incubation with EDTA plasma. Quartz crystal microbalance with dissipation monitoring demonstrated alternative pathway convertase build-up onto CpG as a likely pathway to initiate and sustain complement activation. Specific inhibition of C3 suppressed CpG 2006 uptake into monocytes indicating that C3 fragments are involved in CpG internalization. The interplay between complement and TLR9 signaling demonstrated herein warrants further investigation.

  • 5.
    Nilsson Ekdahl, Kristina
    et al.
    Department of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala.
    Nilsson, U R
    Nilsson, Bo
    Inhibition of factor I by diisopropylfluorophosphate. Evidence of conformational changes in factor I induced by C3b and additional studies on the specificity of factor I1990In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 144, no 11, p. 4269-4274Article in journal (Refereed)
    Abstract [en]

    The factor I-mediated cleavage of C3b, using factor H as a cofactor was completely inhibited by diisopropylfluorophosphate (DFP) when factor I and C3b were incubated with DFP before the addition of factor H. Inhibition, although to a lesser degree, was observed when factor H was present during DFP-exposure. No inhibition in factor I activity was seen when factor I and H were incubated with DFP either alone or together. It was also demonstrated that the 38-kDa subunit of factor I bound radiolabeled DFP when factor I and C3b together were exposed to DFP. These observations suggest that factor I interacts with C3b in a manner that exposes its catalytic site to DFP, an interaction that is independent of factor H. The inhibitory effect by DFP on factor I led us to further investigate the factor I cleavage products of iC3b, inasmuch as previous reports were ambiguous as to whether digestion occurs in the presence of DFP. Digestion of C3b bound to activated thiol Sepharose (ATS-C3b) in the presence of factor H at low pH and ionic strength and in serum by complement activation produced C3d,g- like fragments with apparent molecular mass of 41 and 43 kDa. These fragments were shown to have three different N-terminal and two different C-terminal ends. The major fragments had N-terminal sequences starting with Glu933, as shown by sequence determination. Traces of fragments extending beyond this point were also found, shown by Western blot analysis using a panel of mAb previously shown to bind to epitopes exposed within a region of C3 spanning residues 929 to 943, as well as a shorter fragment starting with Glu938. When digestion of C3b is carried out in the presence of DFP, the factor I level necessary for digestion is elevated and may explain how the first two cleavages producing iC3b but not the following giving C3d,g, can occur. The finding of several factor I cleavage sites in the C3d,g region of C3 demonstrates that factor I has a broad specificity, mainly for arginyl bonds. It has also been shown to digest a lysyl bond exposed in ATS- bound C3b. 

  • 6.
    Nymo, Stig
    et al.
    Nordland Hospital, Norway ; University of Tromsø, Norway ; University of Oslo, Rikshospitalet, Norway.
    Gustavsen, Alice
    University of Oslo, Rikshospitalet, Norway.
    Nilsson, Per H.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Lau, Corinna
    Nordland Hospital, Norway ; University of Tromsø, Norway.
    Espevik, Terje
    Norwegian University of Science and Technology, Norway ; Norwegian University of Science and Technology, Norway.
    Mollnes, Tom E.
    Nordland Hospital, Norway ; University of Tromsø, Norway ; University of Oslo, Rikshospitalet, Norway.
    Human Endothelial Cell Activation by Escherichia coli and Staphylococcus aureus Is Mediated by TNF and IL-1 beta Secondarily to Activation of C5 and CD14 in Whole Blood2016In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 196, no 5, p. 2293-2299Article in journal (Refereed)
    Abstract [en]

    Endothelial cells (EC) play a central role in inflammation. E-selectin and ICAM-1 expression are essential for leukocyte recruitment and are good markers of EC activation. Most studies of EC activation are done in vitro using isolated mediators. The aim of the present study was to examine the relative importance of pattern recognition systems and downstream mediators in bacteria-induced EC activation in a physiological relevant human model, using EC incubated with whole blood. HUVEC were incubated with human whole blood. Escherichia coli-and Staphylococcus aureus-induced EC activation was measured by E-selectin and ICAM-1 expression using flow cytometry. The mAb 18D11 was used to neutralize CD14, and the lipid A analog eritoran was used to block TLR4/MD2. C5 cleavage was inhibited using eculizumab, and C5aR1 was blocked by an antagonist. Infliximab and canakinumab were used to neutralize TNF and IL-1 beta. The EC were minimally activated when bacteria were incubated in serum, whereas a substantial EC activation was seen when the bacteria were incubated in whole blood. E. coli-induced activation was largely CD14-dependent, whereas S. aureus mainly caused a C5aR1-mediated response. Combined CD14 and C5 inhibition reduced E-selectin and ICAM-1 expression by 96 and 98% for E. coli and by 70 and 75% for S. aureus. Finally, the EC activation by both bacteria was completely abolished by combined inhibition of TNF and IL-1 beta. E. coli and S. aureus activated EC in a CD14- and C5-dependent manner with subsequent leukocyte secretion of TNF and IL-1 beta mediating the effect.

  • 7. Sartz, Lisa
    et al.
    Olin, Anders
    Kristoffersson, AC
    Ståhl, AL
    Johansson, ME
    Westman, K
    Fremeaux-Bacchi, V
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Karpman, Diana
    A novel C3 mutation causing increased formation of the C3 convertase in familial atypical hemolytic uremic syndrome.2012In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 188, no 4, p. 2030-2037Article, review/survey (Refereed)
    Abstract [en]

    Atypical hemolytic uremic syndrome has been associated with dysregulation of the alternative complement pathway. In this study, a novel heterozygous C3 mutation was identified in a factor B-binding region in exon 41, V1636A (4973 T > C). The mutation was found in three family members affected with late-onset atypical hemolytic uremic syndrome and symptoms of glomerulonephritis. All three patients exhibited increased complement activation detected by decreased C3 levels and glomerular C3 deposits. Platelets from two of the patients had C3 and C9 deposits on the cell surface. Patient sera exhibited more C3 cleavage and higher levels of C3a. The C3 mutation resulted in increased C3 binding to factor B and increased net formation of the C3 convertase, even after decay induced by decay-accelerating factor and factor H, as assayed by surface plasmon resonance. Patient sera incubated with washed human platelets induced more C3 and C9 deposition on the cell surface in comparison with normal sera. More C3a was released into serum over time when washed platelets were exposed to patient sera. Results regarding C3 and C9 deposition on washed platelets were confirmed using purified patient C3 in C3-depleted serum. The results indicated enhanced convertase formation leading to increased complement activation on cell surfaces. Previously described C3 mutations showed loss of function with regard to C3 binding to complement regulators. To our knowledge, this study presents the first known C3 mutation inducing increased formation of the C3 convertase, thus explaining enhanced activation of the alternative pathway of complement.

  • 8.
    Sfyroera, Georgia
    et al.
    Univ Penn, USA.
    Ricklin, Daniel
    Univ Penn, USA.
    Reis, Edimara
    Univ Penn, USA.
    Chen, Hui
    Univ Penn, USA.
    Wu, Emilia
    Univ Minnesota, USA.
    Kaznessis, Yannis
    Univ Minnesota, USA.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Lambris, John
    Univ Penn, USA.
    Rare loss-of-function mutation in complement component C3 provides insight into molecular and pathophysiological determinants of complement activity2015In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 194, no 7, p. 3305-3316Article in journal (Refereed)
    Abstract [en]

    The plasma protein C3 is a central element in the activation and effector functions of the complement system. A hereditary dysfunction of C3 that prevents complement activation via the alternative pathway (AP) was described previously in a Swedish family, but its genetic cause and molecular consequences have remained elusive. In this study, we provide these missing links by pinpointing the dysfunction to a point mutation in the beta-chain of C3 (c.1180T > C; p.Met(373)Thr). In the patient's plasma, AP activity was completely abolished and could only be reconstituted with the addition of normal C3. The M373T mutation was localized to the macroglobulin domain 4 of C3, which contains a binding site for the complement inhibitor compstatin and is considered critical for the interaction of C3 with the AP C3 convertase. Structural analyses suggested that the mutation disturbs the integrity of macroglobulin domain 4 and induces conformational changes that propagate into adjacent regions. Indeed, C3 M373T showed an altered binding pattern for compstatin and surface-bound C3b, and the presence of Thr(373) in either the C3 substrate or convertase-affiliated C3b impaired C3 activation and opsonization. In contrast to known gain-of-function mutations in C3, patients affected by this loss-of-function mutation did not develop familial disease, but rather showed diverse and mostly episodic symptoms. Our study therefore reveals the molecular mechanism of a relevant loss-of-function mutation in C3 and provides insight into the function of the C3 convertase, the differential involvement of C3 activity in clinical conditions, and some potential implications of therapeutic complement inhibition.

  • 9.
    Shahini, Negar
    et al.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Ueland, Thor
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Auensen, Andreas
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Michelsen, Annika E.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Ludviksen, Judith K.
    Nordland Hosp, Norway.
    Hussain, Amjad, I
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Pettersen, Kjell, I
    Oslo Univ Hosp, Norway.
    Aakhus, Svend
    Norwegian Univ Sci & Technol, Norway.
    Espeland, Torvald
    Norwegian Univ Sci & Technol, Norway;St Olays Hosp, Norway.
    Lunde, Ida G.
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Kirschfink, Michael
    Heidelberg Univ, Germany.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Mollnes, Tom Eirik
    Nordland Hosp, Norway;Univ Tromsö, Norway;Norwegian Univ Sci & Technol, Norway.
    Gullestad, Lars
    Univ Oslo, Norway.
    Aukrust, Pal
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Yndestad, Arne
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Louwe, Mieke C.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Increased Complement Factor B and Bb Levels Are Associated with Mortality in Patients with Severe Aortic Stenosis2019In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 203, no 7, p. 1973-1980Article in journal (Refereed)
    Abstract [en]

    Inflammation is involved in initiation and progression of aortic stenosis (AS). However, the role of the complement system, a crucial component of innate immunity in AS, is unclear. We hypothesized that circulating levels of complement factor B (FB), an important component of the alternative pathway, are upregulated and could predict outcome in patients with severe symptomatic AS. Therefore, plasma levels of FB, Bb, and terminal complement complex were analyzed in three cohorts of patients with severe symptomatic AS and mild-to-moderate or severe asymptomatic AS (population 1, n = 123; population 2, n = 436; population 3, n = 61) and in healthy controls by enzyme immunoassays. Compared with controls, symptomatic AS patients had significantly elevated levels of FB (2.9- and 2.8-fold increase in population 1 and 2, respectively). FB levels in symptomatic and asymptomatic AS patients were comparable (population 2 and 3), and in asymptomatic patients FB correlated inversely with valve area. FB levels in population 1 and 2 correlated with terminal complement complex levels and measures of systemic inflammation (i.e., CRP), cardiac function (i.e., NT-proBNP), and cardiac necrosis (i.e., Troponin T). High FB levels were significantly associated with mortality also after adjusting for clinical and biochemical covariates (hazard ratio 1.37; p = 0.028, population 2). Plasma levels of the Bb fragment showed a similar pattern in relation to mortality. We concluded that elevated levels of FB and Bb are associated with adverse outcome in patients with symptomatic AS. Increased levels of FB in asymptomatic patients suggest the involvement of FB from the early phase of the disease.

  • 10.
    Thomas, Anub M.
    et al.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Gerogianni, Alexandra
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    McAdam, Martin B.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Floisand, Yngvar
    Oslo Univ Hosp, Norway.
    Lau, Corinna
    Nordland Hosp, Norway.
    Espevik, Terje
    Norwegian Univ Sci & Technol, Norway.
    Nilsson, Per H.
    Oslo Univ Hosp, Norway.;Univ Oslo, Norway.
    Mollnes, Tom Eirik
    Oslo Univ Hosp, Norway;Univ Tromso, Norway.
    Barratt-Due, Andreas
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Complement Component C5 and TLR Molecule CD14 Mediate Heme-Induced Thromboinflammation in Human Blood2019In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 203, no 6, p. 1571-1578Article in journal (Refereed)
    Abstract [en]

    Heme is a critical danger molecule liberated from hemeproteins in various conditions, including from hemoglobin in hemolytic diseases. Heme may cause thromboinflammatory damage by activating inflammatory and hemostatic pathways, such as complement, the TLRs, coagulation, and platelets. In this study, we explored the effect of single and dual inhibition of complement component C5 and TLR coreceptor CD14 on heme-induced thromboinflammation in an ex vivo human whole blood model. Heme induced a dose-dependent activation of complement via the alternative pathway. Single inhibition of C5 by eculizumab attenuated the release of IL-6, IL-8, TNF, MCP-1, MIP-1 alpha, IFN-gamma, LTB-4, MMP-8 and -9, and IL-1Ra with more than 60% (p < 0.05 for all) reduced the upregulation of CD11b on granulocytes and monocytes by 59 and 40%, respectively (p < 0.05), and attenuated monocytic tissue factor expression by 33% (p < 0.001). Blocking CD14 attenuated IL-6 and TNF by more than 50% (p < 0.05). In contrast to single inhibition, combined C5 and CD14 was required for a significantly attenuated prothrombin cleavage (72%, p < 0.05). Markers of thromboinflammation were also quantified in two patients admitted to the hospital with sickle cell disease (SCD) crisis. Both SCD patients had pronounced hemolysis and depleted plasma hemopexin and haptoglobin. Plasma heme and complement activation was markedly increased in one patient, a coinciding observation as demonstrated ex vivo. In conclusion, heme-induced thromboinflammation was largely attenuated by C5 inhibition alone, with a beneficial effect of adding a CD14 inhibitor to attenuate prothrombin activation. Targeting C5 has the potential to reduce thromboinflammation in SCD crisis patients.

  • 11.
    Wu, YQ
    et al.
    University of Pennsylvania, USA.
    Qu, H
    University of Pennsylvania, USA.
    Sfyroera, G
    University of Pennsylvania, USA.
    Tzekou, A
    University of Pennsylvania, USA.
    Kay, BK
    University of Illinois at Chicago, USA.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. Uppsala University Hospital.
    Ricklin, D
    University of Pennsylvania, USA.
    Lambris, JD
    University of Pennsylvania, USA.
    Protection of Nonself Surfaces from Complement Attack by Factor H-Binding Peptides: Implications for Therapeutic Medicine2011In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 186, no 7, p. 4269-4277Article in journal (Refereed)
    Abstract [en]

    Exposure of nonself surfaces such as those of biomaterials or transplanted cells and organs to host blood frequently triggers innate immune responses, thereby affecting both their functionality and tolerability. Activation of the alternative pathway of complement plays a decisive role in this unfavorable reaction. Whereas previous studies demonstrated that immobilization of physiological regulators of complement activation (RCA) can attenuate this foreign body-induced activation, simple and efficient approaches for coating artificial surfaces with intact RCA are still missing. The conjugation of small molecular entities that capture RCA with high affinity is an intriguing alternative, as this creates a surface with autoregulatory activity upon exposure to blood. We therefore screened two variable cysteine-constrained phage-displayed peptide libraries for factor H-binding peptides. We discovered three peptide classes that differed with respect to their main target binding areas. Peptides binding to the broad middle region of factor H (domains 5–18) were of particular interest, as they do not interfere with either regulatory or binding activities. One peptide in this group (5C6) was further characterized and showed high factor H-capturing activity while retaining its functional integrity. Most importantly, when 5C6 was coated to a model polystyrene surface and exposed to human lepirudin-anticoagulated plasma, the bound peptide captured factor H and substantially inhibited complement activation by the alternative pathway. Our study therefore provides a promising and novel approach to produce therapeutic materials with enhanced biocompatibility.

1 - 11 of 11
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf