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  • 1.
    Adler, Anna
    et al.
    Uppsala University, Sweden.
    Manivel, Vivek Anand
    Uppsala University, Sweden.
    Fromell, Karin
    Uppsala University, Sweden.
    Teramura, Yuji
    Uppsala University, Sweden;Cellular & Mol Biotechnol Res Inst CMB, Japan.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    A Robust Method to Store Complement C3 With Superior Ability to Maintain the Native Structure and Function of the Protein2022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 891994Article in journal (Refereed)
    Abstract [en]

    Complement components have a reputation to be very labile. One of the reasons for this is the spontaneous hydrolysis of the internal thioester that is found in both C3 and C4 (but not in C5). Despite the fact that approximate to 20,000 papers have been published on human C3 there is still no reliable method to store the protein without generating C3(H2O), a fact that may have affected studies of the conformation and function of C3, including recent studies on intracellular C3(H2O). The aim of this work was to define the conditions for storage of native C3 and to introduce a robust method that makes C3 almost resistant to the generation of C3(H2O). Here, we precipitated native C3 at the isoelectric point in low ionic strength buffer before freezing the protein at -80 degrees C. The formation of C3(H2O) was determined using cation exchange chromatography and the hemolytic activity of the different C3 preparations was determined using a hemolytic assay for the classical pathway. We show that freezing native C3 in the precipitated form is the best method to avoid loss of function and generation of C3(H2O). By contrast, the most efficient way to consistently generate C3(H2O) was to incubate native C3 in a buffer at pH 11.0. We conclude that we have defined the optimal storage conditions for storing and maintaining the function of native C3 without generating C3(H2O) and also the conditions for consistently generating C3(H2O).

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  • 2.
    Aeinehband, Shahin
    et al.
    Karolinska Institutet.
    Lindblom, Rickard P. F.
    Karolinska Institutet.
    Al Nimer, Faiez
    Karolinska Institutet.
    Vijayaraghavan, Swetha
    Karolinska Institutet.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Khademi, Mohsen
    Karolinska Institutet.
    Olsson, Tomas
    Karolinska Institutet.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Darreh-Shori, Taher
    Karolinska Institutet.
    Piehl, Fredrik
    Karolinska Institutet.
    Complement Component C3 and Butyrylcholinesterase Activity Are Associated with Neurodegeneration and Clinical Disability in Multiple Sclerosis2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 4, article id e0122048Article in journal (Refereed)
    Abstract [en]

    Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genomewide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects. We here determined levels of neurofilament-light (NFL), a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE) and BuChE, in cerebrospinal fluid (CSF) from patients with MS (n = 48) and non-inflammatory controls (n = 18). C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with >= 9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. In conclusion, we show that CSF C3 correlates both to a marker for ongoing nerve injury and degree of disease disability. Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation. These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.

  • 3.
    Andersson, Linnea
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Sjöström, Dick J.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Quach, Huy Quang
    Mayo Clin, USA.
    Hägerström, Kim
    Region Kalmar County, Sweden.
    Hurler, Lisa
    Semmelwe Univ, Hungary.
    Kajdacsi, Erika
    Semmelwe Univ, Hungary.
    Cervenak, Laszlo
    Semmelwe Univ, Hungary.
    Prohaszka, Zoltan
    Semmelwe Univ, Hungary.
    Toonen, Erik J. M.
    Hycult Biotechnology, Netherlands.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Mollnes, Tom Eirik
    Univ Oslo, Norway;Oslo Univ Hosp, Norway;Nordland Hosp, Norway.
    Sandgren, Per
    Karolinska Institutet, Sweden.
    Tjernberg, Ivar
    Region Kalmar County, Sweden;Linköping University, Sweden.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Storage of Transfusion Platelet Concentrates is Associated with Complement Activation and Reduced Ability of Platelets to Respond to Protease-Activated Receptor-1 and Thromboxane A2 Receptor2024In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 25, no 2, article id 1091Article in journal (Refereed)
    Abstract [en]

    Platelet activation and the complement system are mutually dependent. Here, we investigated the effects of storage time on complement activation and platelet function in routinely produced platelet concentrates. The platelet concentrates (n = 10) were stored at 22 degrees C for seven days and assessed daily for complement and platelet activation markers. Additionally, platelet function was analyzed in terms of their responsiveness to protease-activated receptor-1 (PAR-1) and thromboxane A2 receptor (TXA(2)R) activation and their capacity to adhere to collagen. Complement activation increased over the storage period for all analyzed markers, including the C1rs/C1-INH complex (fold change (FC) = 1.9; p < 0.001), MASP-1/C1-INH complex (FC = 2.0; p < 0.001), C4c (FC = 1.8, p < 0.001), C3bc (FC = 4.0; p < 0.01), and soluble C5b-9 (FC = 1.7, p < 0.001). Furthermore, the levels of soluble platelet activation markers increased in the concentrates over the seven-day period, including neutrophil-activating peptide-2 (FC = 2.5; p < 0.0001), transforming growth factor beta 1 (FC = 1.9; p < 0.001) and platelet factor 4 (FC = 2.1; p < 0.0001). The ability of platelets to respond to activation, as measured by surface expression of CD62P and CD63, decreased by 19% and 24% (p < 0.05) for PAR-1 and 69-72% (p < 0.05) for TXA(2)R activation, respectively, on Day 7 compared to Day 1. The extent of platelet binding to collagen was not significantly impaired during storage. In conclusion, we demonstrated that complement activation increased during the storage of platelets, and this correlated with increased platelet activation and a reduced ability of the platelets to respond to, primarily, TXA(2)R activation.

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  • 4.
    Ardeshirilajimi, Sheida
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Non-enzymatic activation ofC5 in the tumor microenvironment2021Independent thesis Advanced level (degree of Master (Two Years)), 40 credits / 60 HE creditsStudent thesis
    Abstract [en]

    The complement system is an elegant biochemical cascade consisting of around 50serum soluble and membrane-bound proteins that defend the body from pathogens. It is a central part of the innate immune system, and it is regarded as a first-line defence mechanism of the human body against invading pathogens. The complement system can be activated via three pathways, alternative pathway, classical pathway, and lectin pathway. In all three pathways, C5 convertases are produced to cleave C5 into C5band C5a for host defence. In some environments, such as low pH, pro-oxidative and pro-inflammatory environment; instead, C5 can be activated without any cleavage of the C5 but confronted with a conformational change and expresses a C5b-like structure, still containing the C5a-domain bound to the main molecule. In contrast to normal cells, cancer cells prefer to aspirate in the anaerobic pathway even though there is enough oxygen, so they produce lactic acid, which creates an acidic environment in the tumor microenvironment (TME). The TME is further pro-oxidative and pro-inflammatory, which promotes tumor progression. This thesis aim was to simulate the TME ex vivo to understand the in vivo physiological role of non-enzymatic activation of C5. We hoped to answer whether C5b-like, which existence in vivo has never been proved, was generated in the TME or not.C5 faced a conformational change when serum was acidified with HCl or lactic acid. In a pro-oxidative environment with serum-supplemented with H2O2, a low amount of C5b-like was detected, but by adding iron catalyzer FeCl2, this amount was increased. With adding gallic acid as an antioxidant, the C5 conformational change was increased even further. Hence, C5 non-enzymatic activation in the presence ofH2O2 was iron-dependent, and by adding antioxidants, the turnover of C5b-like increased. In addition, C5b-like was also detected when activating granulocytes in serum. The C5 conformational change was also investigated in conditioned medium from the tumor cell line BXPC-3, an approach to mimic the TME with low pH and pro-oxidative status. BXPC-3 cells produced lactate in cell culture media and C5blikewas produced in the media by adding the serum as a C5 source. In conclusion, we show that a C5 conformational change occurred in low pH, in a prooxidative, and in a pro-inflammatory environment, which are the three characteristics of the TME. Complement activation in the TME may therefore progress without the controlled formation of C5-convertases.

  • 5.
    Asif, Sana
    et al.
    Uppsala University, Sweden.
    Asawa, Kenta
    Univ Tokyo, Japan.
    Inoue, Yuuki
    Univ Tokyo, Japan.
    Ishihara, Kazuhiko
    Univ Tokyo, Japan.
    Lindell, Björn
    Uppsala University, Sweden.
    Holmgren, Robin
    Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Ryden, Anneli
    Swedish University of Agricultural Sciences, Sweden.
    Jensen-Waern, Marianne
    Swedish University of Agricultural Sciences, Sweden.
    Teramura, Yuji
    Uppsala University, Sweden;Univ Tokyo, Japan.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. Uppsala University, Sweden.
    Validation of an MPC Polymer Coating to Attenuate Surface-Induced Crosstalk between the Complement and Coagulation Systems in Whole Blood in In Vitro and In Vivo Models2019In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 19, no 5, article id 1800485Article in journal (Refereed)
    Abstract [en]

    Artificial surfaces that come into contact with blood induce an immediate activation of the cascade systems of the blood, leading to a thrombotic and/or inflammatory response that can eventually cause damage to the biomaterial or the patient, or to both. Heparin coating has been used to improve hemocompatibility, and another approach is 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymer coatings. Here, the aim is to evaluate the hemocompatibility of MPC polymer coating by studying the interactions with coagulation and complement systems using human blood in vitro model and pig in vivo model. The stability of the coatings is investigated in vitro and MPC polymer-coated catheters are tested in vivo by insertion into the external jugular vein of pigs to monitor the catheters' antithrombotic properties. There is no significant activation of platelets or of the coagulation and complement systems in the MPC polymer-coated one, which was superior in hemocompatibility to non-coated matrix surfaces. The protective effect of the MPC polymer coat does not decline after incubation in human plasma for up to 2 weeks. With MPC polymer-coated catheters, it is possible to easily draw blood from pig for 4 days in contrast to the case for non-coated catheters, in which substantial clotting is seen.

  • 6.
    Asif, Sana
    et al.
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Fromell, Karin
    Uppsala University.
    Gustafson, Elisabet
    Uppsala University Hospital.
    Barbu, Andreea
    Uppsala University.
    Le Blanc, Katarina
    Karolinska Institutet;Karolinska University Hospital.
    Nilsson, Bo
    Uppsala University.
    Teramura, Yuji
    Uppsala University;The University of Tokyo, Japan.
    Heparinization of cell surfaces with short peptide-conjugated PEG-lipid regulates thromboinflammation in transplantation of human MSCs and hepatocytes2016In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 35, p. 194-205Article in journal (Refereed)
    Abstract [en]

    Infusion of therapeutic cells into humans is associated with immune responses, including thromboinflammation, which result in a large loss of transplanted cells\ To address these problems, heparinization of the cell surfaces was achieved by a cell-surface modification technique using polyethylene glycol conjugated phospholipid (PEG-lipid) derivatives. A short heparin-binding peptide was conjugated to the PEG-lipid for immobilization of heparin conjugates on the surface of human mesenchymal stem cells (hMSCs) and human hepatocytes. Here three kinds of heparin-binding peptides were used for immobilizing heparin conjugates and examined for the antithrombogenic effects on the cell surface. The heparinized cells were incubated in human whole blood to evaluate their hemocompatibility by measuring blood parameters such as platelet count, coagulation markers, complement markers, and Factor Xa activity. We found that one of the heparin-binding peptides did not show cytotoxicity after the immobilization with heparin conjugates. The degree of binding of the heparin conjugates on the cell surface (analyzed by flow cytometer) depended on the ratio of the active peptide to control peptide. For both human MSCs and hepatocytes in whole-blood experiments, no platelet aggregation was seen in the heparin conjugate-immobilized cell group vs. the controls (non-coated cells or control peptide). Also, the levels of thrombin-antithrombin complex (TAT), C3a, and sC5b-9 were significantly lower than those of the controls, indicating a lower activation of coagulation and complement. Factor Xa analysis indicated that the heparin conjugate was still active on the cell surface at 24 h post-coating. It is possible to immobilize heparin conjugates onto hMSC and human hepatocyte surfaces and thereby protect the cell surfaces from damaging thromboinflammation. Statement of Signigficance We present a promising approach to enhance the biocompatibility of therapeutic cells. Here we used short peptide-conjugated PEG-lipid for cell surface modification and heparin conjugates for the coating of human hepatocytes and MSCs. We screened the short peptides to find higher affinity for heparinization of cell surface and performed hemocompatibility assay of heparinized human hepatocytes and human MSCs in human whole blood. Using heparin-binding peptide with higher affinity, not only coagulation activation but also complement activation was significantly suppressed. Thus, it was possible to protect human hepatocytes and human MSCs from the attack of thromboinflammatory activation, which can contribute to the improvement graft survival. (C) 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  • 7.
    Barbu, Andreea
    et al.
    Uppsala University.
    Hamad, Osama
    Uppsala University.
    Lind, Lars
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Uppsala University.
    Nilsson, Bo
    Uppsala University.
    The role of complement factor C3 in lipid metabolism2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 101-107Article, review/survey (Refereed)
    Abstract [en]

    Abundant reports have shown that there is a strong relationship between C3 and C3a-desArg levels, adipose tissue, and risk factors for cardiovascular disease, metabolic syndrome and diabetes. The data indicate that complement components, particularly C3, are involved in lipid metabolism. The C3 fragment, C3a-desArg, functions as a hormone that has insulin-like effects and facilitates triglyceride metabolism. Adipose tissue produces and regulates the levels of complement components, which promotes generation of inflammatory initiators such as the anaphylatoxins C3a and C5a. The anaphylatoxins trigger a cyto/chemokine response in proportion to the amount of adipose tissue present, and induce inflammation and mediate metabolic effects such as insulin resistance. These observations support the concept that complement is an important participant in lipid metabolism and in obesity, contributing to the metabolic syndrome and to the low-grade inflammation associated with obesity.

  • 8.
    Bergman, I. M.
    et al.
    Aarhus Univ, Denmark.
    Okumura, N.
    Inst Soc Technoinnovat Agr Forestry & Fisheries, Japan.
    Uenishi, H.
    Natl Inst Agrobiol Sci, Japan.
    Hammer, S. E.
    Univ Vet Med Vienna, Austria.
    Knoll, A.
    Mendel Univ Brno, Czech Republic.
    Edfors, Inger
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Juul-Madsen, H. R.
    Aarhus Univ, Denmark.
    Wild boars from Sweden, Austria, the Czech Republic and Japan possess intact mannose-binding lectin 2 (MBL2) genes2015In: International Journal of Immunogenetics, ISSN 1744-3121, E-ISSN 1744-313X, Vol. 42, no 3, p. 204-207Article in journal (Refereed)
    Abstract [en]

    The two-nucleotide deletion recently detected in the mannose-binding lectin 2 gene in purebred and crossbred domestic pigs was not found among 68 wild boars representing 4 populations from Europe and Asia. This suggests that the deletion is a result of breeding and/or genetic drift/bottle necks.

  • 9.
    Bergman, Ingrid-Maria
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Edman, Kjell
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. Uppsala University.
    Rosengren, K. Johan
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. The University of Queensland, Australia.
    Edfors, Inger
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Extensive polymorphism in the porcine Toll-like receptor 10 gene2012In: International Journal of Immunogenetics, ISSN 1744-3121, E-ISSN 1744-313X, Vol. 39, no 1, p. 68-76Article in journal (Refereed)
    Abstract [en]

    The great importance of the Toll-like receptors (TLRs) in innate immunity is well established, but one family member – TLR10 – remains elusive. TLR10 is expressed in various tissues in several species, but its ligand is not known and its function is still poorly understood. The open reading frame of TLR10 was sequenced in 15 wild boars, representing three populations, and in 15 unrelated domestic pigs of Hampshire, Landrace and Large White origin. Amino acid positions corresponding to detected nonsynonymous single nucleotide polymorphisms (SNPs) were analysed in the crystal structures determined for the human TLR1–TLR2–lipopeptide complex and the human TLR10 Toll/Interleukin 1 receptor (TIR) dimer. SNP occurrence in wild boars and domestic pigs was compared, and haplotypes for the TLR10 gene and the TLR6-1-10 gene cluster were reconstructed. Despite the limited number of animals sequenced in the present study (N = 30), a larger number of SNPs were found in TLR10 than recently reported for TLR1, TLR6 and TLR2. Thirty-three SNPs were detected, of which 20 were nonsynonymous. The relative frequency of nonsynonymous (dN) and synonymous (dS) SNPs between wild boars and domestic pigs was higher in TLR10 than recently reported for TLR1, TLR6 and TLR2. However, the polymorphism reported in the present study seems to leave the function of the TLR10 molecule unaffected. Furthermore, no nonsynonymous SNPs were detected in the part of the gene corresponding to the hinge region of the receptor, probably reflecting rigorously acting functional constraint. The total number of SNPs and the number of nonsynonymous SNPs were significantly lower (< 0.05) in the wild boars than in the domestic pigs, and fewer TLR10 haplotypes were present in the wild boars. The majority of the TLR6-1-10 haplotypes were specific for either wild boars or domestic pigs, probably reflecting differences in microbial environment and population history.

  • 10. Biglarnia, Ali Reza
    et al.
    Nilsson, Bo
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Tufveson, Gunnar
    Nilsson, Tomas
    Larsson, Erik
    Wadström, Jonas
    Desenzitation Protocol with Antigen-Specific Immunoadsorption Interferes with Complement in ABO Incompatible Renal Transplantation2012In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 93, no 1, p. 87-92Article, review/survey (Refereed)
    Abstract [en]

    Background. Complement activation was characterized during and after desensitization treatment in 19 consecutive patients receiving ABO-incompatible (ABOi) living donor kidney transplants to assess the effect of desensitization protocol including antigen-specific immunoadsorption (IA) on complement activation.

    Methods. All patients received rituximab- and tacrolimus-based triple treatment. Anti-A/B antibodies were removed by IA. Serial determinations of C3, C3a, the C3a/C3 ratio, and sC5b-9 were carried out between day −30 and postoperative day 30. C1q was measured on day −30 and the day before the transplantation. In two recipients, eluates from immunoadsorbent columns were analyzed for C3a, C1q, and immunoglobulins by western blotting. Same complement analysis was performed in eluate from a control column after in vitro perfusion of AB-plasma.

    Results. Patient and graft survival were 100% for a median follow-up of 40 months (range, 12–60 months). There were no humoral rejections based on ABO-antigen-antibody interactions. C3a and the C3a/C3 ratio declined with the start of IA treatment, and this decline was maintained postoperatively. C1q declined from day −30 to a lower value on the day before transplantation (P<0.05). In eluates from both patient and control, immunoadsorbent column immunoglobulins together with C3a and C1q were detected.

    Conclusions. The current protocol including antigen-specific IA interferes with the complement system; this effect may be partially responsible for the absence of humoral rejection resulting from ABO-antigen-antibody interactions and the excellent outcomes obtained after ABO-incompatible kidney transplantation.

  • 11.
    Biglarnia, Ali-Reza
    et al.
    Skåne University Hospital, Sweden;Lund University, Sweden.
    Huber-Lang, Markus
    Univ Hosp Ulm, Germany.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    The multifaceted role of complement in kidney transplantation2018In: Nature Reviews Nephrology, ISSN 1759-5061, E-ISSN 1759-507X, Vol. 14, no 12, p. 767-781Article, review/survey (Refereed)
    Abstract [en]

    Increasing evidence indicates an integral role for the complement system in the deleterious inflammatory reactions that occur during critical phases of the transplantation process, such as brain or cardiac death of the donor, surgical trauma, organ preservation and ischaemia-reperfusion injury, as well as in humoral and cellular immune responses to the allograft. Ischaemia is the most common cause of complement activation in kidney transplantation and in combination with reperfusion is a major cause of inflammation and graft damage. Complement also has a prominent role in antibody-mediated rejection (ABMR) owing to ABO and HL A incompatibility, which leads to devastating damage to the transplanted kidney. Emerging drugs and treatment modalities that inhibit complement activation at various stages in the complement cascade are being developed to ameliorate the damage caused by complement activation in transplantation. These promising new therapies have various potential applications at different stages in the process of transplantation, including inhibiting the destructive effects of ischaemia and/or reperfusion injury, treating ABMR, inducing accommodation and modulating the adaptive immune response.

  • 12.
    Biglarnia, Alireza
    et al.
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Complement interception across humoral incompatibility in solid organ transplantation: a clinical perspective2015In: Immune Responses to Biosurfaces / [ed] John D. Lambris, Kristina Nilsson-Ekdahl, Daniel Ricklin, Bo Nilsson, Springer, 2015, p. 211-233Chapter in book (Refereed)
    Abstract [en]

    The humoral barrier in transplant biology is the result of preformed donor-specific antibodies (DSAs), directed either against human leukocyte antigens (HLA) or non-HLA antigens such as blood group (ABO) molecules. The term "sensitization" applies to patients carrying these antibodies. Transplantation is widely accepted as a life-saving opportunity for patients with terminal end-organ disease. However, in sensitized patients, transplant outcome is hampered by antibody-mediated rejection (AMR) as a consequence of DSA exposure. Furthermore, sensitized patients have limited access to "matched" organs from the both living and deceased donor pool.Considering the crucial role of the complement system in the pathophysiology of AMR and the availability of complement intervention therapeutics, there is a growing interest in complement-targeting strategies. This review highlights the emerging importance of monitoring and modulation of the complement system in the context of enabling transplantation across humoral incompatibility in sensitized recipients with preformed anti-HLA or natural anti-ABO antibodies. It also discusses the significance of the complement system in the induction of accommodation and further emphasizes current and future perspectives of novel complement therapeutics.

  • 13.
    Bonnedahl, Jonas
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science. Kalmar County Hospital, Sweden.
    Hernandez, Jorge
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science. Uppsala University, Sweden;Kalmar County Hospital, Sweden.
    Stedt, Johan
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Waldenström, Jonas
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Olsen, Bjorn
    Uppsala University, Sweden.
    Drobni, Mirva
    Uppsala University, Sweden.
    Extended-Spectrum beta-Lactamases in Escherichia coli and Klebsiella pneumoniae in Gulls, Alaska, USA2014In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 20, no 5, p. 897-899Article in journal (Refereed)
  • 14. Bäck, Jennie
    et al.
    Huber-Lang, Markus
    Elgue, Graciela
    Kalbitz, Miriam
    Sanchez, Javier
    Nilsson Ekdahl, Kristina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Nilsson, Bo
    Distinctive regulation of contact activation by antithrombin and C1-inhibitor on activated platelets and material surfaces2009In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 30, no 34, p. 6573-6580Article in journal (Refereed)
    Abstract [en]

    Activated human plate lets trigger FXII-mediated contactactivation, which leads to the generation of FXIIa–antithrombin (AT) and FXIa–AT complexes. This suggests that contactactivation takes place at different sites, on activatedplatelets and material surfaces, during therapeutic procedures involving biomaterials in contact with blood and is differentially regulated. Here we show that activation in platelet-poor plasma, platelet-rich plasma (PRP), and whole blood induced by glass, kaolin, and polyphosphate elicited high levels of FXIIa-C1-inhibitor (C1INH), low levels of FXIa–C1INH and KK–C1INH, and almost no AT complexes. Plateletactivation, in both PRP and blood, led to the formation of FXIIa–AT, FXIa–AT, and kallikrein (KK)–AT but almost no C1INH complexes. In severe trauma patients, FXIIa–AT and FXIa–AT were correlated with the release of thrombospondin-1 (TSP-1) from activatedplatelets. In contrast, FXIIa–C1INH complexes were detected when the FXIIa–AT levels were low. No correlations were found between FXIIa–C1INH and FXIIa–AT or TSP-1. Inhibition of FXIIa on material surfaces was also shown to affect the function of aggregating platelets. In conclusion, formation of FXIIa–AT and FXIIa–C1INH complexes can help to distinguish between contactactivation triggered by biomaterial surfaces and by activatedplatelets. Platelet aggregation studies also demonstrated that platelet function is influenced by material surface-mediated contactactivation and that generation of FXIIa–AT complexes may serve as a new biomarker for thrombotic reactions during therapeutic procedures employing biomaterial devices.

  • 15.
    Bäck, Jennie
    et al.
    Uppsala University.
    Lood, Christian
    Skåne University Hospital;Lund University.
    Bengtsson, Anders A.
    Skåne University Hospital;Lund University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Contact activation products are new potential biomarkers to evaluate the risk of thrombotic events in systemic lupus erythematosus2013In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 15, no 6, article id R206Article in journal (Refereed)
    Abstract [en]

    Introduction: Patients with systemic lupus erythematosus (SLE) have persistent platelet activation and an increased risk of thrombotic events, which cannot be accounted for by traditional cardiovascular risk factors. Factor (F)XII has a potentially important role in thrombus formation and is triggered by activated platelets. We therefore asked whether the contact system is involved in inflammation and vascular disease (VD) in SLE. Methods: Fibrin clots were incubated with purified FXII or whole blood, and the activation and regulation of FXII were studied. Plasma from SLE patients with (n = 31) or without (n = 38) previous VD and from matched healthy controls (n = 68) were analyzed for the presence of complexes formed between contact system enzymes and antithrombin (AT) or C1 inhibitor (C1INH) and evaluated with regard to clinical data and laboratory parameters. Results: Fibrin clots elicited FXII activation and acted as co-factors for AT. In clotting plasma, the levels of FXIIa-AT increased, and FXIIa-C1INH decreased. A similar reciprocal relationship existed in SLE patients. FXIIa-AT was elevated in the SLE patients with a history of VD, while the corresponding levels of factor FXIIa-C1INH were significantly decreased. FXIIa-AT correlated strongly with platelet parameters. The odds ratio for VD among the SLE patients was 8.9 if they had low levels of FXIIa-C1INH, 6.1 for those with high levels of FXIIa-AT, and increased to 23.4 for those with both decreased levels of FXIIa-C1INH and increased levels of FXIIa-AT. Conclusions: Activation of FXII is elicited by fibrin during thrombotic reactions in vitro and in vivo, and fibrin acts as a heparin-like co-factor and regulates AT. Patients with SLE had altered levels of FXIIa-serpin complexes, supporting that the contact system is involved in this disease. FXIIa-serpin complexes are strongly associated with previous VD in SLE patients, suggesting that these complexes are potential biomarkers for monitoring and assessing the risk of thrombotic events in SLE.

  • 16.
    Carlsson, Hanna
    et al.
    Kalmar County Hospital.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Tjernberg, Ivar
    Kalmar County Hospital.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Complement activation in asymptomatic Lyme borreliosis and neuroborreliosis2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 128-128Article in journal (Other academic)
  • 17.
    Chapman, Joanne R.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Hellgren, Olof
    Lund University.
    Helin, Anu S.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Kraus, Robert H. S.
    Univ Konstanz, Germany;Max Planck Inst Ornithology, Germany.
    Cromie, Ruth L.
    Wildfowl & Wetlands Trust, UK.
    Waldenström, Jonas
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    The Evolution of Innate Immune Genes: Purifying and Balancing Selection on beta-Defensins in Waterfowl2016In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 33, no 12, p. 3075-3087Article in journal (Refereed)
    Abstract [en]

    In disease dynamics, high immune gene diversity can confer a selective advantage to hosts in the face of a rapidly evolving and diverse pathogen fauna. This is supported empirically for genes involved in pathogen recognition and signalling. In contrast, effector genes involved in pathogen clearance may be more constrained. beta-Defensins are innate immune effector genes; their main mode of action is via disruption of microbial membranes. Here, five beta-defensin genes were characterized in mallards (Anas platyrhynchos) and other waterfowl; key reservoir species for many zoonotic diseases. All five genes showed remarkably low diversity at the individual-, population-, and species-level. Furthermore, there was widespread sharing of identical alleles across species divides. Thus, specific beta-defensin alleles were maintained not only spatially but also over long temporal scales, with many amino acid residues being fixed across all species investigated. Purifying selection to maintain individual, highly efficacious alleles was the primary evolutionary driver of these genes in waterfowl. However, we also found evidence for balancing selection acting on the most recently duplicated beta-defensin gene (AvBD3b). For this gene, we found that amino acid replacements were more likely to be radical changes, suggesting that duplication of beta-defensin genes allows exploration of wider functional space. Structural conservation to maintain function appears to be crucial for avian beta-defensin effector molecules, resulting in low tolerance for new allelic variants. This contrasts with other types of innate immune genes, such as receptor and signalling molecules, where balancing selection to maintain allelic diversity has been shown to be a strong evolutionary force.

  • 18.
    Dantoft, Widad
    et al.
    Stockholm University.
    Lundin, Daniel
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science. Stockholm University.
    Esfahani, Shiva Seyedoleslami
    Stockholm University.
    Engström, Ylva
    Stockholm University.
    The POU/Oct Transcription Factor Pdm1/nub Is Necessary for a Beneficial Gut Microbiota and Normal Lifespan of Drosophila2016In: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 8, no 4, p. 412-426Article in journal (Refereed)
    Abstract [en]

    Maintenance of a stable gut microbial community relies on a delicate balance between immune defense and immune tolerance. We have used Drosophila to study how the microbial gut flora is affected by changes in host genetic factors and immunity. Flies with a constitutively active gut immune system, due to a mutation in the POU transcriptional regulator Pdm1/nubbin (nub) gene, had higher loads of bacteria and a more diverse taxonomic composition than controls. In addition, the microbial composition shifted considerably during the short lifespan of the nub1 mutants. This shift was characterized by a loss of relatively few OTUs (operational taxonomic units) and a remarkable increase in a large number of Acetobacter spp. and Leuconostoc spp. Treating nub1 mutant flies with antibiotics prolonged their lifetime survival by more than 100%. Immune gene expression was also persistently high in the presence of antibiotics, indicating that the early death was not a direct consequence of an overactive immune defense but rather an indirect consequence of the microbial load and composition. Thus, changes in host genotype and an inability to regulate the normal growth and composition of the gut microbiota leads to a shift in the microbial community, dysbiosis and early death.

  • 19.
    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, Sweden.
    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.

  • 20.
    Elmlund, Louise
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Cell-Antibody Interactions Studied Using HerceptinTM (trastuzumab) binding to SKOV-3 epithelial cancer cells characterized by Attana™ Quartz Crystal Microbalance Technology2013Conference paper (Other academic)
  • 21.
    Engberg, Anna E.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Region Skåne.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Oslo Univ Hosp, Rikshosp, Norway;Univ Oslo, Norway.
    Huang, Shan
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Fromell, Karin
    Uppsala University.
    Hamad, Osama A.
    Uppsala University.
    Mollnes, Tom Eirik
    Univ Oslo, Norway;Univ Tromsö, Norway.
    Rosengren-Holmberg, Jenny P.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Swedish Natl Lab Forens Sci, Linköping.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Teramura, Yuji
    Uppsala University;Univ Tokyo, Japan.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma2015In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 36, p. 55-65Article in journal (Refereed)
    Abstract [en]

    Inappropriate complement activation is often responsible for incompatibility reactions that occur when biomaterials are used. Complement activation is therefore a criterion included in legislation regarding biomaterials testing. However, no consensus is yet available regarding appropriate complement-activation-related test parameters. We examined protein adsorption in plasma and complement activation/cytokine release in whole blood incubated with well-characterized polymers. Strong correlations were found between the ratio of C4 to its inhibitor C4BP and generation of 10 (mainly pro-inflammatory) cytokines, including IL-17, IFN-gamma, and IL-6. The levels of complement activation products correlated weakly (C3a) or not at all (C5a, sC5b-9), confirming their poor predictive values. We have demonstrated a direct correlation between downstream biological effects and the proteins initially adhering to an artificial surface after contact with blood. Consequently, we propose the C4/C4BP ratio as a robust, predictor of biocompatibility with superior specificity and sensitivity over the current gold standard. (C) 2014 Elsevier Ltd. All rights reserved.

  • 22.
    Engberg, Anna E.
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson, Per H.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Mollnes, Tom Eirik
    Rosengren-Holmberg, Jenny P.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson, Bo
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    The ratio between C4 and C4BP adsorbed from plasma predicts cytokine generation induced by artificial polymers in contact with whole blood2012In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, no 11, p. 1211-1211Article in journal (Other academic)
  • 23.
    Engberg, Anna E.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Oslo, Rikshosp, Univ Hosp, Norway.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Huang, Shan
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Mollnes, T. E.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala university.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala university.
    The ratio between C4 and C4BP adsorbed to artificial materials is a new predictor for biocompatibility2013In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 56, no 3, p. 309-309Article in journal (Other academic)
  • 24.
    Engberg, Anna E.
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Sandholm, Kerstin
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Bexborn, Fredrik
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Persson, Jenny
    Lund University.
    Nilsson, Bo
    Uppsala University.
    Lindahl, Gunnar
    Lund University.
    Nilsson Ekdahl, Kristina
    University of Kalmar, School of Pure and Applied Natural Sciences. Uppsala University.
    Inhibition of complement activation on a model biomaterial surface by streptococcal M protein-derived peptides2009In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 30, no 13, p. 2653-2659Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to evaluate a new approach to inhibit complement activation triggered by biomaterial surfaces in contact with blood. In order to inhibit complement activation initiated by the classical pathway (CP), we used streptococcal M protein-derived peptides that specifically bind human C4BP, an inhibitor of the CP. The peptides were used to coat polystyrene microtiter wells which served as a model biomaterial. The ability of coated peptides to bind C4BP and to attenuate complement activation via the CP (monitored as generation of fluid-phase C3a and binding of fragments of C3 and C4 to the surface) was investigated using diluted normal human serum, where complement activation by the AP is minimal, as well as serum from a patient lacking alternative pathway activation. Complement activation (all parameters) was significantly decreased in serum incubated in well surfaces coated with peptides. Total inhibition of complement activation was obtained at peptide coating concentrations as low as 1-5 mu g/mL. Successful use of Streptococcus-derived peptides shows that it is feasible to control complement activation at a model biomaterial surface by capturing autologous complement regulatory molecules from plasma. (C) 2009 Elsevier Ltd. All rights reserved.

  • 25.
    Eriksson, Oskar
    et al.
    Uppsala University, Sweden.
    Hultström, Michael
    Uppsala University, Sweden.
    Persson, Barbro
    Uppsala University, Sweden.
    Lipcsey, Miklos
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Frithiof, Robert
    Uppsala University, Sweden.
    Mannose-Binding Lectin is Associated with Thrombosis and Coagulopathy in Critically Ill COVID-19 Patients2020In: Thrombosis and Haemostasis, ISSN 0340-6245, E-ISSN 2567-689X, E-ISSN 2567-689X, Vol. 120, no 12, p. 1720-1724Article in journal (Refereed)
    Abstract [en]

    The ongoing COVID-19 pandemic has caused significant morbidity and mortality worldwide, as well as profound effects on society. COVID-19 patients have an increased risk of thromboembolic (TE) complications, which develop despite pharmacological thromboprophylaxis. The mechanism behind COVID-19-associated coagulopathy remains unclear. Mannose-binding lectin (MBL), a pattern recognition molecule that initiates the lectin pathway of complement activation, has been suggested as a potential amplifier of blood coagulation during thromboinflammation. Here we describe data from a cohort of critically ill COVID-19 patients ( n =65) treated at a tertiary hospital center intensive care unit (ICU). A subset of patients had strongly elevated MBL plasma levels, and activity upon ICU admission, and patients who developed symptomatic TE (14%) had significantly higher MBL levels than patients without TE. MBL was strongly correlated to plasma D-dimer levels, a marker of COVID-19 coagulopathy, but showed no relationship to degree of inflammation or other organ dysfunction. In conclusion, we have identified complement activation through the MBL pathway as a novel amplification mechanism that contributes to pathological thrombosis in critically ill COVID-19 patients. Pharmacological targeting of the MBL pathway could be a novel treatment option for thrombosis in COVID-19. Laboratory testing of MBL levels could be of value for identifying COVID-19 patients at risk for TE events.

  • 26.
    Eriksson, Oskar
    et al.
    Uppsala University, Sweden.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson, Bo
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. Uppsala University, Sweden.
    The Human Platelet as an Innate Immune Cell: Interactions Between Activated Platelets and the Complement System2019In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 10, p. 1-16, article id 1590Article, review/survey (Refereed)
    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.

  • 27.
    Fagerqvist, Therese
    et al.
    Uppsala University.
    Lindström, Veronica
    Uppsala University.
    Nordström, Eva
    BioArctic Neurosci AB, Stockholm.
    Lord, Anna
    BioArctic Neurosci AB, Stockholm.
    Tucker, Stina M. E.
    BioArctic Neurosci AB, Stockholm.
    Su, Xingjian
    Uppsala University.
    Sahlin, Charlotte
    BioArctic Neurosci AB, Stockholm.
    Kasrayan, Alex
    BioArctic Neurosci AB, Stockholm.
    Andersson, Jessica
    BioArctic Neurosci AB, Stockholm.
    Welander, Hedvig
    Uppsala University.
    Näsström, Thomas
    Uppsala University.
    Holmquist, Mats
    BioArctic Neurosci AB, Stockholm.
    Schell, Heinrich
    Hertie Inst Clin Brain Res, Germany;German Ctr Neurodegenerat Dis, Germany.
    Kahle, Philipp J.
    Hertie Inst Clin Brain Res, Germany;German Ctr Neurodegenerat Dis, Germany.
    Kalimo, Hannu
    Univ Helsinki, Finland;Helsinki Univ Hosp, Finland.
    Moller, Christer
    BioArctic Neurosci AB, Stockholm.
    Gellerfors, Par
    BioArctic Neurosci AB, Stockholm.
    Lannfelt, Lars
    Uppsala University.
    Bergström, Joakim
    Uppsala University.
    Ingelsson, Martin
    Uppsala University.
    Monoclonal antibodies selective for α-synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and α-synuclein transgenic mice with the disease-causing A30P mutation2013In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 126, no 1, p. 131-144Article in journal (Refereed)
    Abstract [en]

    Inclusions of intraneuronal alpha-synuclein (-synuclein) can be detected in brains of patients with Parkinson's disease and dementia with Lewy bodies. The aggregation of -synuclein is a central feature of the disease pathogenesis. Among the different -synuclein species, large oligomers/protofibrils have particular neurotoxic properties and should therefore be suitable as both therapeutic and diagnostic targets. Two monoclonal antibodies, mAb38F and mAb38E2, with high affinity and strong selectivity for large -synuclein oligomers were generated. These antibodies, which do not bind amyloid-beta or tau, recognize Lewy body pathology in brains from patients with Parkinson's disease and dementia with Lewy bodies and detect pathology earlier in -synuclein transgenic mice than linear epitope antibodies. An oligomer-selective sandwich ELISA, based on mAb38F, was set up to analyze brain extracts of the transgenic mice. The overall levels of -synuclein oligomers/protofibrils were found to increase with age in these mice, although the levels displayed a large interindividual variation. Upon subcellular fractionation, higher levels of -synuclein oligomers/protofibrils could be detected in the endoplasmic reticulum around the age when behavioral disturbances develop. In summary, our novel oligomer-selective -synuclein antibodies recognize relevant pathology and should be important tools to further explore the pathogenic mechanisms in Lewy body disorders. Moreover, they could be potential candidates both for immunotherapy and as reagents in an assay to assess a potential disease biomarker.

  • 28.
    Fridlund, Jimmy
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Changes in gene expression of β-defensins in ducks infected with H1N1 avian influenza2014Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
  • 29.
    Fromell, Karin
    et al.
    Uppsala university, Sweden.
    Adler, Anna
    Uppsala university, Sweden.
    Åman, Amanda
    Uppsala university, Sweden.
    Manivel, Vivek Anand
    Uppsala university, Sweden.
    Huang, Shan
    University of Gothenburg, Sweden.
    Duhrkop, Claudia
    Uppsala university, Sweden.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. Uppsala university, Sweden.
    Nilsson, Bo
    Uppsala university, Sweden.
    Assessment of the Role of C3(H2O) in the Alternative Pathway2020In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 11, p. 1-13, article id 530Article in journal (Refereed)
    Abstract [en]

    In this study we investigate the hydrolysis of C3 to C3(H2O) and its ability to initiate activation via the alternative pathway (AP) of the complement system. The internal thioester bond within C3 is hydrolyzed by water in plasma because of its inherent lability. This results in the formation of non-proteolytically activated C3(H2O) which is believed have C3b-like properties and be able to form an active initial fluid phase C3 convertase together with Factor B (FB). The generation of C3(H2O) occurs at a low but constant rate in blood, but the formation can be greatly accelerated by the interaction with various surfaces or nucleophilic and chaotropic agents. In order to more specifically elucidate the relevance of the C3(H2O) for AP activation, formation was induced in solution by repeated freeze/thawing, methylamine or KCSN treatment and named C3(x) where the x can be any of the reactive nucleophilic or chaotropic agents. Isolation and characterization of C3(x) showed that it exists in several forms with varying attributes, where some have more C3b-like properties and can be cleaved by Factor I in the presence of Factor H. However, in common for all these variants is that they are less active partners in initial formation of the AP convertase compared with the corresponding activity of C3b. These observations support the idea that formation of C3(x) in the fluid phase is not a strong initiator of the AP. It is rather likely that the AP mainly acts as an amplification mechanism of complement activation that is triggered by deposition of target-bound C3b molecules generated by other means.

  • 30.
    Fromell, Karin
    et al.
    Uppsala University.
    Duhrkop, Claudia
    Uppsala University.
    Johansson, Ulrika
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Forms of contact-activated C3 associated with AP convertase formation2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 141-141Article in journal (Other academic)
  • 31.
    Fromell, Karin
    et al.
    Uppsala University, Sweden.
    Duhrkop, Claudia
    Uppsala University, Sweden.
    Kozarcanin, Huda
    Uppsala University, Sweden.
    Johansson, Ulrika
    Uppsala University, Sweden.
    Skjoedt, Mikkel-Ole
    Rigshosp, Denmark.
    Garred, Peter
    Rigshosp, Denmark.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    The lectin pathway of complement and the contact/kallikrein system are integrated2018In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 102, p. 151-152Article in journal (Other academic)
  • 32.
    Fromell, Karin
    et al.
    Uppsala University, Sweden.
    Johansson, Ulrika
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Duhrkop, Claudia
    Uppsala University, Sweden.
    Adler, Anna
    Uppsala University, Sweden.
    Usterud, Emma
    Uppsala University, Sweden.
    Hamad, Osama A.
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Generation of an alternative pathway convertase by contact-activated C3 is dependent on the conformation of C32018In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 102, p. 193-193Article in journal (Other academic)
  • 33.
    Gerogianni, Alexandra
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    The role of the thromboinflammatory response under hemolytic conditions: pathophysiological mechanisms and therapeutic inhibition2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In blood circulation, the complement and the coagulation cascades, together with platelets and endothelial cells form a complex network of crosstalk. When dysregulated, these interactions can lead to inflammation in combination with thrombosis (thromboinflammation) and the manifestation of pathophysiological complications. As complement activation and thromboinflammation are often associated with intravascular hemolysis, e.g., sickle cell disease (SCD), we aimed to study these reactions in relation to heme, a product of hemolysis. Furthermore, our goal was to evaluate whether exposure to biomaterials results in hemolysis-induced thromboinflammation, and to examine the potential of complement inhibition.

    Our findings show that heme could lead to a significant thromboinflammatory response in our in vitro whole blood model, as seen by complement-, cell- and coagulation- activation, as well as increased cytokine secretion. Inflammation, including complement activation, was also linked with increased heme concentrations in vivo in hemolytic disease in SCD patients. The mechanism of action was attributed to uncontrolled alternative pathway (AP) activation, as heme was shown to bind and inhibit the main AP regulator, factor I, resulting in increased concentrations of fluid phase and surface-bound C3b.

    Moreover, administration of iron oxide nanoparticles (IONPs) in vitro and implantation of left ventricular assist device (LVAD) in vivo were monitored and correlated with increased hemolytic, e.g., heme, and thromboinflammatory markers, e.g., complement-, endothelial cell- and platelet- activation. Targeting complement components C5 and C3 in vitro was shown overall beneficial in the presence of heme or IONPs respectively. In our settings, the majority of the thromboinflammatory markers measured were successfully attenuated, indicating that complement fuels this response.

    In conclusion, the results in this thesis stress that heme-induced complement activation is an important player in thromboinflammation. In addition, we propose that complement inhibition can be used as a therapeutic approach in hemolytic conditions and as a strategy to enhance biomaterials’ biocompatibility.

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  • 34.
    Gerogianni, Alexandra
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Bal, Melissa
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Woodruff, Trent M.
    University of Queensland, Australia.
    Lambris, John D.
    University of Pennsylvania, USA.
    Mollnes, Tom E.
    Oslo University Hospital, Norway;University of Oslo, Norway;Norwegian University of Science and Technology, Norway;Nordland Hospital, Norway.
    Sjöström, Dick J.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Oslo University Hospital, Norway;University of Oslo, Norway.
    In vitro evaluation of iron oxide nanoparticle-induced thromboinflammatory response using a combined human whole blood and endothelial cell model2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1101387Article in journal (Refereed)
    Abstract [en]

    Iron oxide nanoparticles (IONPs) are widely used in diagnostic and therapeutic settings. Upon systemic administration, however, they are rapidly recognized by components of innate immunity, which limit their therapeutic capacity and can potentially lead to adverse side effects. IONPs were previously found to induce the inflammatory response in human whole blood, including activation of the complement system and increased secretion of cytokines. Here, we investigated the thromboinflammatory response of 10-30 nm IONPs in lepirudin anticoagulated whole blood in interplay with endothelial cells and evaluated the therapeutic effect of applying complement inhibitors to limit adverse effects related to thromboinflammation. We found that IONPs induced complement activation, primarily at the C3-level, in whole blood incubated for up to four hours at 37°C with and without human microvascular endothelial cells. Furthermore, IONPs mediated a strong thromboinflammatory response, as seen by the significantly increased release of 21 of the 27 analyzed cytokines (p<0.05). IONPs also significantly increased cell-activation markers of endothelial cells [ICAM-1 (p<0.0001), P/E-selectin (p<0.05)], monocytes, and granulocytes [CD11b (p<0.001)], and platelets [CD62P (p<0.05), CD63 (p<0.05), NAP-2 (p<0.01), PF4 (p<0.05)], and showed cytotoxic effects, as seen by increased LDH (p<0.001) and heme (p<0.0001) levels. We found that inflammation and endothelial cell activation were partly complement-dependent and inhibition of complement at the level of C3 by compstatin Cp40 significantly attenuated expression of ICAM-1 (p<0.01) and selectins (p<0.05). We show that complement activation plays an important role in the IONPs-induced thromboinflammatory response and that complement inhibition is promising in improving IONPs biocompatibility.

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  • 35.
    Gerogianni, Alexandra
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Dimitrov, Jordan D.
    Sorbonne Univ, France.
    Zarantonello, Alessandra
    Sorbonne Univ, France.
    Poillerat, Victoria
    Sorbonne Univ, France.
    Chonat, Satheesh
    Childrens Healthcare Atlanta, USA;Emory Univ, USA.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    McAdam, Karin E.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Mollnes, Tom E.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway;Norwegian Univ Sci & Technol, Norway;Norwegian Univ Sci & Technol, Norway;Nordland Hosp, Norway.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Roumenina, Lubka T.
    Sorbonne Univ, France.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Heme Interferes With Complement Factor I-Dependent Regulation by Enhancing Alternative Pathway Activation2022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 901876Article in journal (Refereed)
    Abstract [en]

    Hemolysis, as a result of disease or exposure to biomaterials, is characterized by excess amounts of cell-free heme intravascularly and consumption of the protective heme-scavenger proteins in plasma. The liberation of heme has been linked to the activation of inflammatory systems, including the complement system, through alternative pathway activation. Here, we investigated the impact of heme on the regulatory function of the complement system. Heme dose-dependently inhibited factor I-mediated degradation of soluble and surface-bound C3b, when incubated in plasma or buffer with complement regulatory proteins. Inhibition occurred with factor H and soluble complement receptor 1 as co-factors, and the mechanism was linked to the direct heme-interaction with factor I. The heme-scavenger protein hemopexin was the main contaminant in purified factor I preparations. This led us to identify that hemopexin formed a complex with factor I in normal human plasma. These complexes were significantly reduced during acute vasoocclusive pain crisis in patients with sickle cell disease, but the complexes were normalized at their baseline outpatient clinic visit. Hemopexin exposed a protective function of factor I activity in vitro, but only when it was present before the addition of heme. In conclusion, we present a mechanistic explanation of how heme promotes uncontrolled complement alternative pathway amplification by interfering with the regulatory capacity of factor I. Reduced levels of hemopexin and hemopexin-factor I complexes during an acute hemolytic crisis is a risk factor for heme-mediated factor I inhibition.

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  • 36.
    Gerogianni, Alexandra
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Sørensen, Gro
    Oslo University Hospital, Norway.
    Nilsen Hoel, Tom
    Oslo University Hospital, Norway.
    McAdam, Karin E.
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Ludviksen, Judith A.K.
    Nordland Hospital, Norway.
    Schjalm, Camilla
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Gude, Einar
    Oslo University Hospital, Norway.
    Sjöström, Dick J.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Henriksson, Carola
    Oslo University Hospital, Norway.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Barratt-Due, Andreas
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Fiane, Arnt
    Oslo University Hospital, Norway.
    Mollnes, Tom E.
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Implantation of a continuous-flow left ventricular assist device is associated with a significant but transient acute thromboinflammatory responseManuscript (preprint) (Other academic)
  • 37.
    Grosso, Giorgia
    et al.
    Karolinska University Hospital, Sweden.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Antovic, Aleksandra
    Karolinska University Hospital, Sweden.
    Gunnarsson, Iva
    Karolinska University Hospital, Sweden.
    Zickert, Agneta
    Karolinska University Hospital, Sweden.
    Vikerfors, Anna
    Swedish Medical Products Agency, Sweden.
    Truedsson, Lennart
    Lund University Hospital, Sweden.
    Bruzelius, Maria
    Karolinska University Hospital, Sweden;Karolinska Institutet, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Svenungsson, Elisabet
    Karolinska University Hospital, Sweden.
    The Complex Relationship between C4b-Binding Protein, Warfarin, and Antiphospholipid Antibodies2021In: Thrombosis and Haemostasis, ISSN 0340-6245, E-ISSN 2567-689X, Vol. 121, no 10, p. 1299-1309Article in journal (Refereed)
    Abstract [en]

    Background Low levels of total C4b-binding protein (C4BPt), a circulating inhibitor of the classical/lectin complement pathways, were observed in patients with antiphospholipid antibodies (aPLs) and during warfarin treatment. Objectives To investigate the associations between aPL and C4BPt in patients with persistently positive (++) aPL, with/without clinical manifestations and systemic lupus erythematosus (SLE), and in controls. Furthermore, we explored the impact of anticoagulation on C4BPt and in relation to complement activation. Methods In a cross-sectional design we investigated defined subgroups: primary (p) antiphospholipid syndrome (APS, N =67), aPL++ individuals without clinical manifestations (aPL carriers, N =15), SLE-aPL++ ( N =118, among them, secondary [s] APS, N =56), aPL negative (-) SLE (SLE-aPL-, N =291), and 322 controls. Clinical characteristics, including treatment, were tabulated. C4BPt was determined with a magnetic bead method. Complement proteins (C1q, C2, C3, C4, C3a, C3dg, sC5b-9, factor I [FI]) were measured. A mediation analysis was performed to decompose the total effect of aPL++ on C4BPt into the direct and indirect effects of aPL++ through warfarin. Results Overall, C4BPt is 20% decreased in aPL++ patients, regardless of SLE, APS, clinical manifestations, and aPL profile. C4BPt levels associate positively with complement proteins C1q, C2, C3, and C4, and negatively with complement activation product C3dg. In the SLE group, warfarin treatment contributes to approximately half of the C4BPt reduction (9%) Conclusion Both aPLs and warfarin are associated with C4BPt reduction. Complement activation in aPL++ patients may partly be explained by impaired inhibition through depressed C4BPt levels. Further studies are needed to understand the clinical implications.

  • 38.
    Gustafson, Elisabet
    et al.
    Uppsala Univ Hospital, Sweden.
    Hamad, Osama A.
    Uppsala University, Sweden.
    Deckmyn, Hans
    Katholieke Univ Leuven, Belgium.
    Barbu, Andreea
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson, Bo
    Uppsala University, Sweden.
    Exposure of von Willebrand Factor on Isolated Hepatocytes Promotes Tethering of Platelets to the Cell Surface2019In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 103, no 8, p. 1630-1638Article in journal (Refereed)
    Abstract [en]

    Background. Hepatocyte transplantation (Hctx) is a potentially attractive method for the treatment of acute liver failure and liver-based metabolic disorders. Unfortunately, the procedure is hampered by the instant blood-mediated inflammatory reaction (IBMIR), a thromboinflammatory response elicited by the vascular innate immune system, causing activation of the coagulation and complement systems and clearance of transplanted cells. Observations have also revealed platelets adhered to the surface of the hepatocytes (Hc). To establish Hctx as a clinical treatment, all factors that trigger IBMIR need to be identified and controlled. This work explores the expression of von Willebrand factor (VWF) on isolated Hc resulting in tethering of platelets. Methods. VWF on Hc was studied by flow cytometry, confocal microscopy, immunoblot, and real-time polymerase chain reaction. Interaction between Hc and platelets was studied in a Chandler loop model. Adhesion of platelets to the hepatocyte surface was demonstrated by flow cytometry and confocal microscopy. Results. Isolated Hc constitutively express VWF on their cell surface and mRNA for VWF was found in the cells. Hc and platelets, independently of coagulation formed complexes, were shown by antibody blocking studies to be dependent on hepatocyte-associated VWF and platelet-bound glycoprotein Ib alpha. Conclusions. VWF on isolated Hc causes, in contact with blood, adhesion of platelets, which thereby forms an ideal surface for coagulation. This phenomenon needs to be considered in hepatocyte-based reconstitution therapy and possibly even in other settings of cell transplantation.

  • 39.
    Halbgebauer, Rebecca
    et al.
    Univ Hosp Ulm, Germany.
    Karasu, Ebru
    Univ Hosp Ulm, Germany.
    Braun, Christian K.
    Univ Hosp Ulm, Germany;Univ Hosp Ulm, Germany.
    Palmer, Annette
    Univ Hosp Ulm, Germany.
    Braumueller, Sonja
    Univ Hosp Ulm, Germany.
    Schultze, Anke
    Univ Hosp Ulm, Germany.
    Schaefer, Fabian
    Univ Hosp Ulm, Germany.
    Bueckle, Sarah
    Univ Hosp Ulm, Germany.
    Eigner, Alica
    Univ Hosp Ulm, Germany.
    Wachter, Ulrich
    Univ Ulm, Germany.
    Radermacher, Peter
    Univ Ulm, Germany.
    Resuello, Ranillo R. G.
    Simian Conservat Breeding & Res Ctr, Philippines.
    Tuplano, Joel V.
    Simian Conservat Breeding & Res Ctr, Philippines.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Armacki, Milena
    Univ Hosp Ulm, Germany.
    Kleger, Alexander
    Univ Hosp Ulm, Germany.
    Seufferlein, Thomas
    Univ Hosp Ulm, Germany.
    Kalbitz, Miriam
    Univ Hosp Ulm, Germany.
    Gebhard, Florian
    Univ Hosp Ulm, Germany.
    Lambris, John D.
    Univ Penn, USA.
    van Griensven, Martijn
    Maastricht Univ, Netherlands.
    Huber-Lang, Markus
    Univ Hosp Ulm, Germany.
    Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock2020In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 11, p. 1-12, article id 2081Article in journal (Refereed)
    Abstract [en]

    Trauma represents a major socioeconomic burden worldwide. After a severe injury, hemorrhagic shock (HS) as a frequent concomitant aspect is a central driver of systemic inflammation and organ damage. The kidney is often strongly affected by traumatic-HS, and acute kidney injury (AKI) poses the patient at great risk for adverse outcome. Recently, thirty-eight-negative kinase 1 (TNK1) was proposed to play a detrimental role in organ damage after trauma/HS. Therefore, we aimed to assess the role of TNK1 in HS-induced kidney injury in a murine and apost hocanalysis of a non-human primate model of HS comparable to the clinical situation. Mice and non-human primates underwent resuscitated HS at 30 mmHg for 60 min. 5 h after the induction of shock, animals were assessed for systemic inflammation and TNK1 expression in the kidney.In vitro, murine distal convoluted tubule cells were stimulated with inflammatory mediators to gain mechanistic insights into the role of TNK1 in kidney dysfunction. In a translational approach, we investigated blood drawn from either healthy volunteers or severely injured patients at different time points after trauma (from arrival at the emergency room and at fixed time intervals until 10 days post injury; identifier: NCT02682550,). A pronounced inflammatory response, as seen by increased IL-6 plasma levels as well as early signs of AKI, were observed in mice, non-human primates, and humans after trauma/HS. TNK1 was found in the plasma early after trauma-HS in trauma patients. Renal TNK1 expression was significantly increased in mice and non-human primates after HS, and these effects with concomitant induction of apoptosis were blocked by therapeutic inhibition of complement C3 activation in non-human primates. Mechanistically,in vitrodata suggested that IL-6 rather than C3 cleavage products induced upregulation of TNK1 and impaired barrier function in renal epithelial cells. In conclusion, these data indicate that C3 inhibitionin vivomay inhibit an excessive inflammatory response and mediator release, thereby indirectly neutralizing TNK1 as a potent driver of organ damage. In future studies, we will address the therapeutic potential of direct TNK1 inhibition in the context of severe tissue trauma with different degrees of additional HS.

  • 40. Hamad, Osama A.
    et al.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson, Bo
    Non-proteolytically activated C3 promotes binding of activated platelets and platelet-derived microparticles to leukocytes via CD11b/CD182012In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, no 11, p. 1191-1191Article in journal (Other academic)
  • 41.
    Hamad, Osama
    et al.
    Rudbeck Laboratory, University hospital, Uppsala.
    Nilsson, Per H.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Lambris, John D.
    University of Pennsylvania, USA.
    Nilsson Ekdahl, Kristina
    University of Kalmar, School of Pure and Applied Natural Sciences. Rudbeck Laboratory, University hospital, Uppsala.
    Nilsson, Bo
    Rudbeck Laboratory, University hospital, Uppsala.
    Binding of complement proteins to activated platelets is independent of complement activation2009In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 46, no 14, p. 2853-2853, article id OP95Article in journal (Refereed)
  • 42. Hancock, Viktoria
    et al.
    Huang, Shan
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson, Anders
    Grundstrom, Gunilla
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Citrate reduces complement and leukocyte activation in vitro in human blood2013In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 28, p. 207-208Article in journal (Other academic)
  • 43.
    Helin, Anu S.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Chapman, Joanne R.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science. University of Kansas, USA.
    Tolf, Conny
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Aarts, Lauren
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Bususu, Isaya
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rosengren, Johan
    University of Queensland, Australia.
    Andersson, Håkan S.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden;Karolinska Institutet, Sweden.
    Waldenström, Jonas
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Relation between structure and function of three AvBD3b variants from mallard (Anas platyrhynchos)Manuscript (preprint) (Other academic)
    Abstract [en]

    Defensins are multifunctional antimicrobial peptides expressed in several tissue types and leucocytes as part of the innate immune response against microbes. Based on the three-dimensional structure and disulfide connectivity, vertebrate defensins are subdivided into α-, β-, and θ-defensins. While all three types have been found in mammals, only β-defensins have been identified in birds. Genetic studies have revealed dozens of different avian β-defensin (AvBD) genes in different bird species, as well as allelic variation for different genes. Knowledge of the relation between avian peptide structure features and antimicrobial activity is however limited. In this study, the structure-functional relations of three variants of AvBD3b, a mallard (Anas platyrhynchos) defensin of evolutionary interest, was investigated. Gene alleles encoding two of these peptides, AvBD3b:1 and AvBD3b:2 are common in mallards, whereas AvBD3b:3 occurs rare. These β-defensin peptides were synthesized as linear peptides and subjected to oxidative folding. The three-dimensional structure of AvBD3b:1, including disulfide bond connectivity, was determined using NMR, and those of AvBD3b:2 and AvBD3b:3 respectively, were modelled using AvBD3b:1 as the template. The antimicrobial activities of folded peptides were compared to those of linear peptides. The NMR analysis showed that folded AvBD3b adopts a three-dimensional structure typical for β-defensins, including C-terminal antiparallel β-sheets and disulfide bond organization between six cysteine (C) residues: C6-C34, C13-C28, and C18-C35. Analyses of antimicrobial activity showed that both folded and linear variants of the three peptides inhibited bacterial growth. However, differences in activity were observed, suggesting that folded AvBD3b:3 was the most efficient against both Gram-negative and Gram-positive bacteria. Taken together, these findings provide additional insight into the influence of amino acid sequence variation and three-dimensional structure on the antimicrobial activity of mallard AvBD3b.

  • 44.
    Helin, Anu S.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Chapman, Joanne R.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science. University of Kansas, USA.
    Tolf, Conny
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Andersson, Håkan S.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden;Karolinska Institutet, Sweden.
    Waldenström, Jonas
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    From genes to function: variation in antimicrobial activity of avian β-defensin peptides from mallardsManuscript (preprint) (Other academic)
    Abstract [en]

    Avian β-defensins are an important class of antimicrobial peptides in birds. These short cationic peptides are directly involved in the clearance of infections by membrane disruption, but can also act as immunomodulators and chemotactic agents recruiting immune cells. Recent genomic studies have shown the presence of several different avian β-defensin (AvBD) genes across the avian phylogeny, but also significant copy number variation and occurrence of pseudogenes. In mallard (Anas platyrhynchos) and other waterfowl AvBD genes are conserved and seem to be maintained by purifying selection. Due to their relatively simple peptide structure and direct mode of action, AvBDs is a potential tractable system to investigate how small differences in the gene sequence translates into differences in immune function. Here, we used genomic information from three different mallard defensin loci (AvBD4, AvBD10 and AvBD13) and synthesized the linear peptides from the most common allele of each locus, plus two rare alleles from AvBD13 locus and measured their antimicrobial activity against Gram-negative (E. coli and S. Typhimurium) and Gram-positive (S. aureus and M. luteus) bacteria. In these assays, AvBD4 showed the most potent antibacterial activity against both Gram-negative and Gram-positive bacteria, with an IC50 value of 0.48 mM against S. Typhimurium. Among AvBD13 peptides, the less frequently observed AvBD13:2 variant, was most potent, with IC50 value against S. aureus approximately 15 times lower than that of the most common AvBD13:1. Interestingly, AvBD10 had no antibacterial effect on the tested bacteria. Thus, antimicrobial function varied substantially among loci, but also within the AvBD13 locus, suggesting a direct link between genetic variation and immune function variation. Interestingly, results from assays with AvBD4 and AvBD13 seem to indicate that a higher positive net charge in peptides is associated with a more potent antibacterial effect.

  • 45.
    Helin, Anu S.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Wille, Michelle
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Atterby, Clara
    Uppsala University, Sweden.
    Jarhult, Josef D.
    Uppsala University, Sweden.
    Waldenström, Jonas
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Chapman, Joanne R.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science. Univ Kansas, USA.
    A rapid and transient innate immune response to avian influenza infection in mallards2018In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 95, p. 64-72Article in journal (Refereed)
    Abstract [en]

    The vertebrate innate immune system provides hosts with a rapid, non-specific response to a wide range of invading pathogens. However, the speed and duration of innate responses will be influenced by the co-evolutionary dynamics of specific host-pathogen combinations. Here, we show that low pathogenic avian influenza virus (LPAI) subtype H1N1 elicits a strong but extremely transient innate immune response in its main wildlife reservoir, the mallard (Anas platyrhynchos). Using a series of experimental and methodological improvements over previous studies, we followed the expression of retinoic acid inducible gene 1 (RIG-I) and myxovirus resistance gene (Mx) in mallards semi-naturally infected with low pathogenic H1N1. One day post infection, both RIG-I and Mx were significantly upregulated in all investigated tissues. By two days post infection, the expression of both genes had generally returned to basal levels, and remained so for the remainder of the experiment. This is despite the fact that birds continued to actively shed viral particles throughout the study period. We additionally show that the spleen plays a particularly active role in the innate immune response to LPAI. Waterfowl and avian influenza viruses have a long co-evolutionary history, suggesting that the mallard innate immune response has evolved to provide a minimum effective response to LPAIs such that the viral infection is brought under control while minimising the damaging effects of a sustained immune response.

  • 46.
    Helin, Anu S.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Wille, Michelle
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Atterby, Clara
    Uppsala University, Sweden.
    Jarhult, Josef
    Uppsala University, Sweden.
    Waldenström, Jonas
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Chapman, Joanne R.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science. Univ Kansas, USA.
    Expression of immune genes RIG-I and Mx in mallard ducks infected with low pathogenic avian influenza (LPAI): A dataset2018In: Data in Brief, E-ISSN 2352-3409, Vol. 18, p. 1562-1566Article in journal (Refereed)
    Abstract [en]

    This article provides data on primer sequences used to amplify the innate immune genes RIG-I and Mx and a set of normalizing reference genes in mallards (Anal platyrhynchos), and shows which reference genes are stable, per tissue, for our experimental settings. Data on the expressional changes of these two genes over a time-course of infection with low pathogenic avian influenza virus (LPAI) are provided. Individual-level data are also presented, including LPAI infection load, and per tissue gene expression of RIG-I and Mx. Gene expression in two outlier individuals is explored in more depth. (C) 2018 The Authors. Published by Elsevier Inc.

  • 47.
    Huang, Shan
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson, Per H.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Elmlund, Louise
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Regulation of complement in whole blood by heparin molecularly imprinted polymer particles2012In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, no 11, p. 1199-1199Article in journal (Other academic)
  • 48.
    Huang, Shan
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Jonsson, Nina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rorsman, Fredrik
    Uppsala University Hospital.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    An assay to monitor in vitro generation of non-proteolytically activated C3 in human plasmaManuscript (preprint) (Other academic)
  • 49.
    Huang, Shan
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    iC3 generation elicited by the presence of ammonia and urea in human plasma2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 145-145Article in journal (Other academic)
  • 50.
    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.

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