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  • 1.
    Aeinehband, Shahin
    et al.
    Karolinska Institutet.
    Lindblom, Rickard P. F.
    Karolinska Institutet.
    Al Nimer, Faiez
    Karolinska Institutet.
    Vijayaraghavan, Swetha
    Karolinska Institutet.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Khademi, Mohsen
    Karolinska Institutet.
    Olsson, Tomas
    Karolinska Institutet.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). 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 Sclerosis2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 4, artikel-id e0122048Artikel i tidskrift (Refereegranskat)
    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.

  • 2.
    Bergman, Ingrid-Maria
    et al.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Juul-Madsen, Helle R.
    Heegaard, Peter M.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Edfors, Inger
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    MBL-A concentrations and MBL1 genotypes in European wild boars, Large White pigs, and wild boar/Large White crossbreds2010Ingår i: 8th European Colloquium on Acute Phase Proteins in Helsinki, 2010.08.25-2010.08.27, 2010, s. 25-26Konferensbidrag (Refereegranskat)
  • 3.
    Bergman, Ingrid-Maria
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Aarhus University, Denmark.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala university.
    Okumura, Naohiko
    Institute of Society for Techno-innovation of Agriculture, Japan.
    Uenishi, Hirohide
    National Institute of Agrobiological Sciences, Japan.
    Guldbrandtsen, Bernt
    Aarhus University, Denmark.
    Essler, Sabine
    Univ of Veterinary Medicine, Austria.
    Knoll, Ales
    Mendel University, Czech Republic.
    Heegaard, Peter
    Technical University of Denmark, Denmark.
    Edfors, Inger
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Juul-Madsen, Helle
    Aarhus University, Denmark.
    MBL1 genotypes in wild boar populations from Sweden, Austria, the Czech Republic and Japan2013Ingår i: International Journal of Immunogenetics, ISSN 1744-3121, E-ISSN 1744-313X, Vol. 40, nr 2, s. 131-139Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The single nucleotide polymorphism (SNP) G949T in the mannose-binding lectin (MBL) 1 gene has been associated with low MBL-A concentration in serum and detected at different frequencies in various European pig populations. However, the origin of this SNP is not known. Part of the MBL1 gene was sequenced in 12 wild boar/Large White crossbred pigs from the second backcross (BC 2) generation in a family material originating from two wild boar x Large White intercrosses. Also, MBL-A serum concentration was measured in the entire BC 2 generation (n = 45). Furthermore, the genotypes of 68 wild boars from Sweden, Austria, the Czech Republic, and Japan were determined in regard to five previously described SNPs in MBL1. The T allele of G949T was present among the BC 2 animals. MBL-A serum concentration in the BC 2 animals showed a bimodal distribution, with one-third of the animals at levels between 0.7 and 1.6 μg mL−1 and the remaining pigs at levels around 13 μg mL−1. There was a co-variation between the presence of the T allele and low MBL-A concentration in serum. The genotyping of the wild boars revealed differences between populations. The T allele of G949T was not detected in the Austrian and Japanese samples and is thus unlikely to be an original feature of wild boars. In contrast, it was present at high frequency (0.35) among the Swedish wild boars, probably representing a founder effect. Five MBL1 haplotypes were resolved. Only two of these were present among the Japanese wild boars compared to four in each of the European populations. This difference may reflect differences in selection pressure and population history.

  • 4.
    Bexborn, Fredrik
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Engberg, Anna E.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Sandholm, Kerstin
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Mollnes, Tom Eirik
    Hong, Jaan
    Nilsson Ekdahl, Kristina
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Hirudin versus heparin for use in whole blood in vitro biocompatibility models2009Ingår i: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 89A, nr 4, s. 951-959Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Heparin has traditionally been a widely used anticoagulant in blood research, but has been shown to be inappropriate for work with the complement system because of its complement-interacting properties. In this work, we have compared the effects of heparin with those of the specific thrombin inhibitor hirudin on complement and blood cells in vitro.

    Methods: Whole blood collected in the presence of hirudin (50 µg/mL) or heparin (1 IU/mL) was incubated in the slide chamber model. The plasma was analyzed for complement activation markers C3a and sC5b-9, and the polyvinylchloride test slides were stained for adhering cells. The integrity of the complement system was tested by incubating serum and hirudin-treated plasma in the presence of various activating agents.

    Results: In contrast to heparin, the addition of hirudin generally preserved the complement reactivity, and complement activation in hirudin plasma closely resembled that in normal serum. Importantly, immunochemical staining of surface-bound cells demonstrated the inducible expression of tissue factor on bound monocytes from hirudin-treated blood, an effect that was completely abolished in heparin-treated blood.

    Conclusion: Our results indicate that hirudin as an anticoagulant produces more physiological conditions than heparin, making hirudin well-suited for in vitro studies, especially those addressing the regulation of cellular processes.

  • 5. Boij, Roland
    et al.
    Svensson, Judit
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Lindahl, Tomas
    Palonek, Elzbieta
    Garle, Mats
    Berg, Mats
    Ernerudh, Jan
    Jenmalm, Mats
    Matthiesen, Leif
    Biomarkers of coagulation, inflammation and angiogenesis are independently associated with preeclampsia2012Ingår i: American Journal of Reproductive Immunology and Microbiology, ISSN 8755-8920, Vol. 68, nr 3, s. 258-270Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Problem Although preeclampsia has been associated with inflammation, coagulation, and angiogenesis, their correlation and relative contribution are unknown. Method of Study About 114 women with preeclampsia, 31 with early onset (EOP) and 83 with late onset preeclampsia (LOP), and 100 normal pregnant controls were included. A broad panel of 32 biomarkers reflecting coagulation, inflammation, and angiogenesis was analyzed. Results Preeclampsia was associated with decreased antithrombin, IL-4 and placental growth factor levels and with increased C3a, pentraxin-3, and sFlt-1 levels, with more marked differences in the EOP group. The Th1-associated chemokines CXCL10 and CXCL11 were significantly higher in the preeclampsia and EOP group than in controls, respectively. No correlations between the biomarkers were found in preeclampsia. Multivariate logistic regression tests confirmed the results. Conclusions Cytokines, chemokines and complement activation seem to be part of a Th1-like inflammatory reaction in preeclampsia, most pronounced in EOP, where chemokines may be more useful than cytokines as biomarkers. Biomarkers were not correlated suggesting partly independent or in time separated mechanisms.

  • 6.
    Carlsson, Hanna
    et al.
    Kalmar County Hospital.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Tjernberg, Ivar
    Kalmar County Hospital.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Complement activation in asymptomatic Lyme borreliosis and neuroborreliosis2015Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, nr 1, s. 128-128Artikel i tidskrift (Övrigt vetenskapligt)
  • 7.
    Ekstrand-Hammarström, Barbro
    et al.
    Swedish Def Res Agcy, Linköping.
    Hong, Jaan
    Uppsala University.
    Davoodpour, Padideh
    Uppsala University.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Bucht, Anders
    Umeå University.
    Nilsson, Bo
    Uppsala University.
    TiO2 nanoparticles tested in a novel screening whole human blood model of toxicity trigger adverse activation of the kallikrein system at low concentrations2015Ingår i: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 51, s. 58-68Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    There is a compelling need to understand and assess the toxicity of industrially produced nanoparticles (NPs). In order to appreciate the long-term effects of NPs, sensitive human-based screening tests that comprehensively map the NP properties are needed to detect possible toxic mechanisms. Animal models can only be used in a limited number of test applications and are subject to ethical concerns, and the interpretation of experiments in animals is also distorted by the species differences. Here, we present a novel easy-to-perform highly sensitive whole-blood model using fresh non-anticoagulated human blood, which most justly reflects complex biological cross talks in a human system. As a demonstrator of the tests versatility, we evaluated the toxicity of TiO2 NPs that are widely used in various applications and otherwise considered to have relatively low toxic properties. We show that TiO2 NPs at very low concentrations (50 ng/mL) induce strong activation of the contact system, which in this model elicits thromboinflammation. These data are in line with the finding of components of the contact system in the protein corona of the TiO2 NPs after exposure to blood. The contact system activation may lead to both thrombotic reactions and generation of bradykinin, thereby representing fuel for chronic inflammation in vivo and potentially long-term risk of autoimmunity, arteriosclerosis and cancer. These results support the notion that this novel whole-blood model represents an important contribution to testing of NP toxicity. (C) 2015 Elsevier Ltd. All rights reserved.

  • 8.
    Engberg, Anna E.
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Region Skåne.
    Nilsson, Per H.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Oslo Univ Hosp, Rikshosp, Norway;Univ Oslo, Norway.
    Huang, Shan
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Fromell, Karin
    Uppsala University.
    Hamad, Osama A.
    Uppsala University.
    Mollnes, Tom Eirik
    Univ Oslo, Norway;Univ Tromsö, Norway.
    Rosengren-Holmberg, Jenny P.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Swedish Natl Lab Forens Sci, Linköping.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Teramura, Yuji
    Uppsala University;Univ Tokyo, Japan.
    Nicholls, Ian A.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma2015Ingår i: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 36, s. 55-65Artikel i tidskrift (Refereegranskat)
    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.

  • 9.
    Engberg, Anna E.
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Nilsson, Per H.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Univ Oslo, Rikshosp, Univ Hosp, Norway.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Huang, Shan
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Mollnes, T. E.
    Nicholls, Ian A.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Nilsson, Bo
    Uppsala university.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala university.
    The ratio between C4 and C4BP adsorbed to artificial materials is a new predictor for biocompatibility2013Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 56, nr 3, s. 309-309Artikel i tidskrift (Övrigt vetenskapligt)
  • 10.
    Engberg, Anna E.
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Sandholm, Kerstin
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Bexborn, Fredrik
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Persson, Jenny
    Lund University.
    Nilsson, Bo
    Uppsala University.
    Lindahl, Gunnar
    Lund University.
    Nilsson Ekdahl, Kristina
    Högskolan i Kalmar, Naturvetenskapliga institutionen. Uppsala University.
    Inhibition of complement activation on a model biomaterial surface by streptococcal M protein-derived peptides2009Ingår i: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 30, nr 13, s. 2653-2659Artikel i tidskrift (Refereegranskat)
    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.

  • 11.
    Huang, Shan
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Engberg, Anna E.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). University and Regional Laboratories Region Skåne.
    Jonsson, Nina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Nicholls, Ian A.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Mollnes, Tom Eirik
    Oslo University Hospital Rikshopsitalet, Norway;University of Oslo, Norway;Nordland Hospital, Norway; University of Tromsø, Norway;Norwegian University of Science and Technology, Norway.
    Fromell, Karin
    Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Reciprocal relationship between contact and complement system activation on artificial polymers exposed to whole human blood.2016Ingår i: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 77, s. 111-119Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Inappropriate and uncontrolled activation of the cascade systems in the blood is a driving force in adverse inflammatory and thrombotic reactions elicited by biomaterials, but limited data are available on the activation of the contact system by polymers and the present study was undertaken to investigate these mechanisms in established models.

    METHODS: Polymer particles were incubated in (1) EDTA-plasma (10 mM) to monitor the adsorption of 20 selected proteins; (2) lepirudin-anticoagulated plasma to evaluate contact system activation, monitored by the formation of complexes between the generated proteases factor[F]XIIa, FXIa and kallikrein and the serpins C1-inhibitor [C1INH] and antithrombin [AT]; (3) lepirudin-anticoagulated whole blood to determine cytokine release.

    RESULTS: Strong negative correlations were found between 10 cytokines and the ratio of deposited FXII/C1INH, generated FXIIa-C1INH complexes, and kallikrein-C1INH complexes. Formation of FXIIa-C1INH complexes correlated negatively with the amount of C3a and positively with deposited IgG.

    CONCLUSIONS: A reciprocal relationship was found between activation of the contact system and the complement system induced by the polymers studied here. The ratios of FXII/C1INH or C4/C4BP, adsorbed from EDTA-plasma are useful surrogate markers for cytokine release and inflammatory response to materials intended for blood contact.

  • 12.
    Huang, Shan
    et al.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Nilsson, Per H.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Elmlund, Louise
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Nicholls, Ian A.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Regulation of complement in whole blood by heparin molecularly imprinted polymer particles2012Ingår i: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, nr 11, s. 1199-1199Artikel i tidskrift (Övrigt vetenskapligt)
  • 13.
    Huang, Shan
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Jonsson, Nina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Nilsson, Anders
    Gambro Lundia AB.
    Wieslander, Anders
    Gambro Lundia AB.
    Grundström, Gunilla
    Gambro Lundia AB.
    Hancock, Viktoria
    Gambro Lundia AB.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Low concentrations of citrate reduce complement and granulocyte activation in vitro in human blood2015Ingår i: Clinical Kidney Journal, ISSN 2048-8505, E-ISSN 2048-8513, Vol. 8, nr 1, s. 31-37Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND:The use of acetate in haemodialysis fluids may induce negative effects in patients including nausea and increased inflammation. Therefore, haemodialysis fluids where acetate is substituted with citrate have recently been developed. In this study, we investigated the biocompatibility of citrate employing concentrations used in haemodialysis.

    METHODS:The effects of citrate and acetate were investigated in human whole blood in vitro under conditions promoting biomaterial-induced activation. Complement activation was measured as generation of C3a, C5a and the sC5b-9 complex, and granulocyte activation as up-regulation of CD11b expression. For the experimental set-up, a mathematical model was created to calculate the concentrations of acetate and citrate attained during haemodialysis.

    RESULTS:Citrate reduced granulocyte activation and did not induce higher complement activation compared with acetate at concentrations attained during haemodialysis. Investigating different citrate concentrations clearly showed that citrate is a potent complement inhibitor already at low concentrations, i.e. 0.25 mM, which is comparable with concentrations detected in the blood of patients during dialysis with citrate-containing fluids. Increased citrate concentration up to 6 mM further reduced the activation of C3a, C5a and sC5b-9, as well as the expression of CD11b.

    CONCLUSIONS:Our results suggest that citrate is a promising substitute for acetate for a more biocompatible dialysis, most likely resulting in less adverse effects for the patients.

  • 14.
    Huang, Shan
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Jonsson, Nina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Rorsman, Fredrik
    Uppsala University Hospital.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    An assay to monitor in vitro generation of non-proteolytically activated C3 in human plasmaManuskript (preprint) (Övrigt vetenskapligt)
  • 15.
    Huang, Shan
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    iC3 generation elicited by the presence of ammonia and urea in human plasma2015Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, nr 1, s. 145-145Artikel i tidskrift (Övrigt vetenskapligt)
  • 16.
    Kozarcanin, H.
    et al.
    Uppsala University.
    Lood, C.
    Skåne University Hospital;Lund University.
    Munthe-Fog, L.
    University of Copenhagen, Denmark.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Hamad, O. A.
    Uppsala University.
    Bengtsson, A. A.
    Skåne University Hospital;Lund University.
    Skjoedt, M. -O
    University of Copenhagen, Denmark.
    Huber-Lang, M.
    University Hospital of Ulm, Germany.
    Garred, P.
    University of Copenhagen, Denmark.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Nilsson, Bo
    Uppsala University.
    The lectin complement pathway serine proteases (MASPs) represent a possible crossroad between the coagulation and complement systems in thromboinflammation2016Ingår i: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 14, nr 3, s. 531-545Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The lectin pathway's MASP-1/2 activates coagulation factors but the trigger of the activation is unknown. MASP-1/2 activation was assessed by quantifying complexes between MASPs and antithrombin/C1-inhibitor. Activated platelets and fibrin were demonstrated to activate MASP-1 and MASP-2 both invitro and invivo. These findings may represent a crossroad between the complement and the coagulation systems. Summary Background The activated forms of the complement lectin pathway (LP) proteases MASP-1 and MASP-2 are able to cleave the coagulation factors prothrombin, fibrinogen, factor XIII and thrombin-activatable fibrinolysis inhibitor invitro. In vivo studies also show that MASP-1 is involved in thrombogenesis. Objectives To clarify the not yet identified mechanisms involved in triggering activation of the LP during thrombotic reactions. Methods Novel sandwich-ELISAs for detection of complexes between MASP-1 or MASP-2 and the serpins C1 inhibitor (C1-INH) or antithrombin (AT), were used to specifically detect and quantify the activated forms of MASP-1 and MASP-2. Results Activated platelets were shown by flow cytometry to bind Ficolin-1, -2 and -3 but not MBL, which was associated with activation of MASP-1 and MASP-2. We also demonstrated that fibrin and the plasmin-generated fibrin fragment DD in plasma, bind and activate MASP-1 and MASP-2. As demonstrated by the ELISA and SDS-PAGE/Western blotting, the fibrin-associated activation was reflected in a specific inactivation by AT during clotting without the assistance of heparin. In all other cases the MASPs were, as previously reported, inactivated by C1-INH. In systemic lupus erythematosus patients with thrombotic disease and in polytrauma patients, the levels of activated MASP-1 and MASP-2 in complex with both AT and C1-INH were associated with markers of thrombotic disease and contact/coagulation system activation. Conclusions MASP-1 and MASP-2 are activated during blood clotting. This activation is triggered by activated platelets and by the generation of fibrin during thrombotic reactions invitro and invivo, and may represent a novel activation/amplification mechanism in thromboinflammation.

  • 17.
    Kozarcanin, Huda
    et al.
    Uppsala University.
    Lood, Christian
    Skåne Univ Hosp, Sweden;Lund Univ, Sweden.
    Munthe-Fog, Lea
    Univ Copenhagen, Denmark.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Hamad, Osama
    Uppsala University.
    Skjoedt, Mikkel-Ole
    Univ Copenhagen, Denmark.
    Bengtsson, Anders
    Skåne Univ Hosp, Sweden;Lund Univ, Sweden.
    Huber-Lang, Markus
    Univ Hosp Ulm, Germany.
    Garred, Peter
    Univ Copenhagen, Denmark.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Nilsson, Bo
    Uppsala University.
    The lectin complement pathway serine proteases bridges the complement and the coagulation systems in thrombotic diseases2015Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, nr 1, s. 153-153Artikel i tidskrift (Övrigt vetenskapligt)
  • 18.
    Labriere, Christophe
    et al.
    UiT Arctic Univ Norway, Norway;Univ Aberdeen, UK.
    Kondori, Nahid
    University of Gothenburg.
    Caous, Josefin Seth
    RISE Res Inst Sweden.
    Boomgaren, Marc
    UiT Arctic Univ Norway, Norway.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Hansen, Jorn H.
    UiT Arctic Univ Norway, Norway.
    Svenson, Johan
    UiT Arctic Univ Norway, Norway;RISE Res Inst Sweden.
    Development and evaluation of cationic amphiphilic antimicrobial 2,5-diketopiperazines2018Ingår i: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 24, nr 7, artikel-id UNSP e3090Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Both pathogenic bacteria and fungi are developing resistance to common antimicrobial treatment at an alarming rate. To counteract this development, it is of essence to develop new classes of antimicrobial agents. One such class is antimicrobial peptides, most of which are derived from the innate immune system. In this study, a series of novel 2,5-diketopiperazines were designed, synthesized, and evaluated for their antimicrobial abilities. The compounds were designed to probe the pharmacophore dictated for short linear mimics of antimicrobial cationic peptides, and as such, the compounds contain a range of cationic and hydrophobic functionalities. Several of the prepared compounds displayed high antimicrobial activities toward bacteria and also against human pathogenic fungi. Of particular interest was the high activity toward fungal strains with an inherent increased resistance toward conventional antifungal agents. The most effective compounds displayed inhibition of Candida glabrata and Candida krusei growth at concentrations between 4 and 8 mu g/mL, which is comparable to commercial antifungal agents in use. Structure activity relationship studies revealed a similar dependence on cationic charge and the volume of the hydrophobic bulk as for linear cationic antimicrobial peptides. Finally, the hemolytic activity of selected compounds was evaluated, which revealed a potential to produce active compounds with attenuation of unwanted hemolysis. The findings highlight the potential of cyclic cationic amphiphilic peptidomimetics as a class of promising compounds for the treatment of infections caused by microorganisms with an increased resistance to conventional antimicrobial agents.

  • 19.
    Lindblom, Rickard P. F.
    et al.
    Karolinska Institutet;Uppsala University.
    Aeinehband, Shainn
    Karolinska Institutet.
    Ström, Mikael
    Karolinska Institutet.
    Al Nimer, Faiez
    Karolinska Institutet.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Khademi, Mohsen
    Karolinska Institutet.
    Nilsson, Bo
    Uppsala University.
    Piehl, Fredrik
    Karolinska Institutet.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Complement receptor 2 is increased in cerebrospinal fluid of multiple sclerosis patients and regulates C3 function2016Ingår i: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 166, s. 89-95Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Besides its vital role in immunity, the complement system also contributes to the shaping of the synaptic circuitry of the brain. We recently described that soluble Complement Receptor 2 (sCR2) is part of the nerve injury response in rodents. We here study CR2 in context of multiple sclerosis (MS) and explore the molecular effects of CR2 on C3 activation.

    Significant increases in sCR2 levels were evident in cerebrospinal fluid (CSF) from both patients with relapsing-remitting MS (n = 33; 6.2 ng/mL) and secondary-progressive MS (n = 9; 7.0 ng/mL) as compared to controls (n = 18; 4.1 ng/mL). Furthermore, CSF sCR2 levels correlated significantly both with CSF C3 and C1q as well as to a disease severity measure. In vitro, sCR2 inhibited the cleavage and down regulation of C3b to iC3b, suggesting that it exerts a modulatory role in complement activation downstream of C3.

    These results propose a novel function for CR2/sCR2 in human neuroinflammatory conditions.

  • 20.
    Mohlin, Camilla
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Petrus-Reurer, S.
    Karolinska Institutet;Karolinska Univ Hosp.
    Lanner, F.
    Karolinska Institutet;Karolinska Univ Hosp.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Kvanta, A.
    Karolinska Institutet.
    Nilsson, B.
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Complement system proteins in human embryonic stem cell-derived retinal pigment epithelial cells co-cultured with or without porcine retina2017Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, s. 162-163Artikel i tidskrift (Övrigt vetenskapligt)
  • 21.
    Mohlin, Camilla
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Petrus-Reurer, Sandra
    Karolinska Institutet;Karolinska University Hospital.
    Lanner, Fredrik
    Karolinska Institutet;Karolinska University Hospital.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Nilsson, Per H.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Univ Oslo, Norway.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Is the polarized secretion of complement factor H of importance in age-related macular degeneration?2018Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 59, nr 9Artikel i tidskrift (Övrigt vetenskapligt)
  • 22.
    Mohlin, Camilla
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Kvanta, Anders
    Karolinska institutet.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala university.
    Johansson, Kjell
    Örebro university.
    A model to study complement involvement in experimental retinal degeneration.2018Ingår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, nr 1, s. 28-42Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The complement system (CS) plays a role in the pathogenesis of a number of ocular diseases, including diabetic retinopathy (DR), glaucoma, uveitis, and age-related macular degeneration (AMD). Given that many of the complex eye-related degenerative diseases have limited treatment opportunities, we aimed to mimic the in vivo retinal degenerative process by developing a relevant co-culture system.

    METHOD AND MATERIALS: The adult porcine retina was co-cultured with the spontaneously arising human retinal pigment epithelial cells-19 (ARPE-19).

    RESULTS: Inflammatory activity was found after culture and included migrating microglial cells, gliosis, cell death, and CS activation (demonstrated by a minor increase in the secreted anaphylotoxin C3a in co-culture). CS components, including C1q, C3, C4, soluble C5b-9, and the C5a receptor, were expressed in the retina and/or ARPE cells after culture. C1q, C3, and CS regulators such as C4 binding protein (C4BP), factor H (CFH), and factor I (CFI) were secreted after culture.

    DISCUSSION: Thus, our research indicates that this co-culturing system may be useful for investigations of the CS and its involvement in experimental neurodegenerative diseases.

  • 23.
    Mohlin, Camilla
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    The link between morphology and complement in ocular disease2017Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, s. 84-99Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The complement system is a vital component of the immune-priveliged human eye that is always active at a low-grade level, preventing harmful intraocular injuries caused by accumulation of turnover products and controlling pathogens to preserve eye homeostasis and vision. The complement system is a double-edged sword that is essential for protection but may also become harmful and contribute to eye pathology. Here, we review the evidence for the involvement of complement system dysregulation in age-related macular degeneration, glaucoma, uveitis, and neuromyelitis optica, highlighting the relationship between morphogical changes and complement system protein expression and regulation in these diseases. The potential benefits of complement inhibition in age-related macular degeneration, glaucoma, uveitis, and neuromyelitis optica are abundant, as are those of further research to improve our understanding of complement-mediated injury in these diseases.

  • 24.
    Nilsson Ekdahl, Kristina
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Blomberg, Carolina
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Henningsson Johnsson, Anna
    Dahle, Charlotte
    Håkansson, Irene
    Sandholm, Kerstin
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Ernerudh, Jan
    Systemic and Intrathecal Complement Activation in Multiple Sclerosis and Guillan-Barré Syndrome2009Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 46, nr 14, s. 2848-2848Artikel i tidskrift (Refereegranskat)
  • 25.
    Nilsson Ekdahl, Kristina
    et al.
    Uppsala University.
    Henningsson, A. J
    Ryhov County Hospital.
    Sandholm, Kerstin
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Forsberg, Pia
    Linköping University.
    Ernerudh, Jan
    Linköping University.
    Ekerfelt, Christina
    Linköping University.
    Immunity in borreliosis with special emphasis on the role of complement2007Ingår i: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 598, s. 198-213Artikel i tidskrift (Refereegranskat)
  • 26.
    Nilsson Ekdahl, Kristina
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala university, Sweden.
    Mohlin, Camilla
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Adler, Anna
    Uppsala university, Sweden.
    Aman, Amanda
    Uppsala university, Sweden.
    Manivel, Vivek Anand
    Uppsala university, Sweden.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Huber-Lang, Markus
    Univ Hosp Ulm, Germany.
    Fromell, Karin
    Uppsala university, Sweden.
    Nilsson, Bo
    Uppsala university, Sweden.
    Is generation of C-3(H2O) necessary for activation of the alternative pathway in real life?2019Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 114, s. 353-361Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In the alternative pathway (AP) an amplification loop is formed, which is strictly controlled by various fluid-phase and cell-bound regulators resulting in a state of homeostasis. Generation of the "C3b-like" C3(H2O) has been described as essential for AP activation, since it conveniently explains how the initial fluid-phase AP convertase of the amplification loop is generated. Also, the AP has a status of being an unspecific pathway despite thorough regulation at different surfaces. During complement attack in pathological conditions and inflammation, large amounts of C3b are formed by the classical/lectin pathway (CP/LP) convertases. After the discovery of LP's recognition molecules and its tight interaction with the AP, it is increasingly likely that the AP acts in vivo mainly as a powerful amplification mechanism of complement activation that is triggered by previously generated C3b molecules initiated by the binding of specific recognition molecules. Also in many pathological conditions caused by a dysregulated AP amplification loop such as paroxysmal nocturnal hemoglobulinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), C3b is available due to minute LP and CP activation and/or generated by non-complement proteases. Therefore, C3(H2O) generation in vivo may be less important for AP activation during specific attack or dysregulated homeostasis, but may be an important ligand for C3 receptors in cell-cell interactions and a source of C3 for the intracellular complement reservoir.

  • 27.
    Nilsson Ekdahl, Kristina
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Persson, Barbro
    Uppsala University.
    Mohlin, Camilla
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Skattum, Lillemor
    Lund University.
    Nilsson, Bo
    Uppsala University.
    Interpretation of Serological Complement Biomarkers in Disease2018Ingår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, artikel-id 2237Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

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

  • 28.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Development and evaluation of immunoassays for complement diagnostics2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Laboratory analyses of human body fluids play an important role in clinical diagnosis. This thesis comprises projects in which various immune assays have been developed and evaluated as complement diagnostics in both plasma and cerebrospinal fluid (CSF). Various methods have been used, such as ELISA, Western blot, flow cytometry, and xMAP technology.

    In paper 1, we monitored complement parameters in EDTA-plasma and CSF from patients with suspected neuroborreliosis (NB) by using in-house sandwich ELISAs.  We found significantly elevated levels of C1q, C4, C3, and C3a in CSF, but not in plasma, suggesting that complement plays a role in the intrathecal immune response in NB.

    Complement is a main player in early inflammation, and in paper 2, we investigated the role of complement activation in phagocytosis and the release of cytokines and chemokines in response to two clinical isolates: Borrelia afzelii K78 and Borrelia garinii LU59. Our results show that complement activation plays an important role in the initial process of phagocytosis, but not in the subsequent cytokine release that occurs in response to live Borrelia spirochetes. C1q, a valuable biomarker of disease activity in systemic lupus erythematosus (SLE), can be quantitated using a number of different immunochemical techniques.

    In paper 3, we developed and validated a magnetic bead-based immunoassay for quantifying C1q in EDTA-plasma and CSF. In contrast to soluble immunoprecipitation assays such as nephelometry and turbidimetry, this new assay was not hampered by the interaction between C1q and detecting antibodies. The novel assay was shown to give a clear correlation between nephritis and SLEDAI score in SLE.

    Warfarin is a commonly used but complicated treatment in patients with thrombosis. It reduces the function of vitamin K-dependent coagulation proteins, including protein S, which is a ligand for C4b-binding protein (C4BP). In paper 4, we demonstrated a decrease in various isoforms of C4BP that resulted in a strong complement activation in patients treated with warfarin, but not in patients treated with other anticoagulants.

    Taken together, the results from the papers included in this thesis stress the importance of validated assays with high sensitivity and specificity in enabling accurate diagnosis in patients with various inflammatory diseases.

  • 29.
    Sandholm, Kerstin
    et al.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Henningsson, Anna J.
    Bergstrom, Sven
    Ernerudh, Jan
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Complement activation and phagocytosis in vitro of two strains of Borrelia burgdorferi S.L2012Ingår i: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, nr 11, s. 1153-1153Artikel i tidskrift (Övrigt vetenskapligt)
  • 30.
    Sandholm, Kerstin
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Henningsson, Anna J.
    Linköping University.
    Säve, Susanne
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Bergström, Sven
    Umeå University.
    Forsberg, Pia
    Linköping University.
    Jonsson, Nina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Ernerudh, Jan
    Linköping University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Early Cytokine Release in Response to Live Borrelia burgdorferi Sensu Lato Spirochetes Is Largely Complement Independent2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 9, s. e108013-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim: Here we investigated the role of complement activation in phagocytosis and the release of cytokines and chemokines in response to two clinical isolates: Borrelia afzelii K78, which is resistant to complement-mediated lysis, and Borrelia garinii LU59, which is complement-sensitive. Methods: Borrelia spirochetes were incubated in hirudin plasma, or hirudin-anticoagulated whole blood. Complement activation was measured as the generation of C3a and sC5b-9. Binding of the complement components C3, factor H, C4, and C4BP to the bacterial surfaces was analyzed. The importance of complement activation on phagocytosis, and on the release of cytokines and chemokines, was investigated using inhibitors acting at different levels of the complement cascade. Results: 1) Borrelia garinii LU59 induced significantly higher complement activation than did Borrelia afzelii K78. 2) Borrelia afzelii K78 recruited higher amounts of factor H resulting in significantly lower C3 binding. 3) Both Borrelia strains were efficiently phagocytized by granulocytes and monocytes, with substantial inhibition by complement blockade at the levels of C3 and C5. 4) The release of the pro-inflammatory cytokines and chemokines IL-1 beta, IL-6, TNF, CCL20, and CXCL8, together with the anti-inflammatory IL-10, were increased the most (by>10-fold after exposure to Borrelia). 5) Both strains induced a similar release of cytokines and chemokines, which in contrast to the phagocytosis, was almost totally unaffected by complement blockade. Conclusions: Our results show that complement activation plays an important role in the process of phagocytosis but not in the subsequent cytokine release in response to live Borrelia spirochetes.

  • 31.
    Sandholm, Kerstin
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Persson, Barbro
    Uppsala University.
    Skattum, Lillemor
    Lund University.
    Eggertsen, Gösta
    Karolinska Institutet;Karolinska University Hospital.
    Nyman, Dag
    Aland Cent Hosp, Finland.
    Gunnarsson, Iva
    Karolinska Institutet;Karolinska University Hospital.
    Svenungson, Elisabet
    Karolinska Institutet;Karolinska University Hospital.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Evaluation of a Novel Immunoassay for Quantification of C1q for Clinical Diagnostic Use2019Ingår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, artikel-id 7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 32.
    Sandholm, Kerstin
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Wijkstrom, Elisabeth
    University Hospital, Uppsala.
    Skattum, Lillemor
    Lund University.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Validations of assays for the evaluation of C1q in inflammatory diseases and thromboinflammation2015Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, nr 1, s. 176-177Artikel i tidskrift (Övrigt vetenskapligt)
  • 33.
    Tjernberg, Anna Rockert
    et al.
    Region Kalmar, Sweden;Örebro University, Sweden.
    Woksepp, Hanna
    Region Kalmar, Sweden.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Johansson, Marcus
    Region Kalmar, SwedenRegion Kalmar, Sweden;Linköping University, Sweden.
    Dahle, Charlotte
    Linköping University, Sweden;Linköping University Hospital, Sweden.
    Ludvigsson, Jonas F.
    Karolinska Institutet, Sweden;Örebro University Hospital, Sweden.
    Bonnedahl, Jonas
    Linköping University, Sweden.
    Nilsson, Per H.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Univ Oslo, Norway.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University, Sweden.
    Celiac disease and complement activation in response to Streptococcus pneumoniae2019Ingår i: European Journal of Pediatrics, ISSN 0340-6199, E-ISSN 1432-1076Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Individuals with celiac disease (CD) are at increased risk of invasive pneumococcal disease (IPD). The aim of this study was to explore whether the complement response to Streptococcus pneumoniae differed according to CD status, and could serve as an explanation for the excess risk of IPD in CD. Twenty-two children with CD and 18 controls, born 1999-2008, were included at Kalmar County Hospital, Sweden. The degree of complement activation was evaluated by comparing levels of activation products C3a and sC5b-9 in plasma incubated for 30 min with Streptococcus pneumoniae and in non-incubated plasma. Complement analyses were performed with enzyme-linked immunosorbent assay (ELISA). Pneumococcal stimulation caused a statistically significant increase in C3a as well as sC5b-9 in both children with CD and controls but there was no difference in response between the groups. After incubation, C3a increased on average 4.6 times and sC5b-9 22 times in both the CD and the control group (p = 0.497 and p = 0.724 respectively). Conclusion: Complement response to Streptococcus pneumoniae seems to be similar in children with and without CD and is thus unlikely to contribute to the increased susceptibility to invasive pneumococcal disease in CD.

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