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2. Complement and platelets: prothrombotic cell activation requires membrane attack complex–induced release of danger signals

Author

Mannes, Marco, Pechtl, Veronika, Hafner, Susanne, Dopler, Arthur, Eriksson, Oskar, Manivel, Vivek Anand, Wohlgemuth, Lisa, Messerer, David Alexander Christian, Schrezenmeier, Hubert, Ekdahl, Kristina N., Nilsson, Bo, Jacobsen, Eva-Maria, Hoenig, Manfred, Huber-Lang, Markus, Braun, Christian K., and Schmidt, Christoph Q.

Published
2023
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30. Citrullination of C1-inhibitor as a mechanism of impaired complement regulation in rheumatoid arthritis

Author

Martin, Myriam, Nilsson, Sara C. C., Eikrem, David, Fromell, Karin, Scavenius, Carsten, Vogt, Leonie M. M., Bielecka, Ewa, Potempa, Jan, Enghild, Jan J. J., Nilsson, Bo, Ekdahl, Kristina N. N., Kapetanovic, Meliha C. C., and Blom, Anna M. M.

Subjects
rheumatoid arthritis, Reumatologi och inflammation, citrullination, synovial fluid, Immunologi inom det medicinska området, Immunology in the medical area, C1-inhibitor, ACPA, complement system, PAD, Rheumatology and Autoimmunity
Abstract

Background Dysregulated complement activation, increased protein citrullination, and production of autoantibodies against citrullinated proteins are hallmarks of rheumatoid arthritis (RA). Citrullination is induced by immune cell-derived peptidyl-Arg deiminases (PADs), which are overactivated in the inflamed synovium. We characterized the effect of PAD2- and PAD4-induced citrullination on the ability of the plasma-derived serpin C1-inhibitor (C1-INH) to inhibit complement and contact system activation. Methods Citrullination of the C1-INH was confirmed by ELISA and Western blotting using a biotinylated phenylglyoxal probe. C1-INH-mediated inhibition of complement activation was analyzed by C1-esterase activity assay. Downstream inhibition of complement was studied by C4b deposition on heat-aggregated IgGs by ELISA, using pooled normal human serum as a complement source. Inhibition of the contact system was investigated by chromogenic activity assays for factor XIIa, plasma kallikrein, and factor XIa. In addition, autoantibody reactivity to native and citrullinated C1-INH was measured by ELISA in 101 RA patient samples. Results C1-INH was efficiently citrullinated by PAD2 and PAD4. Citrullinated C1-INH was not able to bind the serine protease C1s and inhibit its activity. Citrullination of the C1-INH abrogated its ability to dissociate the C1-complex and thus inhibit complement activation. Consequently, citrullinated C1-INH had a decreased capacity to inhibit C4b deposition via the classical and lectin pathways. The inhibitory effect of C1-INH on the contact system components factor XIIa, plasma kallikrein, and factor XIa was also strongly reduced by citrullination. In RA patient samples, autoantibody binding to PAD2- and PAD4-citrullinated C1-INH was detected. Significantly more binding was observed in anti-citrullinated protein antibody (ACPA)-positive than in ACPA-negative samples. Conclusion Citrullination of the C1-INH by recombinant human PAD2 and PAD4 enzymes impaired its ability to inhibit the complement and contact systems in vitro. Citrullination seems to render C1-INH more immunogenic, and citrullinated C1-INH might thus be an additional target of the autoantibody response observed in RA patients.

Published
2023

34. Regulation of the innate immune system by fragmented heparin-conjugated lipids on lipid bilayered membranes in vitro.

Author

Adler, Anna, Fritsch, Marlene, Fromell, Karin, Leneweit, Gero, Ekdahl, Kristina N., Nilsson, Bo, and Teramura, Yuji

Abstract

Surface modification with heparin is a powerful biomaterial coating strategy that protects against innate immunity activation since heparin is a part of the proteoglycan heparan sulfate on cell surfaces in the body. We studied the heparinization of cellular and material surfaces via lipid conjugation to a heparin-binding peptide. In the present study, we synthesized fragmented heparin (fHep)-conjugated phospholipids and studied their regulation of the innate immune system on a lipid bilayered surface using liposomes. Liposomes have versatile applications, such as drug-delivery systems, due to their ability to carry a wide range of molecules. Owing to their morphological similarity to cell membranes, they can also be used to mimic a simple cell-membrane to study protein–lipid interactions. We investigated the interaction of complement-regulators, factor H and C4b-binding protein (C4BP), as well as the coagulation inhibitor antithrombin (AT), with fHep-lipids on the liposomal surface. Herein, we studied the ability of fHep-lipids to recruit factor H, C4BP, and AT using a quartz crystal microbalance with dissipation monitoring. With dynamic light scattering, we demonstrated that liposomes could be modified with fHep-lipids and were stable up to 60 days at 4 °C. Using a capillary western blot-based method (Wes), we showed that fHep-liposomes could recruit factor H in a model system using purified proteins and assist in the degradation of the active complement protein C3b to iC3b. Furthermore, we found that fHep-liposomes could recruit factor H and AT from human plasma. Therefore, the use of fHep-lipids could be a potential coating for liposomes and cell surfaces to regulate the immune system on the lipid surface. [ABSTRACT FROM AUTHOR]

Published
2023
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38. Impaired Antibody Response Is Associated with Histone-Release, Organ Dysfunction and Mortality in Critically Ill COVID-19 Patients

Author

Lagedal, Rickard, Eriksson, Oskar, Sörman, Anna, Huckriede, Joram, Kristensen, Bjarne, Franzén, Stephanie, Larsson, Anders, Bergqvist, Anders, Alving, Kjell, Forslund, Anders, Persson, Barbro, Ekdahl, Kristina N., García de Frutos, Pablo, Nilsson, Bo, Nicolaes, Gerry A. F., Lipcsey, Miklos, Hultström, Michael, Frithiof, Robert, Biochemie, RS: Carim - B01 Blood proteins & engineering, Swedish Heart-Lung Foundation, Swedish Research Council, Swedish Kidney Foundation, Netherlands Thrombosis Foundation, Göran Gustafsson Foundation, and Swedish Society of Medicine

Subjects
NET, critical care, Anestesi och intensivvård, Anesthesiology and Intensive Care, SARS-CoV-2, histones, COVID-19, antibody response, IMMUNITY
Abstract

Purpose: the pathophysiologic mechanisms explaining differences in clinical outcomes following COVID-19 are not completely described. This study aims to investigate antibody responses in critically ill patients with COVID-19 in relation to inflammation, organ failure and 30-day survival. Methods: All patients with PCR-verified COVID-19 and gave consent, and who were admitted to a tertiary Intensive care unit (ICU) in Sweden during March¿September 2020 were included. Demography, repeated blood samples and measures of organ function were collected. Analyses of anti-SARS-CoV-2 antibodies (IgM, IgA and IgG) in plasma were performed and correlated to patient outcome and biomarkers of inflammation and organ failure. Results: A total of 115 patients (median age 62 years, 77% male) were included prospectively. All patients developed severe respiratory dysfunction, and 59% were treated with invasive ventilation. Thirty-day mortality was 22.6% for all included patients. Patients negative for any anti-SARS-CoV-2 antibody in plasma during ICU admission had higher 30-day mortality compared to patients positive for antibodies. Patients positive for IgM had more ICU-, ventilator-, renal replacement therapy- and vasoactive medication-free days. IgA antibody concentrations correlated negatively with both SAPS3 and maximal SOFA-score and IgM-levels correlated negatively with SAPS3. Patients with antibody levels below the detection limit had higher plasma levels of extracellular histones on day 1 and elevated levels of kidney and cardiac biomarkers, but showed no signs of increased inflammation, complement activation or cytokine release. After adjusting for age, positive IgM and IgG antibodies were still associated with increased 30-day survival, with odds ratio (OR) 7.1 (1.5¿34.4) and 4.2 (1.1¿15.7), respectively. Conclusion: In patients with severe COVID-19 requiring intensive care, a poor antibody response is associated with organ failure, systemic histone release and increased 30-day mortality., SciLifeLab/KAW national COVID-19 research program project grant (KAW 2020.0182 and KAW 2020.0241) and from the Swedish Heart-Lung Foundation (20210089) to MH. The Swedish Research Council (2014-02569 and 2014-07606) and The Swedish Kidney Foundation (F2020-0054) to RF. The study was supported by the Netherlands Thrombosis Foundation (2016_01) and Thrombosestichting (2016-1) to GN. OE was supported by grants from the Göran Gustafsson Foundation, the Swedish Society of Medicine (SLS-943007) and the Swedish Research Council (2015-06429).

Published
2022

40. Contributors

Author

Adler, Anna, Agrawal, Mukta, Al-Jamal, Wafa’ T., Alexander, Amit, Amrahli, M., Antimisiaris, Sophia G., Aroffu, Matteo, Benival, Derajram, Berger, Manon, Bhilare, Neha V., Bonaccorso, Angela, Campani, Virginia, Carbone, Claudia, Castangia, Ines, Chakradhar, J.V.U.S., Chaurasiya, Akash, Cheung, Calvin C.L., Chourasia, Manish K., Cressey, P., Dallas, Paraskevas P., Delma, Kouka Luc, De Rosa, Giuseppe, Ebert, Roland, Ekdahl, Kristina N., Evrard, Brigitte, Fatouros, Dimitrios G., Fromell, Karin, Fulgheri, Federica, Giannopoulos-Dimitriou, Alexandros, Gkartziou, Foteini, Gupta, Raghav, Hemmingsen, Lisa Myrseth, Kannavou, Maria, Kelley, Elizabeth G., Kiranraj, G., Kommineni, Nagavendra, Liu, Xiaoyan, Logigan, Corina L., Ma, Xuejiao, Manca, Maria Letizia, Metsiou, Despoina Nektaria, Mineart, Kenneth P., Mishra, Keerti, Missirlis, Athanassios, Mouzoura, Panagiota, Musumeci, Teresa, Naredla, Manusri, Natsaridis, Evangelos, Nele, Valeria, Nilsson, Bo, Osmani, Riyaz Ali M., Paramshetti, Sharanya, Patel, Pranav, Patravale, Vandana, Penoy, Noémie, Peptu, Cristian, Peptu, Catalina A., Perra, Matteo, Petrou, Anthi, Piel, Géraldine, Pippa, Natassa, Rana, Dhwani, Rekkas, Dimitrios M., Saiti, Aikaterini, Sakai-Kato, Kumiko, Salave, Sagar, Singh, Snigdha, Singh, Ekta, Sofou, Stavroula, Stuart, Marc C.A., Suzuki, Haruna, Teramura, Yuji, Thanou, M., Tiwari, Amrendra K., Škalko-Basnet, Nataša, Verma, Sonia, Vizirianakis, Ioannis S., Wang, Ning, Wang, Ting, Yadav, Pooja, and Yadav, Pavan K.

Published
2024
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42. Therapeutic regulation of complement activation in extracorporeal circuits and intravascular treatments with special reference to the alternative pathway amplification loop.

Author

Ekdahl, Kristina N., Fromell, Karin, Mannes, Marco, Grinnemo, Karl‐Henrik, Huber‐Lang, Markus, Teramura, Yuji, and Nilsson, Bo

Subjects
*COMPLEMENT activation, *CARDIOPULMONARY bypass, *PAROXYSMAL hemoglobinuria, *PLASMAPHERESIS, *THERAPEUTICS
Abstract

Summary: A number of clinical treatment modalities involve contact between blood and biomaterials: these include extracorporeal circuits such as hemodialysis, cardiopulmonary bypass, plasmapheresis, and intravascular treatments. Common side effects arising from these treatments are caused by activation of the cascade systems of the blood. Many of these side effects are mediated via the complement system, including thromboinflammatory reactions and rejection of implants. Depending on the composition of the materials, complement activation is triggered via all the activation pathways but is by far mostly driven by the alternative pathway amplification loop. On biomaterial surfaces the alternative pathway amplification is totally unregulated and leads under optimal conditions to deposition of complement fragments, mostly C3b, on the surface leading to a total masking of the underlying surface. In this review, we discuss the mechanism of the complement activation, clinical consequences of the activation, and potential strategies for therapeutic regulation of the activation, using hemodialysis as demonstrator. [ABSTRACT FROM AUTHOR]

Published
2023
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45. Hemocompatibility of Nanotitania-Nanocellulose Hybrid Materials

Author

Svensson, Fredric, Manivel, Vivek Anand, Seisenbaeva, Gulaim, Kessler, Vadim, Nilsson, Bo, Ekdahl, Kristina N., and Fromell, Karin

Subjects
Nano Technology
Abstract

In order to develop a new type of improved wound dressing, we combined the wound healing properties of nanotitania with the advantageous dressing properties of nanocellulose to create three different hybrid materials. The hemocompatibility of the synthesized hybrid materials was evaluated in an in vitro human whole blood model. To our knowledge, this is the first study of the molecular interaction between hybrid nanotitania and blood proteins. Two of the hybrid materials prepared with 3 nm colloidal titania and 10 nm hydrothermally synthesized titania induced strong coagulation and platelet activation but negligible complement activation. Hence, they have great potential as a new dressing for promoting wound healing. Unlike the other two, the third hybrid material using molecular ammonium oxo-lactato titanate as a titania source inhibited platelet consumption, TAT generation, and complement activation, apparently via lowered pH at the surface interface. It is therefore suitable for applications where a passivating surface is desired, such as drug delivery systems and extracorporeal circuits. This opens the possibility for a tailored blood response through the surface functionalization of titania.

Published
2021

46. Heme Interferes With Complement Factor I-Dependent Regulation by Enhancing Alternative Pathway Activation.

Author

Gerogianni, Alexandra, Dimitrov, Jordan D., Zarantonello, Alessandra, Poillerat, Victoria, Chonat, Satheesh, Sandholm, Kerstin, McAdam, Karin E., Ekdahl, Kristina N., Mollnes, Tom E., Mohlin, Camilla, Roumenina, Lubka T., and Nilsson, Per H.

Subjects
HEME, PAROXYSMAL hemoglobinuria, COMPLEMENT factor H, BLOOD proteins, SICKLE cell anemia, COMPLEMENT receptors
Abstract

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. [ABSTRACT FROM AUTHOR]

Published
2022
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50. A Robust Method to Store Complement C3 With Superior Ability to Maintain the Native Structure and Function of the Protein.

Author

Adler, Anna, Manivel, Vivek Anand, Fromell, Karin, Teramura, Yuji, Ekdahl, Kristina N., and Nilsson, Bo

Subjects
COMPLEMENT (Immunology), PROTEIN structure, IONIC strength, ISOELECTRIC point, FREEZING
Abstract

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 ≈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°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). [ABSTRACT FROM AUTHOR]

Published
2022
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