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https://www.readbyqxmd.com/read/28733463/tlr4-and-c5ar-crosstalk-in-dendritic-cells-induces-a-core-regulatory-network-of-rsk2-pi3k%C3%AE-sgk1-and-foxo-transcription-factors
#1
Anouk Zaal, Benjamin Nota, Kat S Moore, Miranda Dieker, S Marieke van Ham, Anja Ten Brinke
Crosstalk between complement component 5a receptors (C5aRs) and TLRs in dendritic cells (DCs) occurs upon pathogen invasion; however, studies on C5aR and TLR crosstalk mainly focused on the modulating effect of C5a on TLR-induced cytokine production. To elucidate the breadth of C5aR and TLR4 crosstalk, the effect of simultaneous treatment with C5a and LPS was investigated in human monocyte-derived DCs (moDCs) 2 h after stimulation using whole transcriptome sequencing analysis. Although the effect of C5a on hallmark genes defining TLR4-induced DC maturation was limited at this time point, RNA sequencing analysis revealed a great variety of novel C5a targets, of which many interfere with TLR4-mediated immune activation...
July 21, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28732748/controlling-the-pro-inflammatory-function-of-6-sulfo-lacnac-slan-dendritic-cells-with-dimethylfumarate
#2
Stephanie Oehrl, Florina Olaru, Anja Kunze, Michael Maas, Silvia Pezer, Marc Schmitz, Knut Schäkel
BACKROUND: The fumaric acid ester (FAE) dimethylfumarate (DMF) is a small molecule immunomodulator successfully used for the treatment of psoriasis and multiple sclerosis (MS). DMF is thought to inhibit pathogenic immune responses with Th17/Th1T cells, and IL-23/IL-12 producing dendritic cells (DCs). 6-sulfo LacNAc expressing dendritic cells (slanDCs) are a human pro-inflammatory cell type found frequently among the infiltrating leukocytes in skin lesions of psoriasis and brain lesions of MS...
June 24, 2017: Journal of Dermatological Science
https://www.readbyqxmd.com/read/28720697/inhibition-of-complement-c5-protects-against-organ-failure-and-reduces-mortality-in-a-baboon-model-of-escherichia-coli-sepsis
#3
Ravi Shankar Keshari, Robert Silasi, Narcis Ioan Popescu, Maulin Mukeshchandra Patel, Hala Chaaban, Cristina Lupu, K Mark Coggeshall, Tom Eirik Mollnes, Steven J DeMarco, Florea Lupu
Bacterial sepsis triggers robust activation of the complement system with subsequent generation of anaphylatoxins (C3a, C5a) and the terminal complement complex (TCC) that together contribute to organ failure and death. Here we tested the effect of RA101295, a 2-kDa macrocyclic peptide inhibitor of C5 cleavage, using in vitro whole-blood assays and an in vivo baboon model of Escherichia coli sepsis. RA101295 strongly inhibited E. coli-induced complement activation both in vitro and in vivo by blocking the generation of C5a and the soluble form of TCC, sC5b-9...
July 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28707765/tissue-microarray-methodology-identifies-complement-pathway-activation-and-dysregulation-in-progressive-multiple-sclerosis
#4
Sam Loveless, James W Neal, Owain W Howell, Katharine E Harding, Patrick Sarkies, Rhian Evans, Ryan J Bevan, Svetlana Hakobyan, Claire L Harris, Neil P Robertson, B Paul Morgan
BACKGROUND: The complement pathway has potential contributions to both white (WM) and grey matter (GM) pathology in Multiple Sclerosis (MS). A quantitative assessment of complement involvement is lacking. OBJECTIVE: Tissue MicroArray methodology was used in conjunction with immunohistochemistry to investigate the localization of complement pathway proteins in progressive MS cortical GM and subcortical WM. METHODS: Antibodies targeting complement proteins C1q, C3b, regulatory proteins C1 inhibitor (C1INH), complement receptor 1 (CR1), clusterin, factor H (FH) and the C5a anaphylatoxin receptor (C5aR) were utilised alongside standard markers of tissue pathology...
July 14, 2017: Brain Pathology
https://www.readbyqxmd.com/read/28706957/the-controversial-c5a-receptor-c5ar2-its-role-in-health-and-disease
#5
REVIEW
Ting Zhang, Malgorzata A Garstka, Ke Li
After the discovery of the C5a receptor C5aR1, C5aR2 is the second receptor found to bind C5a and its des-arginine form. As a heptahelical G protein-coupled receptor but devoid of the intracellular Gα signal, C5aR2 is special and confusing. Ramifications and controversies about C5aR2 are under debate since its identification, from putative ligands and cellular localization to intracellular signals and pathological roles in inflammation and immunity. The ruleless and even conflicting pro- or anti-inflammatory role of C5aR2 in animal models of diverse diseases makes one bewildered...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28672919/brain-injury-with-systemic-inflammation-in-newborns-with-congenital-heart-disease-undergoing-heart-surgery
#6
Rossitza P Pironkova, Joseph Giamelli, Howard Seiden, Vincent A Parnell, Dorota Gruber, Cristina P Sison, Czeslawa Kowal, Kaie Ojamaa
The potential role of systemic inflammation on brain injury in newborns with congenital heart disease (CHD) was assessed by measuring levels of central nervous system (CNS)-derived proteins in serum prior to and following cardiac surgery. A total of 23 newborns (gestational age, 39±1 weeks) with a diagnosis of CHD that required cardiac surgery with cardiopulmonary bypass (CPB) were enrolled in the current study. Serum samples were collected immediately prior to surgery and 2, 24 and 48 h following CPB, and serum levels of phosphorylated neurofilament-heavy subunit (pNF-H), neuron-specific enolase (NSE) and S100B were analyzed...
July 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28671968/systemic-complement-activation-in-central-serous-chorioretinopathy
#7
Elon H C van Dijk, Roula Tsonaka, Ngaisah Klar-Mohamad, Diana Wouters, Aiko P J de Vries, Eiko K de Jong, Cees van Kooten, Camiel J F Boon
PURPOSE: A clear link between several variants in genes involved in the complement system and chronic central serous chorioretinopathy (CSC) has been described. In age-related macular degeneration, a disease that shows clinical features that overlap with CSC, both genetic risk factors and systemic activation of the complement system have previously been found. In this case-control study, we assessed whether there is evidence of either systemic activation or inhibition of the complement system in patients with chronic CSC...
2017: PloS One
https://www.readbyqxmd.com/read/28671713/complement-c5a-induced-changes-in-neutrophil-morphology-during-inflammation
#8
Stephanie Denk, Ronald P Taylor, Rebecca Wiegner, Erika M Cook, Margaret A Lindorfer, Katharina Pfeiffer, Stephan Paschke, Tim Eiseler, Manfred Weiss, Eberhard Barth, John D Lambris, Miriam Kalbitz, Tobias Martin, Holger Barth, David A C Messerer, Florian Gebhard, Markus S Huber-Lang
The complement and neutrophil defense systems, as major components of innate immunity, are activated during inflammation and infection. For neutrophil migration to the inflamed region, we hypothesized that the complement activation product C5a induces significant changes in cellular morphology before chemotaxis. Exposure of human neutrophils to C5a, dose- and time-dependently resulted in a rapid C5a receptor-1 (C5aR1)-dependent shape-change, indicated by enhanced flow cytometric forward-scatter area values...
June 30, 2017: Scandinavian Journal of Immunology
https://www.readbyqxmd.com/read/28671303/increased-complement-activation-during-platelet-storage
#9
Jian Chen, Michael Losos, Shangbin Yang, Junan Li, Haifeng Wu, Spero Cataland
BACKGROUND: It has been shown that platelet transfusion carries a higher incidence of transfusion-related adverse events than any other blood components, and prolonged platelet storage is associated with more transfusion reactions, most of which are considered to be inflammatory responses. However, the role of complement, which has very important proinflammatory activities, in the pathogenesis of platelet-related adverse events has not been fully understood. STUDY DESIGN AND METHODS: Three units of platelets collected by apheresis were stored on a platelet rotator with the temperature controlled between 22 and 24°C...
July 3, 2017: Transfusion
https://www.readbyqxmd.com/read/28670268/serping1-c1-inhibitor-affects-cortical-development-in-a-cell-autonomous-and-non-cell-autonomous-manner
#10
Anna Gorelik, Tamar Sapir, Trent M Woodruff, Orly Reiner
Current knowledge regarding regulation of radial neuronal migration is mainly focused on intracellular molecules. Our unbiased screen aimed at identification of non-cell autonomous mechanisms involved in this process detected differential expression of Serping1 or C1 inhibitor, which is known to inhibit the initiation of the complement cascade. The complement cascade is composed of three pathways; the classical, lectin, and the alternative pathway; the first two are inhibited by C1 inhibitor, and all three converge at the level of C3...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28669410/thrombin-activatable-fibrinolysis-inhibitor-tafi-a-possible-link-between-coagulation-and-complement-activation-in-the-antiphospholipid-syndrome-aps
#11
Giorgia Grosso, Anna Vikerfors, Barry Woodhams, Mariette Adam, Katarina Bremme, Margareta Holmström, Anna Ågren, Anna Eelde, Maria Bruzelius, Elisabet Svenungsson, Aleksandra Antovic
BACKGROUND: Thrombosis and complement activation are pathogenic features of antiphospholipid syndrome (APS). Their molecular link is Plasma carboxypeptidase-B, also known as thrombin activatable fibrinolysis inhibitor (TAFIa), which plays a dual role: anti-fibrinolytic, by cleaving carboxyl-terminal lysine residues from partially degraded fibrin, and anti-inflammatory, by downregulating complement anaphylatoxins C3a and C5a. AIM: To investigate the levels of TAFI (proenzyme) and TAFIa (active enzyme) in relation to complement activation, fibrin clot permeability and fibrinolytic function in clinical and immunological subsets of 52 APS patients and 15 controls...
June 24, 2017: Thrombosis Research
https://www.readbyqxmd.com/read/28663750/anaphylatoxins-activate-ca-2-akt-pi3-kinase-and-foxo1-foxp3-in-the-retinal-pigment-epithelium
#12
Catharina Busch, Balasubramaniam Annamalai, Khava Abdusalamova, Nadine Reichhart, Christian Huber, Yuchen Lin, Emeraldo A H Jo, Peter F Zipfel, Christine Skerka, Gerhild Wildner, Maria Diedrichs-Möhring, Bärbel Rohrer, Olaf Strauß
PURPOSE: The retinal pigment epithelium (RPE) is a main target for complement activation in age-related macular degeneration (AMD). The anaphylatoxins C3a and C5a have been thought to mostly play a role as chemoattractants for macrophages and immune cells; here, we explore whether they trigger RPE alterations. Specifically, we investigated the RPE as a potential immunoregulatory gate, allowing for active changes in the RPE microenvironment in response to complement. DESIGN: In vitro and in vivo analysis of signaling pathways...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28663231/complement-recognition-pathways-in-renal-transplantation
#13
Christopher L Nauser, Conrad A Farrar, Steven H Sacks
The complement system, consisting of soluble and cell membrane-bound components of the innate immune system, has defined roles in the pathophysiology of renal allograft rejection. Notably, the unavoidable ischemia-reperfusion injury inherent to transplantation is mediated through the terminal complement activation products C5a and C5b-9. Furthermore, biologically active fragments C3a and C5a, produced during complement activation, can modulate both antigen presentation and T cell priming, ultimately leading to allograft rejection...
June 29, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28661094/effect-of-temperature-on-granulocyte-and-monocyte-adsorption-to-cellulose-acetate-beads
#14
Shoichi Nishise, Yuji Takeda, Yasuhiko Abe, Yu Sasaki, Hidetoshi Nara, Hironobu Asao, Yoshiyuki Ueno
Granulocyte and monocyte (GM) adsorptive apheresis (GMA) is an effective therapy for inflammatory disorders including inflammatory bowel disease (IBD). During GMA, the blood of a patient with IBD passes through a column to contact cellulose acetate (CA) beads at a temperature below body temperature, likely close to room temperature. Here we investigated the effect of temperature on GM adsorption to CA beads in vitro. We incubated peripheral blood with and without CA beads at 5°C, 25°C, 37°C, and 43°C and calculated the ratios of adsorbed GMs...
June 2017: Therapeutic Apheresis and Dialysis
https://www.readbyqxmd.com/read/28657829/cd55-deficiency-early-onset-protein-losing-enteropathy-and-thrombosis
#15
Ahmet Ozen, William A Comrie, Rico C Ardy, Cecilia Domínguez Conde, Buket Dalgic, Ömer F Beser, Aaron R Morawski, Elif Karakoc-Aydiner, Engin Tutar, Safa Baris, Figen Ozcay, Nina K Serwas, Yu Zhang, Helen F Matthews, Stefania Pittaluga, Les R Folio, Aysel Unlusoy Aksu, Joshua J McElwee, Ana Krolo, Ayca Kiykim, Zeren Baris, Meltem Gulsan, Ismail Ogulur, Scott B Snapper, Roderick H J Houwen, Helen L Leavis, Deniz Ertem, Renate Kain, Sinan Sari, Tülay Erkan, Helen C Su, Kaan Boztug, Michael J Lenardo
BACKGROUND: Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies. METHODS: We studied 11 patients with abdominal pain and diarrhea caused by early-onset protein-losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease; the disorder followed an autosomal recessive pattern of inheritance...
July 6, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28652401/interaction-between-multimeric-von-willebrand-factor-and-complement-a-fresh-look-to-the-pathophysiology-of-microvascular-thrombosis
#16
Serena Bettoni, Miriam Galbusera, Sara Gastoldi, Roberta Donadelli, Chiara Tentori, Giuseppina Spartà, Elena Bresin, Caterina Mele, Marta Alberti, Agustin Tortajada, Hugo Yebenes, Giuseppe Remuzzi, Marina Noris
von Willebrand factor (VWF), a multimeric protein with a central role in hemostasis, has been shown to interact with complement components. However, results are contrasting and inconclusive. By studying 20 patients with congenital thrombotic thrombocytopenic purpura (cTTP) who cannot cleave VWF multimers because of genetic ADAMTS13 deficiency, we investigated the mechanism through which VWF modulates complement and its pathophysiological implications for human diseases. Using assays of ex vivo serum-induced C3 and C5b-9 deposits on endothelial cells, we documented that in cTTP, complement is activated via the alternative pathway (AP) on the cell surface...
June 26, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28648837/integrative-characterization-of-chronic-cigarette-smoke-induced-cardiopulmonary-comorbidities-in-a-mouse-model
#17
Ágnes Kemény, Kata Csekő, István Szitter, Zoltán V Varga, Péter Bencsik, Krisztina Kiss, Róbert Halmosi, László Deres, Krisztián Erős, Anikó Perkecz, László Kereskai, Terézia László, Tamás Kiss, Péter Ferdinandy, Zsuzsanna Helyes
Cigarette smoke-triggered inflammatory cascades and consequent tissue damage are the main causes of chronic obstructive pulmonary disease (COPD). There is no effective therapy and the key mediators of COPD are not identified due to the lack of translational animal models with complex characterization. This integrative chronic study investigated cardiopulmonary pathophysiological alterations and mechanisms with functional, morphological and biochemical techniques in a 6-month-long cigarette smoke exposure mouse model...
June 22, 2017: Environmental Pollution
https://www.readbyqxmd.com/read/28648630/resolution-of-a-steroid-resistant-hypereosinophilic-immune-diathesis-with-mepolizumab-and-concomitant-amelioration-of-a-mixed-thrombotic-microangiopathy
#18
J Justin Mulvey, Cynthia Magro, Amy Chadburn
The anaphylatoxins produced by an unbridled complement cascade in atypical hemolytic uremic syndrome (aHUS) can alter the leukocyte environment in tissues and peripheral blood, causing clinically significant eosinophilia. While the membrane attack complex and C5a anaphlatoxin can be suppressed with anti-C5 biologics, the production of C3a is still capable of driving a destructive hypereosinophilic syndrome in spite of anticomplement therapy. The side-effects of glucocorticoids in treating hypereosinophilic syndrome limit their therapeutic index in long-term treatment and this behooves the use of alternative strategies...
May 2, 2017: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/28647502/alternative-complement-pathway-hemolytic-assays-reveal-incomplete-complement-blockade-in-patients-treated-with-eculizumab
#19
Bénédicte Puissant-Lubrano, Sylvain Puissochet, Nicolas Congy-Jolivet, Dominique Chauveau, Stéphane Decramer, Arnaud Garnier, Antoine Huart, Nassim Kamar, David Ribes, Antoine Blancher
Eculizumab is a monoclonal anti-C5 antibody used in the treatment of atypical hemolytic uremic syndrome (aHUS). We monitored complement inhibition in 16 eculizumab-treated patients suffering from HUS or transplant rejection (not aHUS patients). Blood samples were obtained one to four weeks after the last eculizumab injection. We observed that eculizumab efficiently blocked the terminal pathway (TP) through classical pathway (CP) activation measured by kinetic hemolytic assay (HA) (<10%) but incompletely blocked the TP through alternative pathway (AP) activation measured by rabbit (APH50>23%) or chicken erythrocytes HA (AP100>15%)...
June 21, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28640789/complement-mediated-enhancement-of-monocyte-adhesion-to-endothelial-cells-by-hla-antibodies-and-blockade-by-a-specific-inhibitor-of-the-classical-complement-cascade-tnt003
#20
Nicole M Valenzuela, Kimberly A Thomas, Arend Mulder, Graham C Parry, Sandip Panicker, Elaine F Reed
BACKGROUND: Antibody-mediated rejection (AMR) of most solid organs is characterized by evidence of complement activation and/or intragraft macrophages (C4d + and CD68+ biopsies). We previously demonstrated that crosslinking of HLA I by antibodies triggered endothelial activation and monocyte adhesion. We hypothesized that activation of the classical complement pathway at the endothelial cell surface by HLA antibodies would enhance monocyte adhesion through soluble split product generation, in parallel with direct endothelial activation downstream of HLA signaling...
July 2017: Transplantation
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