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https://www.readbyqxmd.com/read/29144501/novel-mechanisms-and-functions-of-complement
#1
REVIEW
George Hajishengallis, Edimara S Reis, Dimitrios C Mastellos, Daniel Ricklin, John D Lambris
Progress at the beginning of the 21st century transformed the perception of complement from that of a blood-based antimicrobial system to that of a global regulator of immunity and tissue homeostasis. More recent years have witnessed remarkable advances in structure-function insights and understanding of the mechanisms and locations of complement activation, which have added new layers of complexity to the biology of complement. This complexity is readily reflected by the multifaceted and contextual involvement of complement-driven networks in a wide range of inflammatory and neurodegenerative disorders and cancer...
November 16, 2017: Nature Immunology
https://www.readbyqxmd.com/read/29118090/complement-activation-via-a-c3a-receptor-pathway-alters-cd4-t-lymphocytes-and-mediates-lung-cancer-progression
#2
Jeff W Kwak, Jennifer Laskowski, Howard Y Li, Maria V McSharry, Trisha R Sippel, Bonnie L Bullock, Amber M Johnson, Joanna M Poczobutt, Alexander J Neuwelt, Stephen P Malkoski, Mary C Weiser-Evans, John Lambris, Eric T Clambey, Joshua M Thurman, Raphael A Nemenoff
The complement cascade is a part of the innate immune system which acts primarily to remove pathogens and injured cells. However, complement activation is also peculiarly associated with tumor progression. Here we report mechanistic insights into this association in multiple immunocompetent orthotopic models of lung cancer. After tumor engraftment, we observed systemic activation of the complement cascade as reflected by elevated levels of the key regulator C3a. Notably, growth of primary tumors and metastases was both strongly inhibited in C3-deficient mice (C3-/- mice), with tumors undetectable in many subjects...
November 8, 2017: Cancer Research
https://www.readbyqxmd.com/read/29070810/complement-receptors-c5ar1-and-c5ar2-act-differentially-during-the-early-immune-response-after-bone-fracture-but-are-similarly-involved-in-bone-repair
#3
Anna Kovtun, Stephanie Bergdolt, Yvonne Hägele, Rebekka Matthes, John D Lambris, Markus Huber-Lang, Anita Ignatius
Severely injured patients frequently suffer compromised fracture healing because of systemic post-traumatic inflammation. An important trigger of the posttraumatic immune response is the complement anaphylatoxin C5a, which acts via two receptors, C5aR1 and C5aR2, expressed on immune and bone cells. The blockade of C5a-mediated inflammation during the early inflammatory phase was demonstrated to improve fracture healing after severe injury. However, the distinct roles of the two complement receptors C5aR1 and C5aR2 in bone has to date not been studied...
October 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28973891/complement-activation-fragment-c4a-mediates-effector-functions-by-binding-as-untethered-agonist-to-protease-activated-receptors-1-and-4
#4
HongBin Wang, Daniel Ricklin, John D Lambris
C4a is a small protein released from complement component C4 upon activation of the complement system's classical and lectin pathways, which are important constituents of innate immune surveillance. Despite the structural similarity between C4a and well-described anaphylatoxins C3a and C5a, the binding partner and biological function of C4a have remained elusive. Using a cell-based reporter assay, we screened C4a against a panel of both known and orphan G protein-coupled receptors and now provide evidence that C4a is a ligand for protease-activated receptor (PAR)1 and PAR4...
October 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28941899/oxygen-availability-and-strain-combination-modulate-yeast-growth-dynamics-in-mixed-culture-fermentations-of-grape-must-with-starmerella-bacillaris-and-saccharomyces-cerevisiae
#5
Vasileios Englezos, Francesco Cravero, Fabrizio Torchio, Kalliopi Rantsiou, Anne Ortiz-Julien, Milena Lambri, Vincenzo Gerbi, Luca Rolle, Luca Cocolin
Starmerella bacillaris (synonym Candida zemplinina) is a non-Saccharomyces yeast that has been proposed as a co-inoculant of selected Saccharomyces cerevisiae strains in mixed culture fermentations to enhance the analytical composition of the wines. In order to acquire further knowledge on the metabolic interactions between these two species, in this study we investigated the impact of oxygen addition and combination of Starm. bacillaris with S. cerevisiae strains on the microbial growth and metabolite production...
February 2018: Food Microbiology
https://www.readbyqxmd.com/read/28932632/local-endothelial-complement-activation-reverses-endothelial-quiescence-enabling-t-cell-homing-and-tumor-control-during-t-cell-immunotherapy
#6
Andrea Facciabene, Francesco De Sanctis, Stefano Pierini, Edimara S Reis, Klara Balint, John Facciponte, Jens Rueter, Masahiro Kagabu, Paola Magotti, Evripidis Lanitis, Robert A DeAngelis, Ronald J Buckanovich, Wenchao C Song, John D Lambris, George Coukos
Cancer immunotherapy relies upon the ability of T cells to infiltrate tumors. The endothelium constitutes a barrier between the tumor and effector T cells, and the ability to manipulate local vascular permeability could be translated into effective immunotherapy. Here, we show that in the context of adoptive T cell therapy, antitumor T cells, delivered at high enough doses, can overcome the endothelial barrier and infiltrate tumors, a process that requires local production of C3, complement activation on tumor endothelium and release of C5a...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28920587/complement-in-cancer-untangling-an-intricate-relationship
#7
REVIEW
Edimara S Reis, Dimitrios C Mastellos, Daniel Ricklin, Alberto Mantovani, John D Lambris
In tumour immunology, complement has traditionally been considered as an adjunctive component that enhances the cytolytic effects of antibody-based immunotherapies, such as rituximab. Remarkably, research in the past decade has uncovered novel molecular mechanisms linking imbalanced complement activation in the tumour microenvironment with inflammation and suppression of antitumour immune responses. These findings have prompted new interest in manipulating the complement system for cancer therapy. This Review summarizes our current understanding of complement-mediated effector functions in the tumour microenvironment, focusing on how complement activation can act as a negative or positive regulator of tumorigenesis...
September 18, 2017: Nature Reviews. Immunology
https://www.readbyqxmd.com/read/28879212/safety-and-efficacy-of-the-complement-inhibitor-amy-101-in-a-natural-model-of-periodontitis-in-non-human-primates
#8
Tetsuhiro Kajikawa, Ruel A Briones, Ranillo R G Resuello, Joel V Tuplano, Edimara S Reis, Evlambia Hajishengallis, Cristina A G Garcia, Despina Yancopoulou, John D Lambris, George Hajishengallis
Periodontitis is a chronic inflammatory disease associated with overactivation of the complement system. Recent preclinical studies suggest that host-modulation therapies may contribute to effective treatment of human periodontitis, which may lead to loss of teeth and function if untreated. We previously showed that locally administered AMY-101 (Cp40), a peptidic inhibitor of the central complement component C3, can inhibit naturally occurring periodontitis in non-human primates (NHPs) when given once a week...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28759066/structural-changes-and-picosecond-to-second-dynamics-of-cytochrome-c-in-interaction-with-nitric-oxide-in-ferrous-and-ferric-redox-states
#9
Sergei G Kruglik, Byung-Kuk Yoo, Jean-Christophe Lambry, Jean-Louis Martin, Michel Negrerie
Apart from its role in electron transfer, mitochondrial cytochrome c also plays a role in apoptosis and is subject to nitrosylation. The cleavage of the Fe-Met80 bond plays a role in several processes including the release of Cyt c from mitochondria or increase of its peroxidase activity. Nitrosylation of Cyt c precludes the reformation of the disrupted Fe-Met80 bond and was shown to occur during apoptosis. These physiological properties are associated with a conformational change of the heme center of Cyt c...
August 16, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28748042/porphyromonas-gingivalis-disturbs-host-commensal-homeostasis-by-changing-complement-function
#10
REVIEW
Ingar Olsen, John D Lambris, George Hajishengallis
Porphyromonas gingivalis is a Gram-negative anaerobic rod that has been proposed as an orchestrator of complement-dependent dysbiotic inflammation. This notion was suggested from its capacities to manipulate the complement-Toll-like receptor crosstalk in ways that promote dysbiosis and periodontal disease in animal models. Specifically, while at low colonization levels, P. gingivalis interferes with innate immunity and leads to changes in the counts and composition of the oral commensal microbiota. The resulting dysbiotic microbial community causes disruption of host-microbial homeostasis, leading to inflammatory bone loss...
2017: Journal of Oral Microbiology
https://www.readbyqxmd.com/read/28671713/complement-c5a-induced-changes-in-neutrophil-morphology-during-inflammation
#11
S Denk, R P Taylor, R Wiegner, E M Cook, M A Lindorfer, K Pfeiffer, S Paschke, T Eiseler, M Weiss, E Barth, J D Lambris, M Kalbitz, T Martin, H Barth, D A C Messerer, F Gebhard, M S Huber-Lang
The complement and neutrophil defence 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. Similar changes were observed after incubation with zymosan-activated serum and in blood neutrophils during murine sepsis, but not in mice lacking the C5aR1...
September 2017: Scandinavian Journal of Immunology
https://www.readbyqxmd.com/read/28671664/regulator-dependent-mechanisms-of-c3b-processing-by-factor-i-allow-differentiation-of-immune-responses
#12
Xiaoguang Xue, Jin Wu, Daniel Ricklin, Federico Forneris, Patrizia Di Crescenzio, Christoph Q Schmidt, Joke Granneman, Thomas H Sharp, John D Lambris, Piet Gros
The complement system labels microbes and host debris for clearance. Degradation of surface-bound C3b is pivotal to direct immune responses and protect host cells. How the serine protease factor I (FI), assisted by regulators, cleaves either two or three distant peptide bonds in the CUB domain of C3b remains unclear. We present a crystal structure of C3b in complex with FI and regulator factor H (FH; domains 1-4 with 19-20). FI binds C3b-FH between FH domains 2 and 3 and a reoriented C3b C-terminal domain and docks onto the first scissile bond, while stabilizing its catalytic domain for proteolytic activity...
August 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28579778/iron-oxide-nanoparticles-induce-cytokine-secretion-in-a-complement-dependent-manner-in-a-human-whole-blood-model
#13
Susann Wolf-Grosse, Anne Mari Rokstad, Syed Ali, John D Lambris, Tom E Mollnes, Asbjørn M Nilsen, Jørgen Stenvik
Iron oxide nanoparticles (IONPs) are promising nanomaterials for biomedical applications. However, their inflammatory potential has not been fully established. Here, we used a lepirudin anti-coagulated human whole blood model to evaluate the potential of 10 nm IONPs to activate the complement system and induce cytokine production. Reactive oxygen species and cell death were also assessed. The IONPs activated complement, as measured by C3a, C5a and sC5b-9, and induced the production of pro-inflammatory cytokines in a particle-dose dependent manner, with the strongest response at 10 µg/mL IONPs...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/28576714/alginate-microbeads-are-coagulation-compatible-while-alginate-microcapsules-activate-coagulation-secondary-to-complement-or-directly-through-fxii
#14
Caroline Gravastrand, Shamal Hamad, Hilde Fure, Bjørg Steinkjer, Liv Ryan, Josè Oberholzer, John D Lambris, Igor Lacík, Tom Eirik Mollnes, Terje Espevik, Ole-Lars Brekke, Anne Mari Rokstad
Alginate microspheres are presently under evaluation for future cell-based therapy. Their ability to induce harmful host reactions needs to be identified for developing the most suitable devices and efficient prevention strategies. We used a lepirudin based human whole blood model to investigate the coagulation potentials of alginate-based microspheres: alginate microbeads (Ca/Ba Beads), alginate poly-l-lysine microcapsules (APA and AP microcapsules) and sodium alginate-sodium cellulose sulfate-poly(methylene-co-cyanoguanidine) microcapsules (PMCG microcapsules)...
August 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28576690/complement-component-c3ar-constitutes-a-novel-regulator-for-chick-eye-morphogenesis
#15
Erika Grajales-Esquivel, Agustin Luz-Madrigal, Jeffrey Bierly, Tracy Haynes, Edimara S Reis, Zeyu Han, Christian Gutierrez, Zachary McKinney, Apostolia Tzekou, John D Lambris, Panagiotis A Tsonis, Katia Del Rio-Tsonis
Complement components have been implicated in a wide variety of functions including neurogenesis, proliferation, cell migration, differentiation, cancer, and more recently early development and regeneration. Following our initial observations indicating that C3a/C3aR signaling induces chick retina regeneration, we analyzed its role in chick eye morphogenesis. During eye development, the optic vesicle (OV) invaginates to generate a bilayer optic cup (OC) that gives rise to the retinal pigmented epithelium (RPE) and neural retina...
August 1, 2017: Developmental Biology
https://www.readbyqxmd.com/read/28490576/complement-c5a-functions-as-a-master-switch-for-the-ph-balance-in-neutrophils-exerting-fundamental-immunometabolic-effects
#16
Stephanie Denk, Miriam D Neher, David A C Messerer, Rebecca Wiegner, Bo Nilsson, Daniel Rittirsch, Kristina Nilsson-Ekdahl, Sebastian Weckbach, Anita Ignatius, Miriam Kalbitz, Florian Gebhard, Manfred E Weiss, Josef Vogt, Peter Radermacher, Jörg Köhl, John D Lambris, Markus S Huber-Lang
During sepsis, excessive activation of the complement system with generation of the anaphylatoxin C5a results in profound disturbances in crucial neutrophil functions. Moreover, because neutrophil activity is highly dependent on intracellular pH (pHi), we propose a direct mechanistic link between complement activation and neutrophil pHi In this article, we demonstrate that in vitro exposure of human neutrophils to C5a significantly increased pHi by selective activation of the sodium/hydrogen exchanger. Upstream signaling of C5a-mediated intracellular alkalinization was dependent on C5aR1, intracellular calcium, protein kinase C, and calmodulin, and downstream signaling regulated the release of antibacterial myeloperoxidase and lactoferrin...
June 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28430891/development-and-validation-of-diagnostic-criteria-for-ibd-subtypes-including-ibd-unclassified-in-children-a-multicentre-study-from-the-pediatric-ibd-porto-group-of-espghan
#17
Liron Birimberg-Schwartz, David M Zucker, Amichay Akriv, Salvatore Cucchiara, Fiona L Cameron, David C Wilson, Iza Lazowska, Lambri Yianni, Siba Prosad Paul, Claudio Romano, Sanja Kolacek, Stephan Buderus, Anders Pærregaard, Richard K Russell, Johanna C Escher, Dan Turner
Background: The revised Porto criteria identify subtypes of paediatric inflammatory bowel diseases: ulcerative colitis [UC], atypical UC, inflammatory bowel disease unclassified [IBDU], and Crohn's disease [CD]. Others have proposed another subclassifiction of Crohn's colitis. In continuation of the Porto criteria, we aimed to derive and validate criteria, termed "PIBD-classes," for standardising the classification of the different IBD subtypes. Methods: This was a multicentre retrospective longitudinal study from 23 centres affiliated with the Port -group of ESPGHAN...
September 1, 2017: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/28416449/complement-c3-targeted-therapy-replacing-long-held-assertions-with-evidence-based-discovery
#18
REVIEW
Dimitrios C Mastellos, Edimara S Reis, Daniel Ricklin, Richard J Smith, John D Lambris
Complement dysregulation underlies several inflammatory disorders, and terminal complement inhibition has thus far afforded significant clinical gains. Nonetheless, emerging pathologies, fueled by complement imbalance and therapy-skewing genetic variance, underscore the need for more comprehensive, disease-tailored interventions. Modulation at the level of C3, a multifaceted orchestrator of the complement cascade, opens up prospects for broader therapeutic efficacy by targeting multiple pathogenic pathways modulated by C3-triggered proinflammatory crosstalk...
June 2017: Trends in Immunology
https://www.readbyqxmd.com/read/28372238/metabolite-profiling-and-volatiles-of-pineapple-wine-and-vinegar-obtained-from-pineapple-waste
#19
Arianna Roda, Luigi Lucini, Fabrizio Torchio, Roberta Dordoni, Dante Marco De Faveri, Milena Lambri
Vinegar is an inexpensive commodity, and economic considerations require that a relatively low-cost raw material be used for its production. An investigation into the use of a new, alternative substrate - pineapple waste - is described. This approach enables the utilization of the pineapple's (Ananas comosus) peels and core, which are usually discarded during the processing or consumption of the fruit. Using physical and enzymatic treatments, the waste was saccharified, and the resulting substrate was fermented with Saccharomyces cerevisiae for 7-10days under aerobic conditions at 25°C...
August 15, 2017: Food Chemistry
https://www.readbyqxmd.com/read/28344973/coarse-grained-conformational-sampling-of-protein-structure-improves-the-fit-to-experimental-hydrogen-exchange-data
#20
Didier Devaurs, Dinler A Antunes, Malvina Papanastasiou, Mark Moll, Daniel Ricklin, John D Lambris, Lydia E Kavraki
Monitoring hydrogen/deuterium exchange (HDX) undergone by a protein in solution produces experimental data that translates into valuable information about the protein's structure. Data produced by HDX experiments is often interpreted using a crystal structure of the protein, when available. However, it has been shown that the correspondence between experimental HDX data and crystal structures is often not satisfactory. This creates difficulties when trying to perform a structural analysis of the HDX data. In this paper, we evaluate several strategies to obtain a conformation providing a good fit to the experimental HDX data, which is a premise of an accurate structural analysis...
2017: Frontiers in Molecular Biosciences
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