Edimara S Reis, Dimitrios C Mastellos, George Hajishengallis, John D Lambris
The recognition of microbial or danger-associated molecular patterns by complement proteins initiates a cascade of events that culminates in the activation of surface complement receptors on immune cells. Such signalling pathways converge with those activated downstream of pattern recognition receptors to determine the type and magnitude of the immune response. Intensive investigation in the field has uncovered novel pathways that link complement-mediated signalling with homeostatic and pathological T cell responses...
August 2019: Nature Reviews. Immunology
Jeffrey W Hudgens, Elyssia S Gallagher, Ioannis Karageorgos, Kyle W Anderson, James J Filliben, Richard Y-C Huang, Guodong Chen, George M Bou-Assaf, Alfonso Espada, Michael J Chalmers, Eduardo Harguindey, Hui-Min Zhang, Benjamin T Walters, Jennifer Zhang, John D Venable, Caitlin Steckler, Inhee Park, Ansgar Brock, Xiaojun Lu, Ratnesh K Pandey, Arun Chandramohan, Ganesh S Anand, Sasidhar N Nirudodhi, Justin B Sperry, Jason C Rouse, James A Carroll, Kasper D Rand, Ulrike Leurs, David D Weis, Mohammed A Al-Naqshabandi, Tyler S Hageman, Daniel Deredge, Patrick L Wintrode, Malvina Papanastasiou, John D Lambris, Sheng Li, Sarah Urata
Hydrogen-deuterium exchange mass spectrometry (HDX-MS) is an established, powerful tool for investigating protein-ligand interactions, protein folding, and protein dynamics. However, HDX-MS is still an emergent tool for quality control of biopharmaceuticals and for establishing dynamic similarity between a biosimilar and an innovator therapeutic. Because industry will conduct quality control and similarity measurements over a product lifetime and in multiple locations, an understanding of HDX-MS reproducibility is critical...
May 2, 2019: Analytical Chemistry
Ruben Pio, Daniel Ajona, Sergio Ortiz-Espinosa, Alberto Mantovani, John D Lambris
Reactivation of cytotoxic CD8+ T-cell responses has set a new direction for cancer immunotherapy. Neutralizing antibodies targeting immune checkpoint programmed cell death protein 1 (PD-1) or its ligand (PD-L1) have been particularly successful for tumor types with limited therapeutic options such as melanoma and lung cancer. However, reactivation of T cells is only one step toward tumor elimination, and a substantial fraction of patients fails to respond to these therapies. In this context, combination therapies targeting more than one of the steps of the cancer-immune cycle may provide significant benefits...
2019: Frontiers in Immunology
Ebru Karasu, Bo Nilsson, Jörg Köhl, John D Lambris, Markus Huber-Lang
Exposure to traumatic or infectious insults results in a rapid activation of the complement cascade as major fluid defense system of innate immunity. The complement system acts as a master alarm system during the molecular danger response after trauma and significantly contributes to the clearance of DAMPs and PAMPs. However, depending on the origin and extent of the damaged macro- and micro -milieu, the complement system can also be either excessively activated or inhibited. In both cases, this can lead to a maladaptive immune response and subsequent multiple cellular and organ dysfunction...
2019: Frontiers in Immunology
George Hajishengallis, Tetsuhiro Kajikawa, Evlambia Hajishengallis, Tomoki Maekawa, Edimara S Reis, Dimitrios C Mastellos, Despina Yancopoulou, Hatice Hasturk, John D Lambris
Periodontitis is a prevalent inflammatory disease that leads to the destruction of the tooth-supporting tissues. Current therapies are not effective for all patients and this oral disease continues to be a significant public health and economic burden. Central to periodontal disease pathogenesis is a reciprocally reinforced interplay between microbial dysbiosis and destructive inflammation, suggesting the potential relevance of host-modulation therapies. This review summarizes and discusses clinical observations and pre-clinical intervention studies that collectively suggest that complement is hyperactivated in periodontitis and that its inhibition provides a therapeutic benefit...
2019: Frontiers in Immunology
Elia Romanini, Donato Colangelo, Luigi Lucini, Milena Lambri
Oxidative spoilage is a phenomenon that can occur both in winemaking and during bottle storage. The complexity of oxidative spoilage makes it difficult to identify all the products from oxidation processes, especially in bottled wines with varying degrees of oxidative spoilage, i.e., "random oxidation". To this end, this study sought to obtain a deeper insight into the chemistry of white wine samples to identify compounds able to discriminate the different oxidative statuses. The results of metabolomics and VIP analysis outlined molecules such as 3-methylcatechol, cyanidin 3-O-6″-p-coumaroyl-glucoside, delphinidin 3-O-glucoside, quercetin 3-O-glucosyl-xyloside, dihydroquercetin, and quercetin 3-O-glucuronide to be discriminant in the detection of the oxidative status of the white wines under study, which were preliminarily classified in low and high oxidation classes by means of sensory analysis...
August 1, 2019: Food Chemistry
Richard J H Smith, Gerald B Appel, Anna M Blom, H Terence Cook, Vivette D D'Agati, Fadi Fakhouri, Véronique Fremeaux-Bacchi, Mihály Józsi, David Kavanagh, John D Lambris, Marina Noris, Matthew C Pickering, Giuseppe Remuzzi, Santiago Rodriguez de Córdoba, Sanjeev Sethi, Johan Van der Vlag, Peter F Zipfel, Carla M Nester
The C3 glomerulopathies are a group of rare kidney diseases characterized by complement dysregulation occurring in the fluid phase and in the glomerular microenvironment, which results in prominent complement C3 deposition in kidney biopsy samples. The two major subgroups of C3 glomerulopathy - dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) - have overlapping clinical and pathological features suggestive of a disease continuum. Dysregulation of the complement alternative pathway is fundamental to the manifestations of C3 glomerulopathy, although terminal pathway dysregulation is also common...
March 2019: Nature Reviews. Nephrology
Elisabetta Lombardi, Alessandro Matte, Antonio M Risitano, David Ricklin, John D Lambris, Denise De Zanet, Sakari T Jokiranta, Nicola Martinelli, Cinzia Scambi, Gianluca Salvagno, Zeno Bisoffi, Chiara Colato, Angela Siciliano, Oscar Bortolami, Mario Mazzuccato, Francesco Zorzi, Luigi De Marco, Lucia De Franceschi
Sickle cell disease is an autosomal recessive genetic red cell disorder with worldwide distribution. Growing evidence suggests a possible involvement of complement activation in the severity of sickle cell clinical complication. Here, we found activation of the alternative complement pathway with microvascular deposition of C5b-9 on skin biopsies from sickle cell disease patients. This was also supported by sickle red cell membrane the deposition of C3b on sickle red cell membranes, which is locally promoted by the exposure of phosphatidylserine...
January 10, 2019: Haematologica
Dimitrios C Mastellos, Edimara S Reis, Ali-Reza Biglarnia, Meryl Waldman, Richard J Quigg, Markus Huber-Lang, Marc A Seelen, Mohamed R Daha, John D Lambris
Owing to an increasing shortage of donor organs, the majority of patients with end-stage kidney disease remains reliant on extracorporeal hemodialysis (HD) in order to counter the lifelong complications of a failing kidney. While HD remains a life-saving option for these patients, mounting evidence suggests that it also fuels a vicious cycle of thromboinflammation that can increase the risk of cardiovascular disease. During HD, blood-borne innate immune systems become inappropriately activated on the biomaterial surface, instigating proinflammatory reactions that can alter endothelial and vascular homeostasis...
November 22, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Yvonne Mödinger, Anna E Rapp, Anna Vikman, Zhaozhou Ren, Verena Fischer, Stephanie Bergdolt, Melanie Haffner-Luntzer, Wen-Chao Song, John D Lambris, Markus Huber-Lang, Cornelia Neidlinger-Wilke, Rolf Brenner, Anita Ignatius
The terminal complement complex (TCC) is formed on activation of the complement system, a crucial arm of innate immunity. TCC formation on cell membranes results in a transmembrane pore leading to cell lysis. In addition, sublytic TCC concentrations can modulate various cellular functions. TCC-induced effects may play a role in the pathomechanisms of inflammatory disorders of the bone, including rheumatoid arthritis and osteoarthritis. In this study, we investigated the effect of the TCC on bone turnover and repair...
October 17, 2018: American Journal of Pathology
Dimitrios C Mastellos, Edimara S Reis, John D Lambris
In this issue of Cancer Cell, Medler et al. demonstrate that fibrinolytic enzyme-mediated generation of complement C5a reprograms tumor-infiltrating C5aR1+ macrophages into an immunosuppressive phenotype that dampens CD8+ T cell responses during squamous carcinogenesis. C5aR1 blockade combined with chemotherapy offers a promising immunomodulatory strategy for treating squamous cell carcinoma.
October 8, 2018: Cancer Cell
Maisem Laabei, Guanghui Liu, David Ermert, John D Lambris, Kristian Riesbeck, Anna M Blom
The respiratory pathogen Moraxella catarrhalis is a human-specific commensal that frequently causes acute otitis media in children and stimulates acute exacerbations in chronic obstructive pulmonary disease patients. The exact molecular mechanisms defining host-pathogen interactions promoting pathogenesis are not clearly understood. Limited knowledge hampers vaccine and immunotherapeutic development required to treat this emerging pathogen. In this study, we reveal in detail a novel antibacterial role displayed by short leucine-rich proteoglycans (SLRPs) in concert with complement...
November 1, 2018: Journal of Immunology
Edimara S Reis, Nadja Berger, Xin Wang, Sophia Koutsogiannaki, Robert K Doot, Justin T Gumas, Periklis G Foukas, Ranillo R G Resuello, Joel V Tuplano, David Kukis, Alice F Tarantal, Anthony J Young, Tetsuhiro Kajikawa, Athena M Soulika, Dimitrios C Mastellos, Despina Yancopoulou, Ali-Reza Biglarnia, Markus Huber-Lang, George Hajishengallis, Bo Nilsson, John D Lambris
The central component of the complement cascade, C3, is involved in various biological functions, including opsonization of foreign bodies, clearance of waste material, activation of immune cells, and triggering of pathways controlling development. Given its broad role in immune responses, particularly in phagocytosis and the clearance of microbes, a deficiency in complement C3 in humans is often associated with multiple bacterial infections. Interestingly, an increased susceptibility to infections appears to occur mainly in the first two years of life and then wanes throughout adulthood...
December 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Nagihan Bostanci, Kai Bao, Xiaofei Li, Tomoki Maekawa, Jonas Grossmann, Christian Panse, Ruel A Briones, Ranillo R G Resuello, Joel V Tuplano, Cristina A G Garcia, Edimara S Reis, John D Lambris, George Hajishengallis
Periodontitis is a prevalent chronic inflammatory disease associated with dysbiosis. Although complement inhibition has been successfully used to treat periodontitis in animal models, studies globally analyzing inflamed tissue proteins to glean insight into possible mechanisms of action are missing. Using quantitative shotgun proteomics, we aimed to investigate differences in composition of inflammatory gingival tissue exudate ("gingival crevicular fluid"; GCF), before and after local administration of an inhibitor of the central complement component, C3, in nonhuman primates...
September 7, 2018: Journal of Proteome Research
Dimitrios C Mastellos, Edimara S Reis, Despina Yancopoulou, Antonio M Risitano, John D Lambris
Paroxysmal nocturnal hemoglobinuria (PNH) is widely regarded as an archetypal complement-mediated disorder that has propelled complement drug discovery in recent decades. Its pathology is driven by chronic complement dysregulation resulting from the lack of the glycosyl phosphatidyl inositol-linked regulators DAF and CD59 on susceptible erythrocytes. This complement imbalance fuels persistent C3 activation on affected erythrocytes, which culminates in chronic complement-mediated intravascular hemolysis. The clinical application of eculizumab, a humanized anti-C5 antibody that blocks terminal pathway activation, has led to drastic improvement of therapeutic outcomes but has also unveiled hitherto elusive pathogenic mechanisms that are now known to contribute to the clinical burden of a significant proportion of patients with PNH...
July 2018: Seminars in Hematology
Sanjay Khandelwal, Alexandra M Johnson, Jian Liu, David Keire, Cynthia Sommers, Joann Ravi, Grace M Lee, John D Lambris, Edimara S Reis, Gowthami M Arepally
No abstract text is available yet for this article.
August 2018: Thrombosis and Haemostasis
Nadja Berger, Tchilabalo Dilezitoko Alayi, Ranillo R G Resuello, Joel V Tuplano, Edimara S Reis, John D Lambris
Improper regulation of complement is associated with various pathologies, and the clinical demand for compounds that can regulate complement activation is therefore imperative. Cp40, an analog of the peptide compstatin, inhibits all complement pathways at the level of the central component C3. We have further developed Cp40, using either PEGylation at the N-terminus or insertion of charged amino acids at the C-terminus. The PEGylated analogs are highly soluble and retained their inhibitory activity, with C3b binding affinity dependent on the length of the PEG chain...
July 26, 2018: Journal of Medicinal Chemistry
Sonoko Ishino, Stéphane Skouloubris, Hanae Kudo, Caroline l'Hermitte-Stead, Asmae Es-Sadik, Jean-Christophe Lambry, Yoshizumi Ishino, Hannu Myllykallio
The mismatch repair (MMR) system, exemplified by the MutS/MutL proteins, is widespread in Bacteria and Eukarya. However, molecular mechanisms how numerous archaea and bacteria lacking the mutS/mutL genes maintain high replication fidelity and genome stability have remained elusive. EndoMS is a recently discovered hyperthermophilic mismatch-specific endonuclease encoded by nucS in Thermococcales. We deleted the nucS from the actinobacterium Corynebacterium glutamicum and demonstrated a drastic increase of spontaneous transition mutations in the nucS deletion strain...
July 6, 2018: Nucleic Acids Research
Reinhard J Sauter, Manuela Sauter, Edimara S Reis, Frederic N Emschermann, Henry Nording, Sonja Ebenhöch, Peter Kraft, Patrick Münzer, Maximilian Mauler, Johannes Rheinlaender, Johannes Madlung, Frank Edlich, Tilman E Schäffer, Sven G Meuth, Daniel Dürschmied, Tobias Geisler, Oliver Borst, Meinrad Gawaz, Christoph Kleinschnitz, John D Lambris, Harald F Langer
BACKGROUND: Platelets have distinct roles in the vascular system in that they are the major mediator of thrombosis, critical for restoration of tissue integrity, and players in vascular inflammatory conditions. In close spatiotemporal proximity, the complement system acts as the first line of defense against invading microorganisms and is a key mediator of inflammation. Whereas the fluid phase cross-talk between the complement and coagulation systems is well appreciated, the understanding of the pathophysiological implications of such interactions is still scant...
October 16, 2018: Circulation
Nassim Ben Brahim, Mélanie Poggi, Jean-Christophe Lambry, Naim Bel Haj Mohamed, Rafik Ben Chaâbane, Michel Negrerie
We aimed to quantify the interaction of water-soluble-functionalized CdS quantum dots (QDs) with metal cations from their composition and physical properties. From the diameter of thioglycerol-capped nanoparticles (TG-CdS QDs) measured by electronic microscopy ( D = 12.3 ± 0.3 nm), we calculated the molecular mass of the individual particle MAQD = (3 ± 0.5) × 106 g·mol-1 and its molar absorption coefficient ε450 = 21 × 106 M-1 ·cm-1 . We built a three-dimensional model of the TG-CdS QDs in agreement with the structural data, which allowed us to quantify the number of thioglycerol grafted chains to ∼2000 per QD...
May 7, 2018: Inorganic Chemistry
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