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Alternative complement pathway

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https://www.readbyqxmd.com/read/29450785/the-role-of-the-alternative-pathway-of-complement-activation-in-glomerular-diseases
#1
REVIEW
Emilia Łukawska, Magdalena Polcyn-Adamczak, Zofia I Niemir
The complement system (CS) has recently been recognized as a bridge between innate and adaptive immunity that constitutes a very complex mechanism controlling the clearance of pathogens, cellular debris, and immune complexes. Out of three known pathways of complement activation, the alternative pathway (AP) plays a critical role in host defense by amplifying the complement response, independently of initiation pathway and continuously maintaining low-level activity in a process called 'thick-over.' A key molecule of the CS is C3, in which the AP is constantly activated...
February 15, 2018: Clinical and Experimental Medicine
https://www.readbyqxmd.com/read/29450541/induction-of-ocular-complement-activation-by-inflammatory-stimuli-and-intraocular-inhibition-of-complement-factor-d-in-animal-models
#2
Maura A Crowley, Omar Delgado, Adrian Will-Orrego, Natasha M Buchanan, Karen Anderson, Bruce D Jaffee, Thaddeus P Dryja, Sha-Mei Liao
Purpose: Genome-wide association studies suggest a role for the complement system in age-related macular degeneration (AMD). We characterized ocular complement activation and evaluated a complement factor D (FD) neutralizing antibody. Methods: Mice were treated with toll-like receptor (TLR) ligands, intravitreal injection (IVT), or corneal debridement. Levels of complement proteins and mRNA were measured. A FD neutralizing antibody was administered IVT into eyes of rabbits that were challenged with LPS (lipopolysaccharide) administered intravenously...
February 1, 2018: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29449098/quantification-of-human-complement-factor-h-binding-to-asexual-malaria-blood-stages-by-an-enzyme-linked-immunosorbent-assay
#3
Nina Simon, Oliver Friedrich, Barbara Kappes
The human complement system is the most effective defense mechanism of the human innate immune system. One major negative regulator of the alternative pathway in human blood is complement factor H (FH). It binds to autologous cells and thus, prevents complement attack against body-cells or tissues. Various pathogens are known to escape complement recognition by recruiting FH to provide protection against the host's immune system. This immune evasion mechanism was recently qualitatively reported for asexual malaria blood stages...
February 12, 2018: Vaccine
https://www.readbyqxmd.com/read/29447841/crispr-cas9-generated-human-cd46-cd55-and-cd59-knockout-cell-lines-as-a-tool-for-complement-research
#4
Astrid J F Thielen, Iris M van Baarsen, Marlieke L Jongsma, Sacha Zeerleder, Robbert M Spaapen, Diana Wouters
BACKGROUND: To prevent unwanted complement activation and subsequent damage, complement activation must be tightly regulated on healthy host cells. Dysregulation of the complement system contributes to the pathology of diseases like Paroxysmal Nocturnal Hemoglobinuria and atypical Hemolytic Uremic Syndrome. To investigate complement regulator deficiencies, primary patient cells may be used, but access to patient cells may be limited and cells are heterogeneous between different patients...
February 12, 2018: Journal of Immunological Methods
https://www.readbyqxmd.com/read/29446739/role-of-complement-properdin-in-renal-ischemia-reperfusion-injury
#5
Zinah Zwaini, Houyong Dai, Cordula Stover, Bin Yang
Renal ischemia-reperfusion injury (IRI) is one of the main causes of acute kidney injury (AKI), and may lead to chronic kidney disease. The high mortality rate of AKI has not changed in the last 5 decades due to non-recognition, nephrotoxin exposure, delayed diagnosis and lack of specific intervention. Complement activation plays important roles in IRI-induced AKI because of its association with immunity, inflammation, cell death and tissue repair. Nevertheless, the role of complement properdin, the sole positive regulator of the alternative pathway, in IRI-induced AKI has not been well defined...
February 13, 2018: Current Gene Therapy
https://www.readbyqxmd.com/read/29413001/intrinsic-disorder-protein-protein-interactions-and-disease
#6
Vladimir N Uversky
It is recognized now that biologically active proteins without stable tertiary structure (known as intrinsically disordered proteins, IDPs) and hybrid proteins containing ordered domains and intrinsically disordered protein regions (IDPRs) are important players found in any given proteome. These IDPs/IDPRs possess functions that complement functional repertoire of their ordered counterparts, being commonly related to recognition, as well as control and regulation of various signaling pathways. They are interaction masters, being able to utilize a wide spectrum of interaction mechanisms, ranging from induced folding to formation of fuzzy complexes where significant levels of disorder are preserved, to polyvalent stochastic interactions playing crucial roles in the liquid-liquid phase transitions leading to the formation of proteinaceous membrane-less organelles...
2018: Advances in Protein Chemistry and Structural Biology
https://www.readbyqxmd.com/read/29399037/complement-activation-turnover-on-surfaces-of-nanoparticles
#7
S M Moghimi, D Simberg
The complement system is an important component of the innate immune system, which contributes to non-specific host defence. Particulate matters, such as invading pathogens and nanomedicines, in the blood may activate the complement system through classical, lectin and alternative pathways. Complement activation can aid recognition and clearance of particulate matters by immune cells, but uncontrolled complement activation can inflict damage and be life threatening. Plasma proteins on adsorption to surfaces of nanoparticles also play a significant role in complement activation and particularly through the alternative pathway...
August 2017: Nano Today
https://www.readbyqxmd.com/read/29372302/pathogenic-role-of-inflammatory-response-during-shiga-toxin-associated-hemolytic-uremic-syndrome-hus
#8
Ramon Alfonso Exeni, Romina Jimena Fernandez-Brando, Adriana Patricia Santiago, Gabriela Alejandra Fiorentino, Andrea Mariana Exeni, Maria Victoria Ramos, Marina Sandra Palermo
Hemolytic uremic syndrome (HUS) is defined as a triad of noninmune microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The most frequent presentation is secondary to Shiga toxin (Stx)-producing Escherichia coli (STEC) infections, which is termed postdiarrheal, epidemiologic or Stx-HUS, considering that Stx is the necessary etiological factor. After ingestion, STEC colonize the intestine and produce Stx, which translocates across the intestinal epithelium. Once Stx enters the bloodstream, it interacts with renal endothelial and epithelial cells, and leukocytes...
January 25, 2018: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
https://www.readbyqxmd.com/read/29371202/complement-activation-predicts-adverse-pregnancy-outcome-in-patients-with-systemic-lupus-erythematosus-and-or-antiphospholipid-antibodies
#9
Mimi Y Kim, Marta M Guerra, Elianna Kaplowitz, Carl A Laskin, Michelle Petri, D Ware Branch, Michael D Lockshin, Lisa R Sammaritano, Joan T Merrill, T Flint Porter, Allen Sawitzke, Anne M Lynch, Jill P Buyon, Jane E Salmon
OBJECTIVE: Studies in mouse models implicate complement activation as a causative factor in adverse pregnancy outcomes (APOs). We investigated whether activation of complement early in pregnancy predicts APOs in women with systemic lupus erythematosus (SLE) and/or antiphospholipid (aPL) antibodies. METHODS: The PROMISSE Study enrolled pregnant women with SLE and/or aPL antibodies (n=487) and pregnant healthy controls (n=204) at <12 weeks gestation and evaluated them monthly...
January 25, 2018: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/29370420/c3-glomerulonephritis-secondary-to-mutations-in-factors-h-and-i-rapid-recurrence-in-deceased-donor-kidney-transplant-effectively-treated-with-eculizumab
#10
Neetika Garg, Yuzhou Zhang, Anne Nicholson-Weller, Eliyahu V Khankin, Nicolò Ghiringhelli Borsa, Nicole C Meyer, Susan McDermott, Isaac E Stillman, Helmut G Rennke, Richard J Smith, Martha Pavlakis
Background: C3 glomerulonephritis (C3GN) is caused by alternate complement pathway over-activation. It frequently progresses to end-stage renal disease, recurs in two-thirds of transplants and in half of these cases progresses to allograft loss. There is currently no proven treatment for C3GN. Case Presentation: We describe a family segregating pathogenic alleles of complement factor H and I (CFH and CFI). The only member carrying both mutations developed C3GN. Prolonged delayed graft function after deceased donor transplantation, heavy proteinuria and isolated C3 hypocomplementemia prompted an allograft biopsy confirming diagnosis of recurrent C3GN...
January 23, 2018: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/29367209/the-complement-c3a-c3ar-axis-promotes-development-of-thoracic-aortic-dissection-via-regulation-of-mmp2-expression
#11
Weihong Ren, Yan Liu, Xuerui Wang, Chunmei Piao, Youcai Ma, Shulan Qiu, Lixin Jia, Boya Chen, Yuan Wang, Wenjian Jiang, Shuai Zheng, Chang Liu, Nan Dai, Feng Lan, Hongjia Zhang, Wen-Chao Song, Jie Du
Thoracic aortic dissection (TAD), once ruptured, is devastating to patients, and no effective pharmaceutical therapy is available. Anaphylatoxins released by complement activation are involved in a variety of diseases. However, the role of the complement system in TAD is unknown. We found that plasma levels of C3a, C4a, and C5a were significantly increased in patients with TAD. Elevated circulating C3a levels were also detected in the developmental process of mouse TAD, which was induced by β-aminopropionitrile monofumarate (BAPN) treatment, with enhanced expression of C1q and properdin in mouse dissected aortas...
January 24, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29364839/the-functional-amyloid-curli-protects-escherichia-coli-against-complement-mediated-bactericidal-activity
#12
Steven G Biesecker, Lauren K Nicastro, R Paul Wilson, Çağla Tükel
Escherichia coli strains may be beneficial or pathogenic. Many E. coli strains that cause human disease, especially those responsible for bacteremia and sepsis, express virulence factors that impart resistance to the complement system. The bacterial amyloid curli functions in bacterial adherence and enhances the formation of biofilms. Survival of curli-producing parental and curli-deficient mutant E. coli in the context of a human complement response was evaluated using an in vivo murine model of bacteremia...
January 24, 2018: Biomolecules
https://www.readbyqxmd.com/read/29359109/proteome-and-metabolome-of-subretinal-fluid-in-central-serous-chorioretinopathy-and-rhegmatogenous-retinal-detachment-a-pilot-case-study
#13
Laura Kowalczuk, Alexandre Matet, Marianne Dor, Nasim Bararpour, Alejandra Daruich, Ali Dirani, Francine Behar-Cohen, Aurélien Thomas, Natacha Turck
Purpose: To investigate the molecular composition of subretinal fluid (SRF) in central serous chorioretinopathy (CSCR) and rhegmatogenous retinal detachment (RRD) using proteomics and metabolomics. Methods: SRF was obtained from one patient with severe nonresolving bullous CSCR requiring surgical subretinal fibrin removal, and two patients with long-standing RRD. Proteins were trypsin-digested, labeled with Tandem-Mass-Tag and fractionated according to their isoelectric point for identification and quantification by tandem mass spectrometry...
January 2018: Translational Vision Science & Technology
https://www.readbyqxmd.com/read/29356300/pathophysiology-of-thrombotic-thrombocytopenic-purpura-and-hemolytic-uremic-syndrome
#14
Johanna A Kremer Hovinga, Silvan R Heeb, Magdalena Skowronska, Monica Schaller
Thrombotic microangiopathies are rare disorders characterized by the concomitant occurrence of severe thrombocytopenia, microangiopathic hemolytic anemia, and a variable degree of ischemic end organ damage. The latter particularly affects the brain, the heart and the kidneys. The primary forms, thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), although in their clinical presentation often overlapping, have distinctive pathophysiologies. TTP is the consequence of a severe ADAMTS13 deficiency, immune-mediated due to circulating autoantibodies (iTTP), or caused by mutations in the ADAMTS13 gene (cTTP)...
January 22, 2018: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29343274/coexistent-sickle-cell-anemia-and-autoimmune-disease-in-eight-children-pitfalls-and-challenges
#15
Valerie Li-Thiao-Te, Florence Uettwiller, Pierre Quartier, Florence Lacaille, Brigitte Bader-Meunier, Valentine Brousse, Mariane de Montalembert
BACKGROUND: Patients with sickle cell disease (SCD) present a defective activation of the alternate complement pathway that increases the risk of infection and is thought to predispose to autoimmune disease (AID). However, coexisting AID and SCD is rarely reported, suggesting possible underdiagnosis due to an overlapping of the symptoms. STUDY DESIGN: Among 603 patients with SCD followed between 1999 and June 2016, we retrospectively searched for patients with coexisting SCD and AID...
January 17, 2018: Pediatric Rheumatology Online Journal
https://www.readbyqxmd.com/read/29337453/-amd-and-complement-pathway-in-2017
#16
Francine Behar-Cohen
AMD is the major cause of visual loss in individuals older than 50 in the western countries. Whilst tremendous progress has been made by the intraocular repeated injections of anti-VEGFs in wet AMD, no treatment is recognized to prevent progression of dry AMD, which represents more than 50 % of the cases. Interestingly, an over activation of the complement alternative pathway has been associated to both forms of AMD. But, several clinical studies have failed to demonstrate any efficacy of molecules blocking the complement pathway at various stage of its activation...
January 10, 2018: Revue Médicale Suisse
https://www.readbyqxmd.com/read/29335241/the-mfhr1-fusion-protein-is-a-novel-synthetic-multitarget-complement-inhibitor-with-therapeutic-potential
#17
Stefan Michelfelder, Friedericke Fischer, Astrid Wäldin, Kim V Hörle, Martin Pohl, Juliana Parsons, Ralf Reski, Eva L Decker, Peter F Zipfel, Christine Skerka, Karsten Häffner
The complement system is essential for host defense, but uncontrolled complement system activation leads to severe, mostly renal pathologies, such as atypical hemolytic uremic syndrome or C3 glomerulopathy. Here, we investigated a novel combinational approach to modulate complement activation by targeting C3 and the terminal pathway simultaneously. The synthetic fusion protein MFHR1 links the regulatory domains of complement factor H (FH) with the C5 convertase/C5b-9 inhibitory fragment of the FH-related protein 1...
January 15, 2018: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/29329521/treating-c3-glomerulopathy-with-eculizumab
#18
Thomas Welte, Frederic Arnold, Julia Kappes, Maximilian Seidl, Karsten Häffner, Carsten Bergmann, Gerd Walz, Elke Neumann-Haefelin
BACKGROUND: C3 glomerulopathy (C3G) is a rare, but severe glomerular disease with grim prognosis. The complex pathogenesis is just unfolding, and involves acquired as well as inherited dysregulation of the alternative pathway of the complement cascade. Currently, there is no established therapy. Treatment with the C5 complement inhibitor eculizumab may be a therapeutic option. However, due to rarity of the disease, parameters predicting treatment response remain largely unknown. METHODS: Seven patients with C3G (five with C3 glomerulonephritis and two with dense deposit disease) were treated with eculizumab...
January 12, 2018: BMC Nephrology
https://www.readbyqxmd.com/read/29327071/diseases-of-complement-dysregulation-an-overview
#19
REVIEW
Edwin K S Wong, David Kavanagh
Atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), and paroxysmal nocturnal hemoglobinuria (PNH) are prototypical disorders of complement dysregulation. Although complement overactivation is common to all, cell surface alternative pathway dysregulation (aHUS), fluid phase alternative pathway dysregulation (C3G), or terminal pathway dysregulation (PNH) predominates resulting in the very different phenotypes seen in these diseases. The mechanism underlying the dysregulation also varies with predominant acquired autoimmune (C3G), somatic mutations (PNH), or inherited germline mutations (aHUS) predisposing to disease...
January 11, 2018: Seminars in Immunopathology
https://www.readbyqxmd.com/read/29325709/acute-hyperoxia-induces-systemic-responses-with-no-major-changes-in-peripheral-tissues-in-the-senegalese-sole-solea-senegalensis-kaup-1858
#20
Marina Machado, Diogo Malheiro, Ana Couto, Jonathan M Wilson, Matthew Guerreiro, Rita Azeredo, Jon C Svendsen, António Afonso, Renata Serradeiro, Benjamín Costas
Senegalese sole Solea senegalensis is currently farmed in recirculation aquaculture systems that often involve water re-oxygenation, which in turn may cause acute or prolonged hyperoxia exposures. In order to understand the impact of acute hyperoxia on the fish immune system and peripheral tissues such as gills and gut, Senegalese sole juveniles (30.05 ± 1.72 g) were exposed to normoxia (100% O2sat) as control and two hyperoxic conditions (150 and 200% O2sat) and sampled at 4 and 24 h. Fish haematological profile, total and differential blood cell counts and plasma immune parameters were analysed...
January 8, 2018: Fish & Shellfish Immunology
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