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Complement alternative pathway

Fan Zhang, Min Wu, Chee Keong Kwoh, Jie Zheng
Extracellular signals are captured and transmitted by signaling proteins inside a cell. An important type of cellular responses to the signals is the cell fate decision, e.g., apoptosis. However, the underlying mechanisms of cell fate regulation are still unclear, thus comprehensive and detailed kinetic models are not yet available. Alternatively, data-driven models are promising to bridge signaling data with the phenotypic measurements of cell fates. The traditional linear model for data-driven modeling of signaling pathways has its limitations because it assumes that the a cell fate is proportional to the activities of signaling proteins, which is unlikely in the complex biological systems...
2016: PloS One
Fusun Gediz, Bahriye Kadriye Payzin, Sertac Ecemis, Naile Güler, Asu Fergun Yilmaz, Fusun Topcugil, Afig Berdeli
INTRODUCTION: Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy, which develops as a result of defective activity of the alternative complement pathway and excessive complement activation due to genetic or acquired factors. No satisfactory responses were obtained by plasmapheresis, corticosteroids and fresh frozen plasma (FFP) transfusion. However, promising results are obtained in recent years by eculuzimab treatment, which inhibits C5 activation. OBJECTIVE: To evaluate the efficacy, safety and effect of eculizumab on quality of life of adult aHUS patients followed in our center...
September 30, 2016: Transfusion and Apheresis Science
Meng Chen, Nathaniel Rothman, Yuanqing Ye, Jian Gu, Paul A Scheet, Maosheng Huang, David W Chang, Colin P Dinney, Debra T Silverman, Jonine D Figueroa, Stephen J Chanock, Xifeng Wu
Genome-wide association studies (GWAS) are designed to identify individual regions associated with cancer risk, but only explain a small fraction of the inherited variability. Alternative approach analyzing genetic variants within biological pathways has been proposed to discover networks of susceptibility genes with additional effects. The gene set enrichment analysis (GSEA) may complement and expand traditional GWAS analysis to identify novel genes and pathways associated with bladder cancer risk. We selected three GSEA methods: Gen-Gen, Aligator, and the SNP Ratio Test to evaluate cellular signaling pathways involved in bladder cancer susceptibility in a Texas GWAS population...
July 2016: Genes & Cancer
Ursula Unterberger, Beate Eichelberger, Anja Ulz, Simon Panzer
In immune thrombocytopenia (ITP), antibodies reacting with platelet membrane glycoproteins (GP) mediate premature platelet cleavage, resulting in thrombocytopenia and therefore a risk of bleeding. These antibodies may induce complement activation, thus mediating complement-induced platelet destruction. In this study, we investigated the possibility of an additional complement-related pathogenic mechanism, where antibodies against the complement-regulatory factors CD55 and CD59 may directly interfere with normal complement function...
October 13, 2016: Platelets
Christian Pagnoux
Antineutrophil cytoplasm antibody (ANCA)-associated vasculitides are small-vessel vasculitides that include granulomatosis with polyangiitis (formerly Wegener's granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Renal-limited ANCA-associated vasculitides can be considered the fourth entity. Despite their rarity and still unknown cause(s), research pertaining to ANCA-associated vasculitides has been very active over the past decades. The pathogenic role of antimyeloperoxidase ANCA (MPO-ANCA) has been supported using several animal models, but that of antiproteinase 3 ANCA (PR3-ANCA) has not been as strongly demonstrated...
September 2016: Eur J Rheumatol
Lian Li, Yan Li, Danyang Feng, Linghua Xu, Fengxin Yin, Hengchang Zang, Chunhui Liu, Fengshan Wang
Chondroitin sulfate (CS) plays important roles in the complement system. However, the CS structure is complicated due to different sources and the number and positions of sulfate groups. The objective of this study was to prepare different low molecular weight chondroitin sulfates (LMWCSs) and to investigate the biological activity in anti-complement capacity. A series of LMWCSs was prepared from different sources and characterized by ultraviolet-visible (UV) spectroscopy, high-performance liquid chromatography (HPLC), size exclusion chromatography-multiangle laser light scattering (SEC-MALLS) and nuclear magnetic resonance (NMR) spectroscopy...
October 11, 2016: International Journal of Molecular Sciences
Erika van der Maten, Cynthia M de Bont, Ronald de Groot, Marien I de Jonge, Jeroen D Langereis, Michiel van der Flier
Bacterial pathogens not only stimulate innate immune receptors, but also activate the complement system. Crosstalk between complement C5a receptor (C5aR) and other innate immune receptors is known to enhance the proinflammatory cytokine response. An important determinant of the magnitude of complement activation is the activity of the alternative pathway, which serves as an amplification mechanism for complement activation. Both alternative pathway activity as well as plasma levels of factor H, a key inhibitor of the alternative pathway, show large variation within the human population...
October 6, 2016: Cytokine
Dineke Westra, Elena B Volokhina, Renate G van der Molen, Thea J A M van der Velden, Annelies Jeronimus-Klaasen, Joop Goertz, Valentina Gracchi, Eiske M Dorresteijn, Antonia H M Bouts, Mandy G Keijzer-Veen, Joanna A E van Wijk, Jaap A Bakker, Anja Roos, Lambert P van den Heuvel, Nicole C A J van de Kar
BACKGROUND: The role of complement in the atypical form of hemolytic uremic syndrome (aHUS) has been investigated extensively in recent years. As the HUS-associated bacteria Shiga-toxin-producing Escherichia coli (STEC) can evade the complement system, we hypothesized that complement dysregulation is also important in infection-induced HUS. METHODS: Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, αFH) and genetic profiles (CFH, CFI, CD46, CFB, C3) of the alternative complement pathway were prospectively determined in the acute and convalescent phase of disease in children newly diagnosed with STEC-HUS or aHUS...
October 7, 2016: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Tanja Kersnik Levart, Dušan Ferluga, Alenka Vizjak, Jerica Mraz, Nika Kojc
BACKGROUND: Understanding the role of alternative complement pathway dysregulation in membranoproliferative glomerulonephritis (MPGN) has led to a dramatic shift in its classification into two subgroups: immune complex-mediated MPGN and complement-mediated MPGN, consisting of dense deposit disease and C3 glomerulonephritis (C3GN). A limited number of C3GN cases have been published to date with not yet conclusive results since the novel therapeutic approach with eculizumab was introduced...
October 7, 2016: Diagnostic Pathology
Ezequiel Dantas, Fernando Erra Díaz, Pehuén Pereyra Gerber, Antonela Merlotti, Augusto Varese, Matías Ostrowski, Juan Sabatté, Jorge Geffner
Local acidosis is a common feature of allergic, vascular, autoimmune, and cancer diseases. However, few studies have addressed the effect of extracellular pH on the immune response. Here, we analyzed whether low pH could modulate complement-dependent cytotoxicity (CDC) against IgG-coated cells. Using human serum as a complement source, we found that extracellular pH values of 5.5 and 6.0 strongly inhibit CDC against either B lymphoblast cell lines coated with the chimeric anti-CD20 mAb rituximab or PBMCs coated with the humanized anti-CD52 mAb alemtuzumab...
October 3, 2016: Oncotarget
Nirmal K Banda, Sumitra Acharya, Robert I Scheinman, Gaurav Mehta, Marilyne Coulombe, Minoru Takahashi, Hideharu Sekine, Steffen Thiel, Teizo Fujita, V Michael Holers
The complement system is proposed to play an important role in the pathogenesis of rheumatoid arthritis (RA). The complement system mannan-binding lectin-associated serine proteases (MASP)-1/3 cleave pro-factor D (proDf; inactive) into Df (active), but it is unknown where this cleavage occurs and whether inhibition of MASP-1/3 is a relevant therapeutic strategy for RA. In the present study, we show that the cleavage of proDf into Df by MASP-1/3 can occur in the circulation and that inhibition of MASP-1/3 by gene silencing is sufficient to ameliorate collagen Ab-induced arthritis in mice...
October 5, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
B R Leaker, V A Malkov, R Mogg, M K Ruddy, G C Nicholson, A J Tan, C Tribouley, G Chen, I De Lepeleire, N A Calder, H Chung, P Lavender, L N Carayannopoulos, T T Hansel
Non-invasive mucosal sampling (nasosorption and nasal curettage) was used following nasal allergen challenge with grass pollen in subjects with allergic rhinitis, in order to define the molecular basis of the late allergic reaction (LAR). It was found that the nasal LAR to grass pollen involves parallel changes in pathways of type 2 inflammation (IL-4, IL-5 and IL-13), inflammasome-related (IL-1β), and complement and circadian-associated genes. A grass pollen nasal spray was given to subjects with hay fever followed by serial sampling, in which cytokines and chemokines were measured in absorbed nasal mucosal lining fluid, and global gene expression (transcriptomics) assessed in nasal mucosal curettage samples...
September 28, 2016: Mucosal Immunology
Wenjing Cao, Huy P Pham, Lance A Williams, Jenny McDaniel, Rance C Siniard, Robin G Lorenz, Marisa B Marques, X Long Zheng
Acquired thrombotic thrombocytopenic purpura is primarily caused by deficiency of plasma ADAMTS13 activity resulting from autoantibodies against ADAMTS13. However, ADAMTS13 deficiency alone is often not sufficient to cause acute thrombotic thrombocytopenic purpura. Infections or systemic inflammation may precede acute bursts of the disease but the underlying mechanisms are not fully understood. Here, 52 patients with acquired idiopathic thrombotic thrombocytopenic purpura and 30 blood donor controls were recruited for the study...
August 4, 2016: Haematologica
Marta Subías Hidalgo, Hector Martin Merinero, Alicia López, Jaouad Anter, Sheila Pinto García, Fernando Ataúlfo Gonzalez-Fernández, Rafael Forés, Margarita Lopez-Trascasa, Ana Villegas, Emilio Ojeda, Santiago Rodríguez de Córdoba
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia characterized by complement-mediated intravascular hemolysis that is effectively treated with eculizumab. However, treatment responses are reported heterogeneous with some patients presenting residual hemolysis and requiring RBC transfusions. Recent reports have shown that both extravascular hemolysis and incomplete C5 blockade can explain these suboptimal hematological responses. Here we have tested our eculizumab-treated PNH patients (n=12) for signs of hemolysis and assessed complement biomarkers...
September 13, 2016: Immunobiology
Monika Jusko, Beata Miedziak, David Ermert, Michal Magda, Ben C King, Ewa Bielecka, Kristian Riesbeck, Sigrun Eick, Jan Potempa, Anna M Blom
Periodontal disease is one of the most common inflammatory infectious diseases worldwide and it is associated with other syndromes, such as cardiovascular disease or rheumatoid arthritis. Recent advances in sequencing allowed for identification of novel periodontopathogens such as Gram-positive Filifactor alocis, but its virulence mechanisms remain largely unknown. We confirmed that F. alocis is a prevalent species in periodontitis patients, and we also observed strong correlation of this bacterium with clinical parameters, highlighting its role in the pathogenesis of the disease...
September 16, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Diana Karpman, Ramesh Tati
Complement is activated during Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS). There is evidence of complement activation via the alternative pathway in STEC-HUS patients as well as from in vivo and in vitro models. Ozaki et al. demonstrate activation of the mannose-binding lectin (MBL) pathway in Shiga toxin-treated mice expressing human MBL2, but lacking murine Mbls. Treatment with anti-human MBL2 antibody was protective, suggesting that MBL pathway activation also contributes to Shiga toxin-mediated renal injury...
October 2016: Kidney International
Guang Yin, Zhen Cheng, Cai-Hong Zeng, Zhi-Hong Liu
BACKGROUND: C3 glomerulonephritis (C3 GN) is a recently defined entity characterized by predominant C3 deposition in glomeruli due to abnormal activation of the alternative pathway of complement system. C3 GN has been reported to be associated with several systemic diseases. However, the association between C3 GN and multiple myeloma (MM) has not been well established. METHODS: We herein describe a case presenting with C3 GN on top of MM. RESULTS: A 64-year-old Chinese female presented with gross hematuria, renal dysfunction, anemia, and weight loss...
September 2016: Medicine (Baltimore)
Camilla Melin Fürst, Emma Åhrman, Klas Bratteby, Sofia Waldemarson, Johan Malmström, Anna M Blom
Joint diseases are often characterized by inflammatory processes that result in pathological changes in joint tissues, including cartilage degradation and release of components into the synovial fluid. The complement system plays a central role in promoting the inflammation. Because several cartilage proteins are known to interact with complement, causing either activation or inhibition of the system, we aimed to investigate these interactions comprehensively. Bovine cartilage explants were cultured with IL-1α to induce cartilage degradation, followed by incubation with human serum...
September 14, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Rui Bao, Yang Liu, Stephen J Savarino, Di Xia
The assembly of the class 5 colonization factor antigen I (CFA/I) fimbriae of enterotoxigenic E. coli was proposed to proceed via the alternate chaperone-usher pathway. Here, we show that in the absence of the chaperone CfaA, CfaB, the major pilin subunit of CFA/I fimbriae, is able to spontaneously refold and polymerize into cyclic trimers. CfaA kinetically traps CfaB to form a metastable complex that can be stabilized by mutations. Crystal structure of the stabilized complex reveals distinctive interactions provided by CfaA to trap CfaB in an assembly competent state through donor-strand complementation (DSC) and cleft-mediated anchorage...
September 14, 2016: Molecular Microbiology
Melissa Muff-Luett, Carla M Nester
The complement-mediated renal diseases are a group of ultra-rare renal diseases that disproportionately affect children and young adults and frequently lead to irreversible renal failure. Genetic mutations in alternate pathway of complement genes are pathomechanistically involved in a significant number of these unique diseases. Here, we review our current understanding of the role of genetics in the primary complement-mediated renal diseases affecting children, with a focus on atypical hemolytic uremic syndrome and C3 glomerulopathy...
March 2016: Journal of Pediatric Genetics
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