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Complement alternative pathway

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https://www.readbyqxmd.com/read/28210841/rare-genetic-variant-in-the-cfb-gene-presenting-as-atypical-hemolytic-uremic-syndrome-and-immune-complex-diffuse-membranoproliferative-glomerulonephritis-with-crescents-successfully-treated-with-eculizumab
#1
Khalid Alfakeeh, Mohammed Azar, Majid Alfadhel, Alsuayri Mansour Abdullah, Nourah Aloudah, Khaled O Alsaad
BACKGROUND: Complement factor B gene (CFB) is an important component of the alternate pathway of complement activation that provides an active subunit that associates with C3b to form the C3 convertase, which is an essential element in complement activation. Among the complement-associated disorders, mutations and pathogenic variants in the CFB gene are relatively rare phenomena. Moreover, mutated CFB affiliation with immune-complex diffuse membranoproliferative glomerulonephritis (IC-MPGN) and atypical hemolytic uremic syndrome (aHUS) are considered a highly rare occurrence...
February 16, 2017: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
https://www.readbyqxmd.com/read/28195242/the-alternative-complement-pathway-is-dysregulated-in-patients-with-chronic-heart-failure
#2
Negar Shahini, Annika E Michelsen, Per H Nilsson, Karin Ekholt, Lars Gullestad, Kaspar Broch, Christen P Dahl, Pål Aukrust, Thor Ueland, Tom Eirik Mollnes, Arne Yndestad, Mieke C Louwe
The complement system, an important arm of the innate immune system, is activated in heart failure (HF). We hypothesized that HF patients are characterized by an imbalance of alternative amplification loop components; including properdin and complement factor D and the alternative pathway inhibitor factor H. These components and the activation product, terminal complement complex (TCC), were measured in plasma from 188 HF patients and 67 age- and sex- matched healthy controls by enzyme immunoassay. Our main findings were: (i) Compared to controls, patients with HF had significantly increased levels of factor D and TCC, and decreased levels of properdin, particularly patients with advanced clinical disorder (i...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28191609/complement-blockade-in-anca-associated-vasculitis-an-index-case-current-concepts-and-future-perspectives
#3
REVIEW
Lucio Manenti, Maria Letizia Urban, Federica Maritati, Maricla Galetti, Augusto Vaglio
Complement alternative pathway (cAP) hyperactivation seems to be involved in ANCA-associated vasculitis (AAV). We here describe a case of AAV with severe activation of cAP that developed acute renal failure. No mutation predisposing to cAP dysregulation was identified. We treated our patient with the standard immunosuppressive therapy, but disease progression was only reversed after the addition of eculizumab, a monoclonal antibody against C5; the patient eventually achieved an almost complete renal function recovery...
February 13, 2017: Internal and Emergency Medicine
https://www.readbyqxmd.com/read/28188176/lectin-pathway-effector-enzyme-mannan-binding-lectin-associated-serine-protease-2-can-activate-native-complement-c3-in-absence-of-c4-and-or-c2
#4
Sadam Yaseen, Gregory Demopulos, Thomas Dudler, Munehisa Yabuki, Christi L Wood, W Jason Cummings, Larry W Tjoelker, Teizo Fujita, Steven Sacks, Peter Garred, Peter Andrew, Robert B Sim, Peter J Lachmann, Russell Wallis, Nicholas Lynch, Wilhelm J Schwaeble
All 3 activation pathways of complement-the classic pathway (CP), the alternative pathway, and the lectin pathway (LP)- converge into a common central event: the cleavage and activation of the abundant third complement component, C3, via formation of C3-activating enzymes (C3 convertases). The fourth complement component, C4, and the second component, C2, are indispensable constituents of the C3 convertase complex, C4bC2a, which is formed by both the CP and the LP. Whereas in the absence of C4, CP can no longer activate C3, LP retains a residual but physiologically critical capacity to convert native C3 into its activation fragments, C3a and C3b...
February 10, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28176476/recurrent-atypical-haemolytic-uraemic-syndrome-post-kidney-transplant-due-to-a-cd46-mutation-in-the-setting-of-smarcal1-mediated-inherited-kidney-disease
#5
REVIEW
Samuel Chan, Andrew J Mallett, Chirag Patel, Ross S Francis, David W Johnson, David W Mudge, Nicole M Isbel
Disorders in the regulation of the alternate complement pathway often result in complement-mediated damage to the microvascular endothelium and can be associated with both glomerulonephritis and atypical haemolytic uraemic syndrome. Inherited defects in complement regulatory genes or autoantibodies against complement regulatory proteins are predictive of the severity of the disease and the risk of recurrence post kidney transplantation. Heterozygous mutations in CD46, which codes for a transmembrane cofactor glycoprotein membrane cofactor protein, usually have a lower incidence of end-stage kidney disease and decreased risk of recurrent disease post transplant, as wild-type membrane cofactor protein is present in the transplanted kidney...
February 2017: Nephrology
https://www.readbyqxmd.com/read/28176473/durable-remission-of-c3-glomerulonephritis-with-mycophenolate-mofetil
#6
REVIEW
Nicole Lioufas, Moira Finlay, Thomas Barbour
In C3 glomerulopathy, uncontrolled complement C3 activation via the alternative pathway results in glomerular C3 deposition and, in many cases, progressive renal failure. Despite advances in understanding of C3G pathogenesis over the last few years, there are no proven treatments. We describe a patient in whom C3 glomerulopathy was associated with renal impairment and elevated serum free kappa light chains. An initial response to corticosteroids was followed by relapse once steroids were weaned, prompting use of mycophenolate mofetil to maintain remission...
February 2017: Nephrology
https://www.readbyqxmd.com/read/28157704/overlooked-fancd2-variant-encodes-a-promising-portent-tumor-suppressor-and-alternative-polyadenylation-contributes-to-its-expression
#7
Bing Hang, Yihang Shen, Piyan Zhang, Panneerselvam Jayabal, Raymond Che, Jun Zhang, Herbert Yu, Peiwen Fei
Fanconi Anemia (FA) complementation group D2 protein (FANCD2) is the center of the FA tumor suppressor pathway, which has become an important field of investigation in human aging and cancer. Here we report an overlooked central player in the FA pathway, FANCD2 variant 2 (FANCD2-V2), which appears to perform more potent tumor suppressor-function compared to the known variant of FANCD2, namely, FANCD2-V1. Detailed analysis of the FANCD2 gene structure indicated a proximal and distal polyadenylation site (PAS), associated with V2 and V1 transcripts accordingly...
February 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28157311/structure-based-library-design-and-fragment-screening-for-the-identification-of-reversible-complement-factor-d-protease-inhibitors
#8
Anna Vulpetti, Stefan Randl, Simon Rüdisser, Nils Ostermann, Paulus Erbel, Aengus MacSweeney, Thomas Zoller, Bahaa Salem, Bernd Gerhartz, Frederic Cumin, Ulrich Hommel, Claudio Dalvit, Edwige Lorthiois, Jürgen Maibaum
Chronic dysregulation of alternative complement pathway activation has been associated with diverse clinical disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinurea. Factor D is a trypsin-like serine protease with a narrow specificity for arginine in the P1 position, which catalyses the first enzymatic reaction of the amplification loop of the alternative pathway. In this paper, we describe two hit finding approaches leading to the discovery of new chemical matter for this pivotal protease of the complement system: in silico active site mapping for hot spots identification to guide rational structure-based design and NMR screening of focussed and diverse fragment libraries...
February 3, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28139294/c5-inhibition-prevents-renal-failure-in-a-mouse-model-of-lethal-c3-glomerulopathy
#9
Allison Lesher Williams, Damodar Gullipalli, Yoshiyasu Ueda, Sayaka Sato, Lin Zhou, Takashi Miwa, Kenneth S Tung, Wen-Chao Song
C3 glomerulopathy is a potentially life-threatening disease of the kidney caused by dysregulated alternative pathway complement activation. The specific complement mediator(s) responsible for kidney injury in C3 glomerulopathy are yet to be defined and no specific therapy is currently available. We previously developed a mouse model of lethal C3 glomerulopathy with factor H and properdin gene double mutations. Therefore, we used this model to examine the role of C5 and C5a receptor (C5aR) in the pathogenesis of the disease...
January 27, 2017: Kidney International
https://www.readbyqxmd.com/read/28137479/can-innate-and-autoimmune-reactivity-forecast-early-and-advance-stages-of-age-related-macular-degeneration
#10
REVIEW
Grazyna Adamus
Age-related macular degeneration (AMD) is a major cause of central vision loss in persons over 55years of age in developed countries. AMD is a complex disease in which genetic, environmental and inflammatory factors influence its onset and progression. Elevation in serum anti-retinal autoantibodies, plasma and local activation of complement proteins of the alternative pathway, and increase in secretion of proinflammatory cytokines have been seen over the course of disease. Genetic studies of AMD patients confirmed that genetic variants affecting the alternative complement pathway have a major influence on AMD risk...
January 27, 2017: Autoimmunity Reviews
https://www.readbyqxmd.com/read/28130094/a-teleost-complement-factor-ba-possesses-antimicrobial-activity-and-inhibits-bacterial-infection-in-fish
#11
Xue-Peng Li, Li Sun
Complement factor B (Bf) is a component of the complement system. Following activation of the alternative pathway of the complement system, factor B is cleaved into Ba and Bb fragments. In fish, the Bf of rainbow trout is known to act as a C3 convertase, but the function of the Ba fragment is essentially unknown. In this study, we examined the expression patterns of tongue sole Cynoglossus semilaevis Bf (named CsBf) and the biological activity of the Ba fragment of CsBf (named CsBa). CsBf possesses the conserved domains of Bf and shares 39...
January 24, 2017: Developmental and Comparative Immunology
https://www.readbyqxmd.com/read/28125402/a-microplate-assay-to-measure-classical-and-alternative-complement-activity
#12
Bénédicte Puissant-Lubrano, Françoise Fortenfant, Peter Winterton, Antoine Blancher
BACKGROUND: We developed and validated a kinetic microplate hemolytic assay (HA) to quantify classical and alternative complement activity in a single dilution of human plasma or serum. METHODS: The assay is based on monitoring hemolysis of sensitized sheep (or uncoated rabbit) red blood cells by means of a 96-well microplate reader. The activity of the calibrator was evaluated by reference to 200 healthy adults. The conversion of 50% hemolysis time into a percentage of activity was obtained using a calibration curve plotted daily...
January 26, 2017: Clinical Chemistry and Laboratory Medicine: CCLM
https://www.readbyqxmd.com/read/28123945/the-neuropeptide-tlqp-21-opposes-obesity-via%C3%A2-c3ar1-mediated-enhancement-of-adrenergic-induced-lipolysis
#13
Cheryl Cero, Maria Razzoli, Ruijun Han, Bhavani Shankar Sahu, Jessica Patricelli, ZengKui Guo, Nathan A Zaidman, John M Miles, Scott M O'Grady, Alessandro Bartolomucci
OBJECTIVES: Obesity is characterized by excessive fat mass and is associated with serious diseases such as type 2 diabetes. Targeting excess fat mass by sustained lipolysis has been a major challenge for anti-obesity therapies due to unwanted side effects. TLQP-21, a neuropeptide encoded by the pro-peptide VGF (non-acronymic), that binds the complement 3a receptor 1 (C3aR1) on the adipocyte membrane, is emerging as a novel modulator of adipocyte functions and a potential target for obesity-associated diseases...
January 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28105653/properdin-and-factor-h-production-by-human-dendritic-cells-modulates-their-t-cell-stimulatory-capacity-and-is-regulated-by-ifn-%C3%AE
#14
Karen O Dixon, Joseph O'Flynn, Ngaisah Klar-Mohamad, Mohamed R Daha, Cees van Kooten
Dendritic cells (DCs) and complement are both key members of the innate and adaptive immune response. Recent experimental mouse models have shown that production of alternative pathway (AP) components by DCs strongly affects their ability to activate and regulate T-cell responses. In this study we investigated the production and regulation of properdin (fP) and factor H (fH) both integral regulators of the AP, by DCs and tolerogenic DCs (tolDCs). Both fP and fH were produced by DCs, with significantly higher levels of both AP components produced by tolDCs...
January 20, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28104134/eculizumab-and-belatacept-for-de-novo-atypical-hemolytic-uremic-syndrome-associated-with-cfhr3-cfhr1-deletion-in-a-kidney-transplant-recipient-a-case-report
#15
P Dedhia, A Govil, G Mogilishetty, R R Alloway, E S Woodle, B G Abu Jawdeh
BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is associated with significant morbidity and mortality and occurs due to genetic or acquired abnormalities that result in the dysregulation of the alternative complement pathway. CASE REPORT: We report a case of post-living kidney transplantation de novo aHUS in a setting of heterozygous deletion in the complement factor H-related protein (CFHR)3-CFHR1 gene. The aHUS episode was possibly triggered by antibody-mediated rejection or tacrolimus...
January 2017: Transplantation Proceedings
https://www.readbyqxmd.com/read/28101432/atypical-hemolytic-uremic-syndrome-in-first-trimester-pregnancy-successfully-treated-with-eculizumab
#16
Gabriela Andries, Michael Karass, Srikanth Yandrapalli, Katherine Linder, Delong Liu, John Nelson, Rahul Pawar, Savneek Chugh
BACKGROUND: Atypical hemolytic uremic syndrome is a rare disorder which is known to cause acute thrombotic microangiopathy during pregnancy with poor maternal and fetal outcomes. Atypical hemolytic uremic syndrome is caused mostly by dysregulation of alternative complement pathway secondary to genetic mutations. Most of the cases reported have been in the post-partum period. We report a rare case of a patient who presents with thrombotic microangiopathy in the first trimester of her eleventh pregnancy and was successfully treated with eculizumab...
2017: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/28096309/anti-factor-b-and-anti-c3b-autoantibodies-in-c3-glomerulopathy-and-ig-associated-membranoproliferative-gn
#17
Maria Chiara Marinozzi, Lubka T Roumenina, Sophie Chauvet, Alexandre Hertig, Dominique Bertrand, Jérome Olagne, Marie Frimat, Tim Ulinski, Georges Deschênes, Stephane Burtey, Michel Delahousse, Bruno Moulin, Christophe Legendre, Véronique Frémeaux-Bacchi, Moglie Le Quintrec
In C3 glomerulopathy (C3G), the alternative pathway of complement is frequently overactivated by autoantibodies that stabilize the C3 convertase C3bBb. Anti-C3b and anti-factor B (anti-FB) IgG have been reported in three patients with C3G. We screened a cohort of 141 patients with C3G and Ig-associated membranoproliferative GN (Ig-MPGN) for anti-FB and anti-C3b autoantibodies using ELISA. We identified seven patients with anti-FB IgG, three patients with anti-C3b IgG, and five patients with anti-FB and anti-C3b IgG...
January 17, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28087810/akt1-lkb1-and-yap1-revealed-as-myc-interactors-with-nanoluc-based-protein-fragment-complementation-assay
#18
Xiu-Lei Mo, Qi Qi, Andrei A Ivanov, Qiankun Niu, Yin Luo, Jonathan Havel, Russell Goetze, Sydney Bell, Carlos S Moreno, Lee A D Cooper, Margaret A Johns, Fadlo R Khuri, Yuhong Du, Haian Fu
The c-Myc (MYC) transcription factor is a major cancer driver and a well-validated therapeutic target. However, directly targeting MYC has been challenging. Thus, identifying proteins that interact with and regulate MYC may provide alternative strategies to inhibit its oncogenic activity. Here we report the development of a NanoLuc®-based protein-fragment complementation assay (NanoPCA) and mapping of the MYC protein interaction hub in live mammalian cells. The NanoPCA system was configured to enable detection of protein-protein interactions (PPI) at the endogenous level, as shown with PRAS40 dimerization, and detection of weak interactions, such as PINCH1-NCK2...
January 13, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28062698/monoclonal-antibodies-against-epidermal-growth-factor-receptor-acquire-an-ability-to-kill-tumor-cells-through-complement-activation-by-mutations-that-selectively-facilitate-the-hexamerization-of-igg-on-opsonized-cells
#19
Annalina Tammen, Stefanie Derer, Ralf Schwanbeck, Thies Rösner, Anna Kretschmer, Frank J Beurskens, Janine Schuurman, Paul W H I Parren, Thomas Valerius
Triggering of the complement cascade induces tumor cell lysis via complement-dependent cytotoxicity (CDC) and attracts and activates cytotoxic cells. It therefore represents an attractive mechanism for mAb in cancer immunotherapy development. The classical complement pathway is initiated by IgG molecules that have assembled into ordered hexamers after binding their Ag on the tumor cell surface. The requirements for CDC are further impacted by factors such as Ab epitope, valency, and affinity. Thus, mAb against well-validated solid tumor targets, such as the epidermal growth factor receptor (EGFR) that effectively induces complement activation and CDC, are highly sought after...
January 6, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28058212/complement-related-kidney-diseases-recurrence-after-transplantation
#20
REVIEW
Maurizio Salvadori, Elisabetta Bertoni
The recurrence of renal disease after renal transplantation is becoming one of the main causes of graft loss after kidney transplantation. This principally concerns some of the original diseases as the atypical hemolytic uremic syndrome (HUS), the membranoproliferative glomerulonephritis (MPGN), in particular the MPGN now called C3 glomerulopathy. Both this groups of renal diseases are characterized by congenital (genetic) or acquired (auto-antibodies) modifications of the alternative pathway of complement...
December 24, 2016: World Journal of Transplantation
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