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Complement alternative pathway

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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
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
https://www.readbyqxmd.com/read/28040558/complement-in-autoimmune-diseases
#8
REVIEW
Pandiarajan Vignesh, Amit Rawat, Madhubala Sharma, Surjit Singh
The complement system is an ancient and evolutionary conserved element of the innate immune mechanism. It comprises of more than 20 serum proteins most of which are synthesized in the liver. These proteins are synthesized as inactive precursor proteins which are activated by appropriate stimuli. The activated forms of these proteins act as proteases and cleave other components successively in amplification pathways leading to exponential generation of final effectors. Three major pathways of complement pathways have been described, namely the classical, alternative and lectin pathways which are activated by different stimuli...
December 28, 2016: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28028023/incomplete-inhibition-by-eculizumab-mechanistic-evidence-for-residual-c5-activity-during-strong-complement-activation
#9
Markus J Harder, Nadine Kuhn, Hubert Schrezenmeier, Britta Höchsmann, Inge von Zabern, Christof Weinstock, Thomas Simmet, Daniel Ricklin, John D Lambris, Arne Skerra, Markus Anliker, Christoph Q Schmidt
Eculizumab inhibits the terminal, lytic pathway of complement by blocking the activation of the complement protein C5 and shows remarkable clinical benefits in certain complement-mediated diseases. However, several reports suggest that activation of C5 is not always completely suppressed in patients even under excess of eculizumab over C5 indicating that residual C5 activity may derogate the drug's therapeutic benefit under certain conditions. By using eculizumab and the tick-derived C5 inhibitor coversin we determine conditions ex vivo in which C5-inhibition is incomplete...
December 27, 2016: Blood
https://www.readbyqxmd.com/read/28019718/excretions-secretions-from-medicinal-larvae-lucilia-sericata-inhibit-complement-activation-by-two-mechanisms
#10
Tetsuro Tamura, Gwendolyn Cazander, Suzan H M Rooijakkers, Leendert A Trouw, Peter H Nibbering
Larvae of the blowfly Lucilia sericata facilitate wound healing by removing dead tissue and biofilms from non-healing and necrotic wounds. Another beneficial action of larvae and their excretions/secretions (ES) is down-regulation of excessive inflammation. As prolonged complement activation is key to excessive inflammation, the aim of this study was to elucidate the mechanisms underlying the anti-complement activities of ES. Results revealed that heat sensitive serine proteases in ES degrade multiple complement proteins in all steps of the three complement activation pathways...
December 26, 2016: Wound Repair and Regeneration
https://www.readbyqxmd.com/read/28012609/lutein-and-atherosclerosis-belfast-versus-toulouse-revisited
#11
A N Howard, D I Thurnham
In 1995 we reported that mean plasma lutein concentrations in salaried men and women from Toulouse in Southern France were double those in subjects recruited from general practitioner lists in Belfast, Northern Ireland. At the time incidence of coronary heart disease (CHD) in Southern France was among the lowest in Europe and was much higher in Northern Ireland. Plasma lutein is a biomarker of vegetable and fruit intake and evidence suggests that high concentrations are generally associated with better cardiometabolic health...
January 2017: Medical Hypotheses
https://www.readbyqxmd.com/read/27994856/c3-glomerulopathy-in-adults-a-distinct-patient-subset-showing-frequent-association-with-monoclonal-gammopathy-and-poor-renal-outcome
#12
Isaac E Lloyd, Alexander Gallan, Hunter K Huston, Kalani L Raphael, Dylan V Miller, Monica P Revelo, Mazdak A Khalighi
BACKGROUND: C3 glomerulopathy (C3G) includes both C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) and is defined by C3-dominant deposits on immunofluorescence. Dysfunction of the alternative pathway (AP) of complement is central to the pathophysiology of C3G and young patients often harbor genetic alterations of AP mediators. Recently, a link between C3G and paraproteinemia has been established. We performed this study to better characterize older patients with C3G where this association is more frequently seen...
December 2016: Clinical Kidney Journal
https://www.readbyqxmd.com/read/27994744/buried-hydrogen-bond-interactions-contribute-to-the-high-potency-of-complement-factor-d-inhibitors
#13
Chao-Yie Yang, James G Phillips, Jeanne A Stuckey, Longchuan Bai, Haiying Sun, James Delproposto, William Clay Brown, Krishnapriya Chinnaswamy
Aberrant activation of the complement system is associated with diseases, including paroxysmal nocturnal hemoglobinuria and age-related macular degeneration. Complement factor D is the rate-limiting enzyme for activating the alternative pathway in the complement system. Recent development led to a class of potent amide containing pyrrolidine derived factor D inhibitors. Here, we used biochemical enzymatic and biolayer interferometry assays to demonstrate that the amide group improves the inhibitor potency by more than 80-fold...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27992410/complement-proteins-bind-to-nanoparticle-protein-corona-and-undergo-dynamic-exchange-in-vivo
#14
Fangfang Chen, Guankui Wang, James I Griffin, Barbara Brenneman, Nirmal K Banda, V Michael Holers, Donald S Backos, LinPing Wu, Seyed Moein Moghimi, Dmitri Simberg
When nanoparticles are intravenously injected into the body, complement proteins deposit on the surface of nanoparticles in a process called opsonization. These proteins prime the particle for removal by immune cells and may contribute toward infusion-related adverse effects such as allergic responses. The ways complement proteins assemble on nanoparticles have remained unclear. Here, we show that dextran-coated superparamagnetic iron oxide core-shell nanoworms incubated in human serum and plasma are rapidly opsonized with the third complement component (C3) via the alternative pathway...
December 19, 2016: Nature Nanotechnology
https://www.readbyqxmd.com/read/27984711/evaluation-of-anaphylactoid-constituents-in-vitro-and-in-vivo
#15
Yubin Xu, Chunyan Liu, Deqiang Dou, Qiuhong Wang
Natural medicine injections have been widely used in clinics, while adverse reaction reports also have increased rapidly in recent years. To examine the anaphylactoid constituents of natural medicine injections, RBL-2H3 cell degranulation and human serum complement activation models were used to screen the anaphylactoid constituents, and the BN rat model was used to explore the anaphylactoid mechanism of these constituents. The result of an in vitro study showed that the individual compounds of natural medicine injections (chlorogenic acid, hyodeoxycholic acid, cholalic acid, ginkgolic acid, phillyrin, schisandrin B, schisandrin A, puerarin, and tanshinone IIA) and polysaccharide could not induce RBL-2H3 to release histamine and β-hexosaminidase, while proteins Tween-80 and tannic acid were the main anaphylactoid constituents in the natural medicine injections...
February 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/27960595/meningococcal-serogroup-b-vaccines-estimating-breadth-of-coverage
#16
Robert G K Donald, Julio Cesar Hawkins, Li Hao, Paul Liberator, Thomas R Jones, Shannon L Harris, John L Perez, Joseph J Eiden, Kathrin U Jansen, Annaliesa S Anderson
Neisseria meningitidis serogroup B (MenB) is an important cause of invasive meningococcal disease. The development of safe and effective vaccines with activity across the diversity of MenB strains has been challenging. While capsular polysaccharide conjugate vaccines have been highly successful in the prevention of disease due to meningococcal serogroups A, C, W, and Y, this approach has not been possible for MenB owing to the poor immunogenicity of the MenB capsular polysaccharide. Vaccines based on outer membrane vesicles have been successful in the prevention of invasive MenB disease caused by the single epidemic strain from which they were derived, but they do not confer broad protection against diverse MenB strains...
December 14, 2016: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/27959629/complement-dysregulation-and-disease-insights-from-contemporary-genetics
#17
M Kathryn Liszewski, Anuja Java, Elizabeth C Schramm, John P Atkinson
The vertebrate complement system consists of sequentially interacting proteins that provide for a rapid and powerful host defense. Nearly 60 proteins comprise three activation pathways (classical, alternative, and lectin) and a terminal cytolytic pathway common to all. Attesting to its potency, nearly half of the system's components are engaged in its regulation. An emerging theme over the past decade is that variations in these inhibitors predispose to two scourges of modern humans. One, occurring most often in childhood, is a rare but deadly thrombomicroangiopathy called atypical hemolytic uremic syndrome...
December 5, 2016: Annual Review of Pathology
https://www.readbyqxmd.com/read/27956602/pathway-swapping-toward-modular-engineering-of-essential-cellular-processes
#18
Niels G A Kuijpers, Daniel Solis-Escalante, Marijke A H Luttik, Markus M M Bisschops, Francine J Boonekamp, Marcel van den Broek, Jack T Pronk, Jean-Marc Daran, Pascale Daran-Lapujade
Recent developments in synthetic biology enable one-step implementation of entire metabolic pathways in industrial microorganisms. A similarly radical remodelling of central metabolism could greatly accelerate fundamental and applied research, but is impeded by the mosaic organization of microbial genomes. To eliminate this limitation, we propose and explore the concept of "pathway swapping," using yeast glycolysis as the experimental model. Construction of a "single-locus glycolysis" Saccharomyces cerevisiae platform enabled quick and easy replacement of this yeast's entire complement of 26 glycolytic isoenzymes by any alternative, functional glycolytic pathway configuration...
December 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27942176/identification-of-urinary-proteins-potentially-associated-with-diabetic-kidney-disease
#19
R K Marikanty, M K Gupta, S V B Cherukuvada, S S S Kompella, A K Prayaga, S Konda, R V Polisetty, M M Idris, P V Rao, G R Chandak, K V Dakshinamurty
Diabetic nephropathy (DN) is the most common cause of chronic kidney disease. Although several parameters are used to evaluate renal damage, in many instances, there is no pathological change until damage is already advanced. Mass spectrometry-based proteomics is a novel tool to identify newer diagnostic markers. To identify urinary proteins associated with renal complications in diabetes, we collected urine samples from 10 type 2 diabetes patients each with normoalbuminuria, micro- and macro-albuminuria and compared their urinary proteome with that of 10 healthy individuals...
November 2016: Indian Journal of Nephrology
https://www.readbyqxmd.com/read/27939215/the-functional-activities-of-complement-factor-h-are-impaired-in-patients-with-anca-positive-vasculitis
#20
Su-Fang Chen, Feng-Mei Wang, Zhi-Ying Li, Feng Yu, Min Chen, Ming-Hui Zhao
Increasing evidences have demonstrated that the activation of the alternative complement pathway is crucial for the pathogenesis of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). Our recent study found that circulating levels of complement factor H (FH), a key regulator of the alternative pathway, were associated with disease activity. In the current study, functional activities of FH were assessed to further explore the potential role of FH in the pathogenesis of AAV. We found that the two patients with ANCA-negative pauci-immune necrotizing crescentic glomerulonephritis exhibited relatively normal functional activities of FH...
December 6, 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
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