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Complement alternative pathway

Xiaobo Wu, Irina Hutson, Antonina M Akk, Smita Mascharak, Christine T N Pham, Dennis E Hourcade, Rebecca Brown, John P Atkinson, Charles A Harris
Factor D (FD) is an essential component of the complement alternative pathway (AP). It is an attractive pharmaceutical target because it is an AP-specific protease circulating in blood. Most components of the complement activation pathways are produced by the liver, but FD is highly expressed by adipose tissue. Two critical questions are: 1) to what degree does adipose tissue contribute to circulating FD levels and 2) what quantity of FD is sufficient to maintain a functional AP? To address these issues, we studied a novel mouse strain with complete lipodystrophy (LD), the fld mouse with partial LD, an FD-deficient mouse, and samples from lipodystrophic patients...
March 12, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Peter J Lachmann
The alternative pathway of complement originated from the Properdin pathway originally described by the Pillemer laboratory in the 1950s. This work generated great controversy and it took several decades for a consensus on its components, its reaction sequence and its functions to emerge. This paper reviews this history and attempts to clarify some of the ambiguities that remain.
March 6, 2018: Immunobiology
Christopher C T Sng, Sorcha O'Byrne, Daniil M Prigozhin, Matthias R Bauer, Jennifer C Harvey, Michelle Ruhle, Ben G Challis, Sara Lear, Lee D Roberts, Sarita Workman, Tobias Janowitz, Lukasz Magiera, Rainer Doffinger, Matthew S Buckland, Duncan J Jodrell, Robert K Semple, Timothy J Wilson, Yorgo Modis, James E D Thaventhiran
No abstract text is available yet for this article.
March 6, 2018: Journal of Allergy and Clinical Immunology
Jonathan H Foley, Edward M Conway
The complement system, comprising over 30 soluble and cell-based proteins, is a major component of innate immunity, providing mechanisms of surveillance to detect and discard invading pathogens and damaged host cells (reviewed in [1, 2]). Triggered by recognition of altered molecular complexes on membrane surfaces that are sensed as danger signals, complement activation proceeds via three cascade-like pathways - lectin, classical, and alternative - which converge with the formation of a C3 convertase. Subsequent downstream generation of multiple complement byproducts, including the anaphylatoxins, C3a and C5a, leads to inflammation, opsonization, phagocytosis, and destruction of the target cell/pathogen, with recruitment of an adaptive immune response to effect long-term protection and repair...
March 8, 2018: Journal of Thrombosis and Haemostasis: JTH
H Terence Cook
PURPOSE OF REVIEW: The current review will discuss recent advances in our understanding of the pathology of C3 glomerulopathy and atypical haemolytic uremic syndrome (aHUS). RECENT FINDINGS: C3 glomerulopathy and aHUS are associated with abnormalities of control of the alternative pathway of complement. Recent articles have provided new insights into the classification of C3 glomerulopathy and its relationship to idiopathic immune complex-mediated glomerulonephritis...
March 6, 2018: Current Opinion in Nephrology and Hypertension
Samuel Deshayes, Nicolas Martin Silva, Valérie Chatelet, Sylvain Chantepie, Moglie Le Quintrec, François Comoz, Frank Bridoux, Marie-Agnès Dragon-Durey, Achille Aouba
B-cell clones can produce a monoclonal immunoglobulin, which may be responsible for visceral involvements. Kidney involvement is frequent, affecting 20 to 50% of patients with multiple myeloma. One mechanism underlying this involvement is a dysregulation of the complement alternative pathway, leading to C3 glomerulopathies. We report a patient who had a multiple myeloma, C3 glomerulopathy related to factor H autoantibody, and digital ischemia, who was treated successfully with eculizumab, an anti-complement therapy, without any relapse in 2 years of follow-up...
March 7, 2018: Clinical Rheumatology
Cecilia Hagert, Outi Sareila, Tiina Kelkka, Kutty Selva Nandakumar, Mattias Collin, Bingze Xu, Simon Guérard, Johan Bäcklund, Sirpa Jalkanen, Rikard Holmdahl
OBJECTIVE: To develop a new chronic RA model which is driven by the innate immune system. METHOD: The injection of a cocktail of four monoclonal antibodies against collagen type II followed by intra-peritoneal injections of mannan (from Saccharomyces cerevisiae) on days 5 and 60 led to the development of chronic arthritis in B10.Q mice. The role of the innate versus the adaptive immune system in this arthritis model was investigated using genetically modified mouse strains...
March 7, 2018: Arthritis & Rheumatology
David Goldsmith, Frank Dellanna, Martin Schiestl, Andriy Krendyukov, Christian Combe
Biosimilars are biological medicines that are approved via stringently defined regulatory pathways on the basis that comparable safety, efficacy, and quality have been demonstrated to their reference medicine. The advantage of biosimilar drugs is that they may be less expensive than the reference medicine, allowing for greater patient access and cost savings in already stretched healthcare budgets. Biosimilar epoetins have been available in Europe for a decade. Complementing in vitro and preclinical characterization, and pharmacokinetic/pharmacodynamic studies, clinical trials provided the additional data needed to reassure European authorities that biosimilar epoetins were sufficiently similar to the reference epoetin to warrant approval...
March 2, 2018: Clinical Drug Investigation
Amy J Osborne, Matteo Breno, Nicolo Ghiringhelli Borsa, Fengxiao Bu, Véronique Frémeaux-Bacchi, Daniel P Gale, Lambertus P van den Heuvel, David Kavanagh, Marina Noris, Sheila Pinto, Pavithra M Rallapalli, Giuseppe Remuzzi, Santiago Rodríguez de Cordoba, Angela Ruiz, Richard J H Smith, Paula Vieira-Martins, Elena Volokhina, Valerie Wilson, Timothy H J Goodship, Stephen J Perkins
Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) are associated with dysregulation and overactivation of the complement alternative pathway. Typically, gene analysis for aHUS and C3G is undertaken in small patient numbers, yet it is unclear which genes most frequently predispose to aHUS or C3G. Accordingly, we performed a six-center analysis of 610 rare genetic variants in 13 mostly complement genes ( CFH , CFI , CD46 , C3 , CFB , CFHR1 , CFHR3 , CFHR4 , CFHR5 , CFP , PLG , DGKE , and THBD ) from >3500 patients with aHUS and C3G...
March 2, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Rasmus K Jensen, Rasmus Pihl, Trine A F Gadeberg, Jan K Jensen, Kasper R Andersen, Steffen Thiel, Nick S Laursen, Gregers Rom Andersen
The complement system is a complex, carefully regulated proteolytic cascade for which suppression of aberrant activation is of increasing clinical relevance and inhibition of the complement alternative pathway is a subject of intense research. Here, we describe the nanobody hC3Nb1 that binds to multiple functional states of C3 with sub-nanomolar affinity. The nanobody causes a complete shutdown of alternative pathway activity in human and murine serum when present in concentrations comparable to C3, and hC3Nb1 is shown to prevent both proconvertase assembly as well as binding of the C3 substrate to C3 convertases...
March 1, 2018: Journal of Biological Chemistry
Hiroyuki Nakamura, Kenji Oku, Yusuke Ogata, Kazumasa Ohmura, Yoko Yoshida, Etsuko Kitano, Yuichiro Fujieda, Masaru Kato, Toshiyuki Bohgaki, Olga Amengual, Shinsuke Yasuda, Yoshihiro Fujimura, Tsukasa Seya, Tatsuya Atsumi
INTRODUCTION: Although complement activation has been proposed as a possible thrombophilic mechanism in antiphospholipid syndrome (APS), the origin of complement activation in APS remains unclear. Here, we focused on complement regulatory factors (CRF), which control the complement system to prevent damage to host tissue. We evaluated the function of two major CRF, membrane cofactor protein (MCP) and factor H (FH), in APS patients. MATERIALS AND METHODS: In this study, we analyzed preserved serum samples from 27 patients with primary APS (PAPS), 20 with APS complicated with SLE (APS + SLE), 24 with SLE (SLE), and 25 with other connective tissue diseases (Other CTD)...
February 21, 2018: Thrombosis Research
Dong-Sheng Du, Zhi-Hong Cheng, Dao-Feng Chen
Fifteen alkaloids were isolated from the 95% ethanol extract of the whole plants of Viola yedoensis by various column chromatographic techniques such as silica gel and Sephadex LH-20. Their structures were identified as neoechinulin A(1),N-benzoyl-L-p-hydroxy-phenylalaninol(2),aurantiamide acetate(3),aurantiamide(4),anabellamide(5),trichosanatine(6),indole-3-carboxylic acid methyl ester(7),3-carboxyindole(8),N-trans-feruloyl-tyramine(9),paprazine(10),7'-(3', 4'-dihydroxyphenyl)-N-[(4-methoxyphenyl)ethyl]propenamide(11),cannabisin F(12),N-(4-hydroxyphenethyl)octacosanamide(13),N-(4-hydroxyphenethyl)hexacosanamide(14)and N-benzoyl-L-phenylalaninol(15)...
December 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
Lubna Kouser, Basudev Paudyal, Anuvinder Kaur, Gudrun Stenbeck, Lucy A Jones, Suhair M Abozaid, Cordula M Stover, Emmanuel Flahaut, Robert B Sim, Uday Kishore
Development of nanoparticles as tissue-specific drug delivery platforms can be considerably influenced by the complement system because of their inherent pro-inflammatory and tumorigenic consequences. The complement activation pathways, and its recognition subcomponents, can modulate clearance of the nanoparticles and subsequent inflammatory response and thus alter the intended translational applications. Here, we report, for the first time, that human properdin, an upregulator of the complement alternative pathway, can opsonize functionalized carbon nanotubes (CNTs) via its thrombospondin type I repeat (TSR) 4 and 5...
2018: Frontiers in Immunology
Marco Incarbone, Christophe Ritzenthaler, Patrice Dunoyer
Peroxisomes are organelles that play key roles in eukaryotic metabolism. Their protein complement is entirely imported from the cytoplasm thanks to a unique pathway that is able to translocate folded proteins and protein complexes across the peroxisomal membrane. The import of molecules bound to a protein targeted to peroxisomes is an active process known as 'piggybacking' and we have recently shown that P15, a virus-encoded protein possessing a peroxisomal targeting sequence, is able to piggyback siRNAs into peroxisomes...
2018: Frontiers in Plant Science
Manoj K Pandey, Gregory A Grabowski, Jörg Köhl
The complement system is well appreciated for its role as an important effector of innate immunity that is activated by the classical, lectin or alternative pathway. C5a is one important mediator of the system that is generated in response to canonical and non-canonical C5 cleavage by circulating or cell-derived proteases. In addition to its function as a chemoattractant for neutrophils and other myeloid effectors, C5a and its sister molecule C3a have concerted roles in cell homeostasis and surveillance. Through activation of their cognate G protein coupled receptors, C3a and C5a regulate multiple intracellular pathways within the mitochondria and the lysosomal compartments that harbor multiple enzymes critical for protein, carbohydrate and lipid metabolism...
February 22, 2018: Seminars in Immunology
Jose Luis Espinosa-Figueroa, Marta Cano-Megías, Patricia Martínez-Miguel, Mercedes Velo-Plaza
Acute endocapillary glomerulonephritis, as its name suggests, is a one-time process, which usually resolves within weeks. However, in a small percentage of patients, the disease becomes chronic. In these cases, a deregulation in the alternative complement pathway, which can be caused by mutations or autoantibodies, has been proposed as a pathophysiological mechanism. As a result, the alternative complement pathway remains active after resolution of infection. We report a patient with two episodes of acute renal failure, both times diagnosed by renal biopsy of acute endocapillary glomerulonephritis, with slow recovery after two episodes of low-serum complement C3, haematuria and proteinuria...
February 23, 2018: BMJ Case Reports
Katalin Paréj, Andrea Kocsis, Csenge Enyingi, Ráhel Dani, Gábor Oroszlán, László Beinrohr, József Dobó, Péter Závodszky, Gábor Pál, Péter Gál
The complement system is a sophisticated network of proteases. In this article, we describe an unexpected link between two linear activation routes of the complement system: the lectin pathway (LP) and the alternative pathway (AP). Mannose-lectin binding-associated serine protease (MASP)-1 is known to be the initiator protease of the LP. Using a specific and potent inhibitor of MASP-1, SGMI-1, as well as other MASP-1 inhibitors with different mechanisms of action, we demonstrated that, in addition to its functions in the LP, MASP-1 is essential for bacterial LPS-induced AP activation, whereas it has little effect on zymosan-induced AP activation...
February 23, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Su-Fang Chen, Feng-Mei Wang, Zhi-Ying Li, Feng Yu, Min Chen, Ming-Hui Zhao
Objective: The interaction between neutrophils and activation of alternative complement pathway plays a critical role in the pathogenesis of ANCA-associated vasculitis (AAV). MPO, which can be released from ANCA-stimulated neutrophils, was recently demonstrated to be capable of activating the alternative complement pathway. Here we aimed to investigate the interaction between MPO and factor H (FH), a key regulator of the alternative pathway, and its effect on the functional activities of FH...
February 19, 2018: Rheumatology
Larissa F Marchi, Adriana B Paoliello-Paschoalato, Renê D R Oliveira, Ana Elisa C S Azzolini, Luciana M Kabeya, Eduardo A Donadi, Yara Maria Lucisano-Valim
We examined the functional activity of peripheral blood neutrophils and the complement system activation status in patients with rheumatoid arthritis (RA) undergoing infliximab/methotrexate combined therapy. We studied female RA patients under treatment with infliximab (3-5 mg/kg) and methotrexate (15-25 mg/week) who presented inactive (i-RA; n = 34, DAS-28 ≤ 2.6) or at least moderately active disease (a-RA; n = 29, DAS-28 > 3.2), and age-matched healthy women (n = 38). We measured the levels of reactive oxygen species (ROS) generation (chemiluminescence assay) and membrane expression of FcγRIIa/CD32, FcγRIIIb/CD16, CR1/CD35, and CR3/CD11b receptors (ELISA assay) in neutrophils...
February 20, 2018: Rheumatology International
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
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