The Experts below are selected from a list of 2343 Experts worldwide ranked by ideXlab platform
Dennis E. Hourcade - One of the best experts on this subject based on the ideXlab platform.
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antibody directs Properdin dependent activation of the complement alternative pathway in a mouse model of abdominal aortic aneurysm
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Huifang Zhou, Wenchao Song, Cordula M Stover, John P Atkinson, Huimin Yan, Tamara Montes Fernandez, Robert W Thompson, Wilhelm J Schwaeble, Dennis E. HourcadeAbstract:Abdominal aortic aneurysm (AAA) is a complex inflammatory vascular disease. There are currently limited treatment options for AAA when surgery is inapplicable. Therefore, insights into molecular mechanisms underlying AAA pathogenesis may reveal therapeutic targets that could be manipulated pharmacologically or biologically to halt disease progression. Using an elastase-induced AAA mouse model, we previously established that the complement alternative pathway (AP) plays a critical role in the development of AAA. However, the mechanism by which complement AP is initiated remains undefined. The complement protein Properdin, traditionally viewed as a positive regulator of the AP, may also initiate complement activation by binding directly to target surfaces. In this study, we sought to determine whether Properdin serves as a focal point for the initiation of the AP complement activation in AAA. Using a Properdin loss of function mutation in mice and a mutant form of the complement factor B protein that produces a stable, Properdin-free AP C3 convertase, we show that Properdin is required for the development of elastase-induced AAA in its primary role as a convertase stabilizer. Unexpectedly, we find that, in AAA, natural IgG antibodies direct AP-mediated complement activation. The absence of IgG abrogates C3 deposition in elastase-perfused aortic wall and protects animals from AAA development. We also determine that blockade of Properdin activity prevents aneurysm formation. These results indicate that an innate immune response to self-antigens activates the complement system and initiates the inflammatory cascade in AAA. Moreover, the study suggests that Properdin-targeting strategies may halt aneurysmal growth.
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the complement protein Properdin binds apoptotic t cells and promotes complement activation and phagocytosis
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Claudia Kemper, Lynne M Mitchell, Lijuan Zhang, Dennis E. HourcadeAbstract:Apoptotic cells must be rapidly eliminated to avoid harmful inflammatory and autoimmune reactions. Innate immunity is designed/poised to identify dying cells by their unique surface-associated molecular patterns. Here we demonstrate for the first time, to our knowledge, that the human complement protein Properdin binds to early apoptotic T cells and initiates complement activation, leading to C3b opsonization and ingestion by phagocytic cells. Properdin binding was facilitated by the glycosaminoglycan chains of surface proteoglycans. Properdin released by activated neutrophils was particularly effective at recognition of apoptotic T cells, whereas the binding activity of Properdin in the serum appeared to be inhibited. “Properdin tagging” of apoptotic T cells also induced their uptake by phagocytes independent of complement activation or other complement proteins. Although our findings were made primarily with apoptotic T cells, they suggest that Properdin could play a similar role during apoptosis of other cell types.
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Properdin can initiate complement activation by binding specific target surfaces and providing a platform for de novo convertase assembly
Journal of Immunology, 2007Co-Authors: Dirk Spitzer, John P Atkinson, Lynne M Mitchell, Dennis E. HourcadeAbstract:Complement promotes the rapid recognition and elimination of pathogens, infected cells, and immune complexes. The biochemical basis for its target specificity is incompletely understood. In this report, we demonstrate that Properdin can directly bind to microbial targets and provide a platform for the in situ assembly and function of the alternative pathway C3 convertases. This mechanism differs from the standard model wherein nascent C3b generated in the fluid phase attaches nonspecifically to its targets. Properdin-directed complement activation occurred on yeast cell walls (zymosan) and Neisseria gonorrhoeae. Properdin did not bind wild-type Escherichia coli, but it readily bound E. coli LPS mutants, and the Properdin-binding capacity of each strain correlated with its respective serum-dependent AP activation rate. Moreover, Properdin:single-chain Ab constructs were used to direct serum-dependent complement activation to novel targets. We conclude Properdin participates in two distinct complement activation pathways: one that occurs by the standard model and one that proceeds by the Properdin-directed model. The Properdin-directed model is consistent with a proposal made by Pillemer and his colleagues >50 years ago.
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The Role of Properdin in the Assembly of the Alternative Pathway C3 Convertases of Complement
Journal of Biological Chemistry, 2005Co-Authors: Dennis E. HourcadeAbstract:Complement is a powerful host defense system that contributes to both innate and acquired immunity. There are three pathways of complement activation, the classical pathway, lectin pathway, and alternative pathway. Each generates a C3 convertase, a serine protease that cleaves the central complement protein, C3. Nearly all the biological consequences of complement are dependent on the resulting cleavage products. Properdin is a positive regulator of complement activation that stabilizes the alternative pathway convertases (C3bBb). Properdin is composed of multiple identical protein subunits, with each subunit carrying a separate ligand-binding site. Previous reports suggest that Properdin function depends on multiple interactions between its subunits with its ligands. In this study I used surface plasmon resonance assays to examine Properdin interactions with C3b and factor B. I demonstrated that Properdin promotes the association of C3b with factor B and provides a focal point for the assembly of C3bBb on a surface. I also found that Properdin binds to preformed alternative pathway C3 convertases. These findings support a model in which Properdin, bound to a target surface via C3b, iC3b, or other ligands, can use its unoccupied C3b-binding sites as receptors for nascent C3b, bystander C3b, or pre-formed C3bB and C3bBb complexes. New C3bP and C3bBP intermediates can lead to in situ assembly of C3bBbP. The full stabilizing effect of Properdin on C3bBb would be attained as Properdin binds more than one ligand at a time, forming a lattice of Properdin: ligand interactions bound to a surface scaffold.
Tom Eirik Mollnes - One of the best experts on this subject based on the ideXlab platform.
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soluble collectin 12 mediates c3 independent docking of Properdin that activates the alternative pathway of complement
eLife, 2020Co-Authors: Tom Eirik Mollnes, Gregers R Andersen, Dennis Pedersen, Jie Zhang, Lihong Song, John D LambrisAbstract:Properdin stabilizes the alternative C3 convertase (C3bBb), whereas its role as pattern recognition molecule mediating complement activation is disputed for decades. Previously, we have found that soluble collectin-12 (sCL-12) synergizes complement alternative pathway (AP) activation. However, whether this observation is C3 dependent is unknown. By application of the C3-inhibitor Cp40, we found that Properdin in normal human serum bound to Aspergillus fumigatus solely in a C3b-dependent manner. Cp40 also prevented Properdin binding when Properdin-depleted serum reconstituted with purified Properdin was applied, in analogy with the findings achieved by C3-depleted serum. However, when opsonized with sCL-12, Properdin bound in a C3-independent manner exclusively via its tetrameric structure and directed in situ C3bBb assembly. In conclusion, a prerequisite for Properdin binding and in situ C3bBb assembly was the initial docking of sCL-12. This implies a new important function of Properdin in host defence bridging pattern recognition and specific AP activation.
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The alternative complement pathway is dysregulated in patients with chronic heart failure.
Scientific Reports, 2017Co-Authors: Negar Shahini, Karin Ekholt, Christen P. Dahl, Kaspar Broch, Thor Ueland, Pal Aukrust, Per H. Nilsson, Lars Gullestad, Annika E Michelsen, Tom Eirik MollnesAbstract: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.e., NYHA functional class IV), (ii) Levels of factor D and Properdin in HF patients were correlated with measures of systemic inflammation (i.e., C-reactive protein), neurohormonal deterioration (i.e., Nt-proBNP), cardiac function, and deteriorated diastolic function, (iii) Low levels of factor H and Properdin were associated with adverse outcome in univariate analysis and for factor H, this was also seen in an adjusted model. Our results indicate that dysregulation of circulating components of the alternative pathway explain the increased degree of complement activation and is related to disease severity in HF patients.
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the role of Properdin in zymosan and escherichia coli induced complement activation
Journal of Immunology, 2012Co-Authors: M Harboe, John D Lambris, P Garred, Julie Katrine Lindstad, Anne Pharo, Fredrik Muller, Gregory L Stahl, Tom Eirik MollnesAbstract:Properdin is well known as an enhancer of the alternative complement amplification loop when C3 is activated, whereas its role as a recognition molecule of exogenous pathogen-associated molecular patterns and initiator of complement activation is less understood. We therefore studied the role of Properdin in activation of complement in normal human serum by zymosan and various Escherichia coli strains. In ELISA, microtiter plates coated with zymosan induced efficient complement activation with deposition of C4b and terminal complement complex on the solid phase. Virtually no deposition of C4b or terminal complement complex was observed with mannose-binding lectin (MBL)-deficient serum. Reconstitution with purified MBL showed distinct activation in both readouts. In ELISA, normal human serum-induced deposition of Properdin by zymosan was abolished by the C3-inhibiting peptide compstatin. Flow cytometry was used to further explore whether Properdin acts as an initial recognition molecule reacting directly with zymosan and three E. coli strains. Experiments reported by other authors were made with EGTA Mg²⁺ buffer, permitting autoactivation of C3. We found inhibition by compstatin on these substrates, indicating that Properdin deposition depended on initial C3b deposition followed by Properdin in a second step. Properdin released from human polymorphonuclear cells stimulated with PMA did not bind to zymosan or E. coli, but when incubated in Properdin-depleted serum this form of Properdin bound efficiently to both substrates in a strictly C3-dependent manner, as the binding was abolished by compstatin. Collectively, these data indicate that Properdin in serum as well as polymorphonuclear-released Properdin is unable to bind and initiate direct alternative pathway activation on these substrates.
Giménez-júlvez T. - One of the best experts on this subject based on the ideXlab platform.
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Assessment of health information available online regarding meningococcal B vaccine recommendations
2018Co-Authors: Giménez-júlvez T.Abstract:Fundamentos: La calidad de la información sanitaria en internet preocupa a gobiernos y usuarios. Nuestro objetivo fue determinar en qué medida la información disponible en la red sobre las recomendaciones de vacunación frente al meningococo B se adhiere a lo indicado por el Ministerio de Sanidad español. Métodos: Estudio transversal realizado en abril de 2017. Se evaluó la adhesión de la información sobre recomendaciones de recibir la vacuna. La información se obtuvo a través de Google utilizando veinte palabras clave. Se utilizó la prueba chi-cuadrado para estudiar la asociación entre obtener información adherida y el tipo de origen de la misma. Resultados: Se analizaron 186 enlaces web. Se detectaron recomendaciones adheridas entre el 52, 2% (97/186) de los enlaces para la indicación en personas con deficiencia de Properdina/factores terminales del complemento, y el 79, 6% para las situaciones de brotes. Vacunar a niños a partir de los dos meses de edad fue una recomendación no elaborada por el Ministerio que se detectó en el 72, 6% de los enlaces. Para cada una de las recomendaciones del Ministerio, los organismos oficiales de salud pública siempre proporcionaron información adherida. Medios de comunicación digitales aportaron con una frecuencia significativamente mayor, que las Sociedades Científicas, información adherida sobre vacunar a personas con deficiencia de Properdina/factores terminales del complemento (OR: 2, 72; IC95%: 1, 18-6, 28) y asplenia (OR: 3, 83; IC95%: 1, 66-8, 86). Conclusiones: Se evidencia una dificultad para obtener información adherida a lo indicado por la ponencia de vacunación del Ministerio de Sanidad, Servicios Sociales e Igualdad. Se debe promocionar en los usuarios la consulta de páginas web de organismos oficiales de salud pública cuando busquen información sobre esta vacuna. OBJECTIVE: The quality of health information online is a concern to governments and users. Our objective was to determine the extent to which the information available online regarding meningococcal B vaccine recommendations adhere to the guidelines of the Spanish Ministry of Health. METHODS: Cross-sectional study carried out in April 2017. The study assessed adherence of information regarding vaccine recommendations to official guidelines. The information was collected via Google with 20 keywords. The Chi-squared test was used to analyze the association between the adhered information and its origin. RESULTS: In total, 186 web links were analyzed. Adhered recommendations were found in a range of links, from 52.2% (97/186) with an indication for people with Properdin deficiency/terminal component pathway deficiency, to 79.6% for outbreak situations. Vaccinating children from two months of age was a recommendation not issued by the Ministry that was found in 72.6% of the links. For each of the Ministry recommendations, official public health institutions always provide information adhering to them. Digital media provided information about vaccination adhering to official guidelines with a significantly higher frequency than scientific societies in cases of people with Properdin deficiency/terminal component pathway deficiency (OR: 2.72; 95%CI: 1.18-6.28) and asplenia (OR: 3.83; 95%CI: 1.66-8.86). CONCLUSIONS: We have observed a difficulty to obtain adhered information. Users must be encouraged to access websites of official public health institutions when looking for information about this vaccine.OBJETIVO: La calidad de la información sanitaria en internet preocupa a gobiernos y usuarios
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Evaluación de la información sanitaria disponible en Internet sobre las recomendaciones de vacunación frente al Meningococo B
2018Co-Authors: Giménez-júlvez T.Abstract:Fundamentos. La calidad de la información sanitaria en internet preocupa a gobiernos y usuarios. Nuestro objetivo fue determinar en qué medida la información disponible en la red sobre las recomendaciones de vacunación frente al meningococo B se adhiere a lo indicado por el Ministerio de Sanidad español. Métodos. Estudio transversal realizado en abril de 2017. Se evaluó la adhesión de la información sobre recomendaciones de recibir la vacuna. La información se obtuvo a través de Google utilizando veinte palabras clave. Se utilizó la prueba chi-cuadrado para estudiar la asociación entre obtener información adherida y el tipo de origen de la misma. Resultados. Se analizaron 186 enlaces web. Se detectaron recomendaciones adheridas entre el 52, 2% (97/186) de los enlaces para la indicación en personas con deficiencia de Properdina/factores terminales del complemento, y el 79, 6% para las situaciones de brotes. Vacunar a niños a partir de los dos meses de edad fue una recomendación no elaborada por el Ministerio que se detectó en el 72, 6% de los enlaces. Para cada una de las recomendaciones del Ministerio, los organismos oficiales de salud pública siempre proporcionaron información adherida. Medios de comunicación digitales aportaron con una frecuencia significativamente mayor, que las Sociedades Científicas, información adherida sobre vacunar a personas con deficiencia de Properdina/factores terminales del complemento (OR: 2, 72; IC95%: 1, 18-6, 28) y asplenia (OR: 3, 83; IC95%: 1, 66-8, 86). Conclusiones. Se evidencia una dificultad para obtener información adherida a lo indicado por la ponencia de vacunación del Ministerio de Sanidad, Servicios Sociales e Igualdad. Se debe promocionar en los usuarios la consulta de páginas web de organismos oficiales de salud pública cuando busquen información sobre esta vacuna. Background. The quality of health information online is a concern to governments and users. Our objective was to determine the extent to which the information available online regarding meningococcal B vaccine recommendations adhere to the guidelines of the Spanish Ministry of Health. Methods. Cross-sectional study carried out in April 2017. The study assessed adherence of information regarding vaccine recommendations to official guidelines. The information was collected via Google with 20 keywords. The Chi-squared test was used to analyze the association between the adhered information and its origin. Results. In total, 186 web links were analyzed. Adhered recommendations were found in a range of links, from 52.2% (97/186) with an indication for people with Properdin deficiency/termial component pathway deficiency, to 79.6% for outbreak situations. Vaccinating children from two months of age was a recommendation not issued by the Ministry that was found in 72.6% of the links. For each of the Ministry recommendations, official public health institutions always provide information adhering to them. Digital media provided information about vaccination adhering to official guidelines with a significantly higher frequency than scientific societies in cases of people with . Properdin deficiency/terminal component pathway deficiency (OR: 2.72; 95%CI: 1.186.28) and asplenia (OR: 3.83; 95%CI: 1.66-8.86). Conclusions. We have observed a difficulty to obtain adhered information. Users must be encouraged to access websites of official public health institutions when looking for information about this vaccine
Munirah Abdulaziz - One of the best experts on this subject based on the ideXlab platform.
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human Properdin modulates macrophage mycobacterium bovis bcg interaction via thrombospondin repeats 4 and 5
Frontiers in Immunology, 2018Co-Authors: Maha Ahmed Almozaini, Munirah Abdulaziz, Anthony G Tsolaki, Suhair M Abozaid, Mohammed N Alahdal, Ansar A Pathan, Valarmathy Murugaiah, Evgeny M Makarov, Anuvinder KaurAbstract:Mycobacterium tuberculosis can proficiently enter phagocytes and diminish complement activation on its cell surface. Within phagocytes, the mycobacterium can suppress macrophage apoptosis and survive the intracellular environment. Complement regulatory proteins such as factor H may facilitate pathogen-macrophage interactions during tuberculosis infection. In this study, we show that M. bovis BCG binds Properdin, an up-regulator of the complement alternative pathway. TSR4+5, a recombinant form of thrombospondin repeats 4 and 5 of human Properdin expressed in tandem, which is an inhibitor of the alternative pathway, was also able to bind M. bovis BCG. Properdin and TSR4+5 were found to inhibit uptake of M. bovis BCG by THP-1 macrophage cells in a dose-dependent manner. Quantitative real-time PCR assays using transcripts from the THP-1 cells revealed elevated pro-inflammatory responses (TNF-α, IL-1β and IL-6) in the presence of Properdin and TSR4+5, which gradually decreased over 6 hours. Correspondingly, anti-inflammatory responses (IL-10, TGF-β and IL-12) showed suppressed levels of expression in the presence of Properdin, which gradually increased over 6 hours. Multiplex cytokine array analysis further revealed that Properdin and TSR4+5 significantly enhanced the pro-inflammatory response (TNF-α, IL-1β and IL-1α) at 24 hours, which declined at 48 hours, whereas the anti-inflammatory response (IL-10 and IL-12) was suppressed. Our results suggest that Properdin may interfere with mycobacterial entry into macrophages involving TSR4 and TSR5, particularly during the initial stages of infection, thus affecting the extracellular survival of the pathogen. This study offers novel insights into non-complement related functions of Properdin, which may be independent of other complement proteins during host-pathogen interactions in tuberculosis. Thus, human Properdin modulates macrophage-M. bovis BCG interaction via TSR4+5. Properdin residing in the granules of neutrophils is secreted upon stimulation and may also be produced by other cell types such as monocytes, bone marrow progenitor cell lines and T cells. The local production of Properdin may be crucial for recruitment at sites of infection and in the control of M. tuberculosis infection.
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a recombinant two module form of human Properdin is an inhibitor of the complement alternative pathway
Molecular Immunology, 2016Co-Authors: Lubna Kouser, Munirah Abdulaziz, Robert B Sim, Wilhelm J Schwaeble, Anthony G Tsolaki, Dipti Singhal, Britta C Urban, Haseeb A Khan, Uday KishoreAbstract:Properdin upregulates the alternative complement pathway by binding and stabilising the C3 convertase complex (C3bBb). Properdin is a soluble glycoprotein and its flexible rod-like 53 kDa monomers form cyclic polymers (dimers, trimers, tetramers and pentamers). The Properdin monomer consists of seven thrombospondin type I repeats (TSR 0–6), which are similar and homologous to domains found in circumsporozoite and thrombospondin-related anonymous proteins of Plasmodium species, ETP100 of Eimeria tenella, various complement components C6-C9, and thrombospondin I and II. Using deletion constructs, TSR4 and TSR5 of human Properdin were implicated in C3b binding and stabilising C3 convertase. However, individually expressed TSR4 or TSR5 failed to bind Properdin ligands. Here, we have expressed and characterized biologically active TSR4 and TSR5 together (TSR4 + 5) in tandem in Escherichia coli, fused to maltose-binding protein. MBP-TSR4 + 5 bind solid-phase C3b, sulfatides and glycosaminoglycans. In addition, functionally active recombinant TSR4 + 5 modules inhibit the alternative pathway of complement.
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Properdin and factor h opposing players on the alternative complement pathway see saw
Frontiers in Immunology, 2013Co-Authors: Lubna Kouser, Munirah Abdulaziz, Annapurna Nayak, Cordula M Stover, Robert B Sim, Uday KishoreAbstract:Properdin and factor H are two key regulatory proteins having opposite functions in the alternative complement pathway. Properdin up-regulates the alternative pathway by stabilising the C3bBb complex, whereas factor H down-regulates the pathway by promoting proteolytic degradation of C3b. While factor H is mainly produced in the liver, there are several extrahepatic sources. In addition to the liver, factor H is also synthesized in fetal tubuli, keratinocytes, skin fibroblasts, ocular tissue, adipose tissue, brain, lungs, heart, spleen, pancreas, kidney, muscle, and placenta. Neutrophils are the major source of Properdin, and it is also produced by monocytes, T cells and bone marrow progenitor cell line. Properdin is released by neutrophils from intracellular stores following stimulation by N-formyl-methionine-leucine-phenylalanine and tumour necrosis factor alpha. The HEP G2 cells derived from human liver has been found to produce functional Properdin. Endothelial cells also produce Properdin when induced by shear stress, thus is a physiological source for plasma Properdin.. The diverse range of extrahepatic sites for synthesis of these two complement regulators suggests the importance and need for local availability of the proteins. Here, we discuss the significance of the local synthesis of Properdin and factor H. This assumes greater importance in view of recently identified unexpected and novel roles of Properdin and factor H that are potentially independent of their involvement in the complement regulation.
Cordula M Stover - One of the best experts on this subject based on the ideXlab platform.
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Properdin Deficiency Impairs Phagocytosis and Enhances Injury at Kidney Repair Phase Post Ischemia–Reperfusion
'Frontiers Media SA', 2021Co-Authors: Zinah D. Zwaini, Cordula M Stover, Nigel J. Brunskill, Xinyue Zhang, Hui Wang, Ravinder Chana, Bin YangAbstract:Properdin, a positive regulator of complement alternative pathway, participates in renal ischemia–reperfusion (IR) injury and also acts as a pattern-recognition molecule affecting apoptotic T-cell clearance. However, the role of Properdin in tubular epithelial cells (TECs) at the repair phase post IR injury is not well defined. This study revealed that Properdin knockout (PKO) mice exhibited greater injury in renal function and histology than wild-type (WT) mice post 72-h IR, with more apoptotic cells and macrophages in tubular lumina, increased active caspase-3 and HMGB1, but better histological structure at 24 h. Raised erythropoietin receptor by IR was furthered by PKO and positively correlated with injury and repair markers. Properdin in WT kidneys was also upregulated by IR, while H2O2-increased Properdin in TECs was reduced by its small-interfering RNA (siRNA), with raised HMGB1 and apoptosis. Moreover, the phagocytic ability of WT TECs, analyzed by pHrodo Escherichia coli bioparticles, was promoted by H2O2 but inhibited by PKO. These results were confirmed by counting phagocytosed H2O2-induced apoptotic TECs by in situ end labeling fragmented DNAs but not affected by additional serum with/without Properdin. Taken together, PKO results in impaired phagocytosis at the repair phase post renal IR injury. Properdin locally produced by TECs plays crucial roles in optimizing damaged cells and regulating phagocytic ability of TECs to effectively clear apoptotic cells and reduce inflammation
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Characterisation of the Properdin-deficient immune phenotype
2018Co-Authors: Fatima Mohamed Makhlouf Mohamed, Cordula M StoverAbstract:Properdin (complement factor P) is a conserved serum glycoprotein of the immune defence. It plays a role in strengthening the activation of complement, a system of proteins important in the first line defence against infection. Properdin is active in the alternative pathway of complement within the innate immune system. It is the sole regulator of complement activation and plays a major role in regulating the alternative pathway by binding to and stabilising the inherently labile C3 convertase enzymes, C3bBb and C3bBbC3b. The Properdin-deficient mouse line was used in various studies in order to investigate the role of Properdin in disease models of immunity, infection and inflammation. It was shown that Properdin controls the strength of immune responses by affecting both humoral and cellular phenotypes during acute bacterial infection and resulting inflammation. A clear overview of the measurements for which Properdin-deficient and wild-type mice are similar or different in their unstimulated state is lacking. This review shows the cumulative analysis in mouse regarding the effect of Properdin-deficiency on baseline immune measurements, and will consider all studies on Properdin-deficient and wild-type mice, where inflammatory cellular or humoral mediators, activities and metabolism were measured. The analysis lends support to the concept that systemic therapeutic targeting of Properdin may influence Properdin-dependent cellular crosstalks within tissues
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Human Properdin opsonizes nanoparticles and triggers a potent pro-inflammatory response by macrophages without involving complement activation
Frontiers in Immunology, 2018Co-Authors: Lubna Kouser, Cordula M Stover, Robert B Sim, Suhair M Abozaid, Anuvinder Kaur, Basudev Paudyal, Gudrun Stenbeck, Lucy A. Jones, Emmanuel Flahaut, Uday KishoreAbstract:Development of nanoparticles as tissue-specific drug delivery platforms can be consid erably 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. Binding of Properdin and TSR4+5 is likely to involve charge pattern/ polarity recognition of the CNT surface since both carboxymethyl cellulose-coated carbon nanotubes (CMC-CNT) and oxidized (Ox-CNT) bound these proteins well. Properdin enhanced the uptake of CMC-CNTs by a macrophage cell line, THP-1, mounting a robust pro-inflammatory immune response, as revealed by qRT-PCR, multiplex cytokine array, and NF-κB nuclear translocation analyses. Properdin can be locally synthesized by immune cells in an inflammatory microenvironment, and thus, its interaction with nanoparticles is of considerable importance. In addition, recombinant TSR4+5 coated on the CMC-CNTs inhibited complement consumption by CMC-CNTs, suggesting that nanoparticle decoration with TSR4+5, can be potentially used as a complement inhibitor in a number of pathological contexts arising due to exaggerated complement activation.
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Properdin provides protection from citrobacter rodentium induced intestinal inflammation in a c5a il 6 dependent manner
Journal of Immunology, 2015Co-Authors: Umang Jain, Cordula M Stover, Wilhelm J Schwaeble, Qi Cao, Nikhil A Thomas, Trent M Woodruff, Andrew W StadnykAbstract:Citrobacter rodentium is an attaching and effacing mouse pathogen that models enteropathogenic and enterohemorrhagic Escherichia coli in humans. The complement system is an important innate defense mechanism; however, only scant information is available about the role of complement proteins during enteric infections. In this study, we examined the impact of the lack of Properdin, a positive regulator of complement, in C. rodentium-induced colitis. Following infection, Properdin knockout (P(KO)) mice had increased diarrhea and exacerbated inflammation combined with defective epithelial cell-derived IL-6 and greater numbers of colonizing bacteria. The defect in the mucosal response was reversed by administering exogenous Properdin to P(KO) mice. Then, using in vitro and in vivo approaches, we show that the mechanism behind the exacerbated inflammation of P(KO) mice is due to a failure to increase local C5a levels. We show that C5a directly stimulates IL-6 production from colonic epithelial cells and that inhibiting C5a in infected wild-type mice resulted in defective epithelial IL-6 production and exacerbated inflammation. These outcomes position Properdin early in the response to an infectious challenge in the colon, leading to complement activation and C5a, which in turn provides protection through IL-6 expression by the epithelium. Our results unveil a previously unappreciated mechanism of intestinal homeostasis involving complement, C5a, and IL-6 during bacteria-triggered epithelial injury.
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protective role for Properdin in progression of experimental murine atherosclerosis
PLOS ONE, 2014Co-Authors: T. Steiner, Cordula M Stover, Lorenza Francescut, Simon Byrne, T. Hughes, A. Jayanthi, I. Guschina, K. Cianflone, John L Harwood, Sheila E FrancisAbstract:Genetic, dietary and immune factors contribute to the pathogenesis of atherosclerosis in humans and mice. Complement activation is an integral part of the innate immune defence but also shapes cellular responses and influences directly triglyceride synthesis. Deficiency of Factor B of the alternative pathway (AP) of complement is beneficial in LDLR−/− mice fed a high fat diet. The serum glycoprotein Properdin is a key positive regulator of the AP but has not been studied in experimental atherosclerosis. Atherosclerosis was assessed after feeding low fat (LFD) or high fat (HFD) Western type diets to newly generated LDLR−/− ProperdinKO (LDLR−/−PKO) and LDLR−/−PWT mice. Lipids, lymphocytes and monocytes were similar among genotypes, genders and diets. Complement C3, but not C3adesarg, levels were enhanced in LDLR−/−PKO mice regardless of diet type or gender. Non-esterified fatty acids (NEFA) were decreased in male LDLR−/−PKO fed a HFD compared with controls. All mice showed significant atherosclerotic burden in aortae and at aortic roots but male LDLR−/− mice fed a LFD were affected to the greatest extent by the absence of Properdin. The protective effect of Properdin expression was overwhelmed in both genders of LDLR−/−mice when fed a HFD. We conclude that Properdin plays an unexpectedly beneficial role in the development and progression of early atherosclerotic lesions.
