scholarly journals Molecular engineering of an efficient four-domain DAF-MCP chimera reveals the presence of functional modularity in RCA proteins

2019 ◽  
Vol 116 (20) ◽  
pp. 9953-9958 ◽  
Author(s):  
Hemendra Singh Panwar ◽  
Hina Ojha ◽  
Payel Ghosh ◽  
Sagar H. Barage ◽  
Sunil Raut ◽  
...  
Keyword(s):  
Complement Activation ◽  
Cell Damage ◽  
Alternative Pathway ◽  
Molecular Engineering ◽  
Dual Function ◽  
Complement Control Protein ◽  
Regulators Of Complement Activation ◽  
Functional Units ◽  
Regulatory Functions ◽  
The Complement System

The complement system is highly efficient in targeting pathogens, but lack of its apposite regulation results in host-cell damage, which is linked to diseases. Thus, complement activation is tightly regulated by a series of proteins, which primarily belong to the regulators of complement activation (RCA) family. Structurally, these proteins are composed of repeating complement control protein (CCP) domains where two to four successive domains contribute to the regulatory functions termed decay-accelerating activity (DAA) and cofactor activity (CFA). However, the precise constitution of the functional units and whether these units can be joined to form a larger composition with dual function have not been demonstrated. Herein, we have parsed the functional units for DAA and CFA by constructing chimeras of the decay-accelerating factor (DAF) that exhibits DAA and membrane cofactor protein (MCP) that exhibits CFA. We show that in a four-CCP framework, a functional unit for each of the regulatory activities is formed by only two successive CCPs wherein each participates in the function, albeit CCP2 has a bipartite function. Additionally, optimal activity requires C-terminal domains that enhance the avidity of the molecule for C3b/C4b. Furthermore, by composing a four-CCP DAF-MCP chimera with robust CFA (for C3b and C4b) and DAA (for classical and alternative pathway C3 convertases), named decay cofactor protein, we show that CCP functional units can be linked to design a dual-activity regulator. These data indicate that the regulatory determinants for these two biological processes are distinct and modular in nature.

scholarly journals Influence of Mannan and Glucan on Complement Activation and C3 Binding by Candida albicans

2009 ◽  
Vol 78 (3) ◽  
pp. 1250-1259 ◽  
Author(s):  
Gayle M. Boxx ◽  
Thomas R. Kozel ◽  
Casey T. Nishiya ◽  
Mason X. Zhang
Keyword(s):  
Candida Albicans ◽  
Complement System ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Surface Expression ◽  
Human Neutrophils ◽  
Intact Cells ◽  
Independent Mechanism ◽  
The Complement System ◽  
Wall Components

ABSTRACT The complement system is important for host resistance to hematogenously disseminated candidiasis. However, modulation of complement activation by cell wall components of Candida albicans has not been characterized. Although intact yeast display mannan on the surface, glucan, typically located in the interior, becomes exposed during C. albicans infection. We show here the distinct effects of mannan and glucan on complement activation and opsonophagocytosis. Previous studies showed that intact cells are resistant to initiation of complement activation through the alternative pathway, and antimannan antibody reverses this resistance via an Fc-independent mechanism. The present study shows that this mannan-dependent resistance can be overcome by periodate-borohydride conversion of mannose polysaccharides to polyalcohols; cells treated with periodate-borohydride initiate the alternative pathway without the need for antibody. These observations identify an inhibitory role for intact mannan in complement activation. Next, removal of the surface-displayed mannan by acid treatment of periodate-borohydride cells exposes glucan. Glucan-displaying cells or purified β-glucan initiate the alternative pathway when incubated with the purified proteins of the alternative pathway alone, suggesting that C. albicans glucan is a natural activator of the alternative pathway. Finally, ingestion of mannan-displaying cells by human neutrophils requires anti-mannan antibody, whereas ingestion of glucan-displaying cells requires complement. These results demonstrate a contrasting requirement of natural antibody and complement for opsonophagocytosis of C. albicans cells displaying mannan or glucan. Thus, differential surface expression of mannan and glucan may influence recognition of C. albicans by the complement system.

scholarly journals Time-Dependent Activation of Complement system during Storage of Platelet Product

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4287-4287
Author(s):  
Jian Chen ◽  
Shangbin Yang ◽  
Spero R Cataland ◽  
Haifeng M Wu
Keyword(s):  
Complement System ◽  
Complement Activation ◽  
Research Funding ◽  
Storage Time ◽  
Adverse Reactions ◽  
Alternative Pathway ◽  
Pathway Activation ◽  
The Complement System ◽  
Transfusion Reactions

Abstract Platelet transfusion is known for carrying a high incidence of clinically significant transfusion reactions such as febrile nonhemolytic transfusion reaction. The mechanism responsible for these transfusion-associated adverse events, however, is poorly understood. In this study, we hypothesize that prolonged in vitro storage activates the complement system in the platelet product that in turn causes a high frequency of transfusion reactions. Fresh platelet units obtained from three blood donors were stored on a temperature controlled platelet rotator between 22-24 C°. An aliquot of platelet product was obtained using sterile techniques from each unit on day 2 through day 7. The platelet product from each collection was then immediately centrifuged to obtain platelet poor plasma for the study of complement activation levels. For all study samples, C4d levels were assayed to evaluate the activation of the classical pathway, factor Bb levels were measured to determine the status of the complement alternative pathway, C3a levels were used to examine common pathway activation, and C5a and C5b-9 were assayed for determination of the terminal pathway activation of the complement system. The reference range for each complement factor was determined using citrated plasma from 40 healthy donors. As shown in table 1, both C4d and C3a demonstrated time-dependent increases relevant to storage time. On day 7, C4d and C3a levels were five-fold higher than their baseline levels measured on day 2. In contrast, factor Bb levels remained stable and within the normal range throughout the study. Over a storage span of seven days, the terminal complement factors C5a and C5b-9 were also significantly increased, although not as dramatically as C4d and C3a. Figure 1 illustrates a progressive increase of C3 activation in all three study donors over the time of storage (2-7 days). This report, for the first time, provides strong evidence that substantial complement activation occurs in the platelet products under standard storage conditions. A longer storage time of platelet product in vitro is accompanied by a remarkable elevation of complement activation biomarkers. By examining the pattern of complement profiles in the stored platelets, we further demonstrated that the activation of the classic pathway, rather than alternative pathway, appears to be the driving event that leads up to a level of over-reactivity of the complement system. Given the fact that complement hyperactivation is known to disrupt host homeostasis and cause disease, the adverse reactions seen in platelet recipients is likely related to the infusion of C3a and C5a which are known to be potent inflammatory cytokines. The observations from this study therefore provide a new perspective in understanding the pathophysiology responsible for adverse reactions from platelet transfusions. Further studies will be required to fully evaluate the clinical impact of complement activation in transfused platelet products. Figure 1 Figure 1. Disclosures Cataland: Alexion Corporation: Honoraria, Research Funding, Speakers Bureau. Wu:Alexion Corporation: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Primer komplementdefektusok által okozott atípusos haemolyticus uraemiás szindróma

2018 ◽  
Vol 159 (23) ◽  
pp. 929-936 ◽  
Author(s):  
György Reusz
Keyword(s):  
Complement Activation ◽  
Alternative Pathway ◽  
Critical Role ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Genetic Diagnostics ◽  
Activation Process ◽  
Phagocytic Cells ◽  
Uremic Syndrome ◽  
The Complement System

Abstract: Complement is one of the most archaic parts of the innate immune system, which enhances the ability of antibodies and phagocytic cells to clear cell debris, and microorganisms. The complement system promotes inflammation and attacks the pathogen’s plasma membrane. Malfunction of the system may lead to the development of autoimmunity or uncontrolled infections. Further, dysregulation of the tightly controlled complement activation process may lead to thrombotic microangiopathies with consequent multiorgan involvement. The present paper gives a short overview of the different pathways of complement activation. It focuses on primary genetic defects of components of the alternative pathway that result in dysregulation as well as on pathomechanism, classification, diagnostics and treatment of atypical hemolytic uremic syndrome (aHUS) based on the most recent international recommendations and guidelines. Finally the critical role of complement in host immunity and genetic diagnostics of complement deficiencies are illustrated with two cases of aHUS. Orv Hetil. 2018; 159(23): 929–936.

scholarly journals Role of the complement system in the tumor microenvironment

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Ronghua Zhang ◽  
Qiaofei Liu ◽  
Tong Li ◽  
Quan Liao ◽  
Yupei Zhao
Keyword(s):  
Tumor Microenvironment ◽  
Complement System ◽  
Complement Activation ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Biological Properties ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Regulators Of Complement Activation ◽  
The Complement System

AbstractThe complement system has traditionally been considered a component of innate immunity against invading pathogens and “nonself” cells. Recent studies have demonstrated the immunoregulatory functions of complement activation in the tumor microenvironment (TME). The TME plays crucial roles in tumorigenesis, progression, metastasis and recurrence. Imbalanced complement activation and the deposition of complement proteins have been demonstrated in many types of tumors. Plasma proteins, receptors, and regulators of complement activation regulate several biological functions of stromal cells in the TME and promote the malignant biological properties of tumors. Interactions between the complement system and cancer cells contribute to the proliferation, epithelial-mesenchymal transition, migration and invasion of tumor cells. In this review, we summarize recent advances related to the function of the complement system in the TME and discuss the therapeutic potential of targeting complement-mediated immunoregulation in cancer immunotherapy.

scholarly journals Complement-mediated adipocyte lysis by nephritic factor sera.

1993 ◽  
Vol 177 (6) ◽  
pp. 1827-1831 ◽  
Author(s):  
P W Mathieson ◽  
R Würzner ◽  
D B Oliveria ◽  
P J Lachmann ◽  
D K Peters
Keyword(s):  
Complement Activation ◽  
Ethylenediaminetetraacetic Acid ◽  
Cell Damage ◽  
Alternative Pathway ◽  
Human Condition ◽  
Tissue Loss ◽  
Fat Cell ◽  
Partial Lipodystrophy ◽  
Nephritic Factor

Recent data indicate a previously unsuspected link between the complement system and adipocyte biology. Murine adipocytes produce key components of the alternative pathway of complement and are able to activate this pathway. This suggested to us an explanation for adipose tissue loss in partial lipodystrophy, a rare human condition usually associated with the immunoglobulin G(IgG) autoantibody nephritic factor (NeF) which leads to enhanced alternative pathway activation in vivo. We hypothesized that in the presence of NeF, there is dysregulated complement activation at the membrane of the adipocyte, leading to adipocyte lysis. Here we show that adipocytes explanted from rat epididymal fat pads are lysed by NeF-containing sera but not by control sera. A similar pattern is seen with IgG fractions of these sera. Adipocyte lysis in the presence of NeF is associated with the generation of fluid-phase terminal complement complexes, the level of which correlates closely with the level of lactate dehydrogenase, a marker of cell lysis. Lysis is abolished by ethylenediaminetetraacetic acid, which chelates divalent cations and prevents complement activation, and reduced by an antibody to factor D, a key component of the alternative pathway. These data provide an explanation for the previously obscure link between NeF and fat cell damage.

The alternative pathway of complement is activated in the glomeruli and tubulointerstitium of mice with adriamycin nephropathy

2007 ◽  
Vol 293 (2) ◽  
pp. F555-F564 ◽  
Author(s):  
Amanda M. Lenderink ◽  
Katharine Liegel ◽  
Danica Ljubanović ◽  
Kathrin E. Coleman ◽  
Gary S. Gilkeson ◽  
...  
Keyword(s):  
Renal Disease ◽  
Complement System ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Host Cells ◽  
Renal Tubules ◽  
Wild Type ◽  
Tubulointerstitial Injury ◽  
Factor B ◽  
The Complement System

The complement system effectively identifies and clears invasive pathogens as well as injured host cells. Uncontrolled complement activation can also contribute to tissue injury, however, and inhibition of this system may ameliorate many types of inflammatory injury. Several studies have demonstrated that the filtration of complement proteins into the renal tubules, as occurs during proteinuric renal disease, causes tubular inflammation and injury. In the present study, we tested the hypothesis that activation of the complement system in the urinary space requires an intact alternative pathway. Using a model of adriamycin-induced renal injury, which induces injury resembling focal segmental glomerulosclerosis, we examined whether mice deficient in factor B would be protected from the development of progressive tubulointerstitial injury. Complement activation was attenuated in the glomeruli and tubulointerstitium of mice with congenital deficiency of factor B ( fB−/−) compared with wild-type controls, demonstrating that complement activation does occur through the alternative pathway. Deficiency in factor B did not significantly protect the mice from tubulointerstitial injury. However, treatment of wild-type mice with an inhibitory monoclonal antibody to factor B did delay the development of renal failure. These results demonstrate that complement activation in this nonimmune complex-mediated model of progressive renal disease requires an intact alternative pathway.

scholarly journals A Review of Complement Activation in SLE

2021 ◽  
Vol 23 (3) ◽  
Author(s):  
Arthur Weinstein ◽  
Roberta V. Alexander ◽  
Debra J. Zack
Keyword(s):  
Disease Activity ◽  
Lupus Erythematosus ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Adverse Outcomes ◽  
Pathogenetic Mechanism ◽  
Activation Products ◽  
The Complement System ◽  
Anti Phospholipid Syndrome ◽  
Lupus Disease Activity

Abstract Purpose of Review Complement activation is a key event in the pathogenesis of tissue inflammation and injury in systemic lupus erythematosus (SLE). This review is aimed at comparing the usefulness of measurement of complement proteins in serum/plasma (C3, C4) to complement activation (split) products in plasma and on circulating blood cells for SLE diagnosis, disease monitoring, and prognosis. Recent Findings Complement split products, C3dg, iC3b, and C4d, are elevated in SLE, and C3dg/C3 and iC3b/C3 ratios correlate with active SLE. C4d also is higher in patients with lupus nephritis. An elevated level of the alternative pathway split product, Bb, in early lupus pregnancy is a predictor of adverse outcomes in SLE patients with antiphospholipid antibodies. Elevated levels of cell-bound complement activation products (CB-CAPs), namely, B cell-bound C4d (BC4d) and erythrocyte-bound C4d (EC4d), within a multiparameter assay panel, may predict transition to SLE more than other lupus biomarkers. EC4d better correlates with lupus disease activity than low plasma complement levels. Elevated platelet-bound C4d (PC4d) correlates with thrombosis in SLE. Both EC4d and PC4d are increased in primary and secondary anti-phospholipid syndrome, and anti-beta2glycoproteinI antibodies may directly activate the complement system. Summary Abnormal levels of plasma complement split products and CB-CAPs support complement activation as an important pathogenetic mechanism in SLE and the antiphospholipid syndromes. These tests show promise for the diagnosis of SLE and monitoring of disease activity.

scholarly journals The complement system in age-related macular degeneration

2021 ◽  
Author(s):  
Angela Armento ◽  
Marius Ueffing ◽  
Simon J. Clark
Keyword(s):  
Risk Factors ◽  
Macular Degeneration ◽  
Complement System ◽  
Complement Activation ◽  
Molecular Mechanisms ◽  
Alternative Pathway ◽  
Disease Onset ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
The Complement System

AbstractAge-related macular degeneration (AMD) is a chronic and progressive degenerative disease of the retina, which culminates in blindness and affects mainly the elderly population. AMD pathogenesis and pathophysiology are incredibly complex due to the structural and cellular complexity of the retina, and the variety of risk factors and molecular mechanisms that contribute to disease onset and progression. AMD is driven by a combination of genetic predisposition, natural ageing changes and lifestyle factors, such as smoking or nutritional intake. The mechanism by which these risk factors interact and converge towards AMD are not fully understood and therefore drug discovery is challenging, where no therapeutic attempt has been fully effective thus far. Genetic and molecular studies have identified the complement system as an important player in AMD. Indeed, many of the genetic risk variants cluster in genes of the alternative pathway of the complement system and complement activation products are elevated in AMD patients. Nevertheless, attempts in treating AMD via complement regulators have not yet been successful, suggesting a level of complexity that could not be predicted only from a genetic point of view. In this review, we will explore the role of complement system in AMD development and in the main molecular and cellular features of AMD, including complement activation itself, inflammation, ECM stability, energy metabolism and oxidative stress.

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