scholarly journals AAV-mediated expression of human PRELP inhibits complement activation, choroidal neovascularization and deposition of membrane attack complex in mice

Gene Therapy ◽  
2014 ◽  
Vol 21 (5) ◽  
pp. 507-513 ◽  
Author(s):  
M T Birke ◽  
E Lipo ◽  
M Adhi ◽  
K Birke ◽  
R Kumar-Singh
Keyword(s):  
Choroidal Neovascularization ◽  
Complement Activation ◽  
Membrane Attack Complex

Mitochondrial calcium overload triggers complement-dependent superoxide-mediated programmed cell death in Trypanosoma cruzi

2009 ◽  
Vol 418 (3) ◽  
pp. 595-604 ◽  
Author(s):  
Florencia Irigoín ◽  
Natalia M. Inada ◽  
Mariana P. Fernandes ◽  
Lucía Piacenza ◽  
Fernanda R. Gadelha ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Trypanosoma Cruzi ◽  
Complement Activation ◽  
Superoxide Radical ◽  
Membrane Attack Complex ◽  
Cell Respiration ◽  
Mitochondrial Uncoupling ◽  
O2 Production ◽  
Complement Deposition

The epimastigote stage of Trypanosoma cruzi undergoes PCD (programmed cell death) when exposed to FHS (fresh human serum). Although it has been known for over 30 years that complement is responsible for FHS-induced death, the link between complement activation and triggering of PCD has not been established. We have previously shown that the mitochondrion participates in the orchestration of PCD in this model. Several changes in mitochondrial function were described, and in particular it was shown that mitochondrion-derived O2•− (superoxide radical) is necessary for PCD. In the present study, we establish mitochondrial Ca2+ overload as the link between complement deposition and the observed changes in mitochondrial physiology and the triggering of PCD. We show that complement activation ends with the assembly of the MAC (membrane attack complex), which allows influx of Ca2+ and release of respiratory substrates to the medium. Direct consequences of these events are accumulation of Ca2+ in the mitochondrion and decrease in cell respiration. Mitochondrial Ca2+ causes partial dissipation of the inner membrane potential and consequent mitochondrial uncoupling. Moreover, we provide evidence that mitochondrial Ca2+ overload is responsible for the increased O2•− production, and that if cytosolic Ca2+ rise is not accompanied by the accumulation of the cation in the mitochondrion and consequent production of O2•−, epimastigotes die by necrosis instead of PCD. Thus our results suggest a model in which MAC assembly on the parasite surface allows Ca2+ entry and its accumulation in the mitochondrion, leading to O2•− production, which in turn constitutes a PCD signal.

The complement membrane attack complex and the bystander effect in cerebral vasospasm

1997 ◽  
Vol 3 (4) ◽  
pp. E7
Author(s):  
Charles C. Park ◽  
Moon L. Shin ◽  
J. Marc Simard
Keyword(s):  
Smooth Muscle ◽  
Cerebral Vasospasm ◽  
Complement Activation ◽  
Bystander Effect ◽  
Cell Damage ◽  
Membrane Attack Complex ◽  
Membrane Conductance ◽  
Autologous Serum ◽  
Innocent Bystander ◽  
Patch Clamp Technique

Activation of complement results in formation of membrane attack complexes (MACs) that can insert themselves either into cells that initiate complement activation or into nearby (“innocent bystander”) cells. The MACs form large-conductance, nonspecific ion channels that can cause lytic or sublytic cell damage. The authors used a highly sensitive patch clamp technique to assess the contribution of the bystander effect to the pathophysiology of cerebral vasospasm. They compared the effect of complement activation by autologous aged versus fresh erythrocytes on the membrane conductance of freshly isolated rat cerebral artery smooth-muscle cells. In the presence of autologous serum, aged, but not fresh, erythrocytes caused a large increase in membrane conductance, an effect that was prevented by heat-inactivating the serum. Ethyleneglycol tetraacetic acid in the presence of Mg++ attenuated the effect, indicating that complement activation was taking place via the classic pathway. The effect was reproduced by zymosan-activated autologous serum, suggesting that such changes in conductance could result from insertion of MACs secondary to a bystander effect. Both C8- and C9-depleted heterologous sera produced minimal effects that were converted to full effect by addition of the missing complement component. Superoxide dismutase plus catalase did not attenuate the conductance changes produced by autologous serum plus aged erythrocytes. Autologous serum plus aged erythrocyte membrane ghosts that were free of lysate caused a typical increase in conductance. This study demonstrates that complement activation by aged erythrocytes can result in MAC insertion into innocent bystander smooth-muscle cell membranes and that this mechanism, heretofore undescribed, may contribute to development of vasospasm after subarachnoid hemorrhage.

scholarly journals Extracellular Vesicle-Induced Classical Complement Activation Leads to Retinal Endothelial Cell Damage via MAC Deposition

2020 ◽  
Vol 21 (5) ◽  
pp. 1693 ◽  
Author(s):  
Chao Huang ◽  
Kiera P. Fisher ◽  
Sandra S. Hammer ◽  
Julia V. Busik
Keyword(s):  
Extracellular Vesicles ◽  
Complement Activation ◽  
Cell Damage ◽  
Membrane Attack Complex ◽  
Extracellular Vesicle ◽  
Rat Plasma ◽  
Classical Complement Pathway ◽  
Endothelium Damage ◽  
Classical Complement

Several studies have suggested that there is a link between membrane attack complex (MAC) deposition in the retina and the progression of diabetic retinopathy (DR). Our recent investigation demonstrated that circulating IgG-laden extracellular vesicles contribute to an increase in retinal vascular permeability in DR through activation of the complement system. However, the mechanism through which extracellular vesicle-induced complement activation contributes to retinal vascular cytolytic damage in DR is not well understood. In this study, we demonstrate that IgG-laden extracellular vesicles in rat plasma activate the classical complement pathway, and in vitro Streptozotocin (STZ)-induced rat diabetic plasma results in MAC deposition and cytolytic damage in human retinal endothelial cells (HRECs). Moreover, removal of the plasma extracellular vesicles reduced the MAC deposition and abrogated cytolytic damage seen in HRECs. Together, the results of this study demonstrate that complement activation by IgG-laden extracellular vesicles in plasma could lead to MAC deposition and contribute to endothelium damage and progression of DR.

Immunohistochemistry of Complement Response on Human Renal Cell Carcinoma Biopsies

1996 ◽  
Vol 82 (5) ◽  
pp. 473-479 ◽  
Author(s):  
Tamás Magyarlaki ◽  
Szilvia Mosolits ◽  
Ferenc Baranyay ◽  
István Buzogány
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Complement Activation ◽  
Renal Cell ◽  
Membrane Attack Complex ◽  
Tumor Infiltrating Lymphocytes ◽  
Complement Pathway ◽  
Histocompatibility Complex ◽  
Pathway Activation ◽  
Infiltrating Lymphocytes

The goal of the study was to characterize the complement humoral and cellular antitumor responses on primary renal cell carcinoma biopsies. As an original observation, complement activation was found on 11/22 cases. Classical complement pathway activation was characterized by tumor C1q complement protein and IgG deposition (5/22 cases). Alternative or nonimmune complement pathway activation was seen as tissue deposition of C3 (6/22 cases). The membrane attack complex was present in cases with alternative complement pathway activation at the sites of tumor necrosis. Renal cell carcinomas with complement activation overexpressed at least one of the complement regulatory factors (membrane cofactor protein, decay accelerating factor, membrane attack complex inhibitor) and major histocompatibility complex class II molecules. Tumor infiltrating lymphocytes were present in most of the renal cell carcinomas with complement activation (8/11). However, the number of tumor-infiltrating lymphocytes was correlated with the intensity of major histocompatibility complex-ll expression in 18/22 cases. Detection of complement activation and immune cell infiltrates on renal cell carcinoma primary biopsies may serve as a new predictive factor for immunotherapy.

scholarly journals Complement Activation via Alternative Pathway Is Critical in the Development of Laser-Induced Choroidal Neovascularization: Role of Factor B and Factor H

2006 ◽  
Vol 177 (3) ◽  
pp. 1872-1878 ◽  
Author(s):  
Nalini S. Bora ◽  
Sankaranarayanan Kaliappan ◽  
Purushottam Jha ◽  
Qin Xu ◽  
Jeong-Hyeon Sohn ◽  
...  
Keyword(s):  
Choroidal Neovascularization ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Factor H ◽  
Factor B

scholarly journals Infectious diseases associated with complement deficiencies.

1991 ◽  
Vol 4 (3) ◽  
pp. 359-395 ◽  
Author(s):  
J E Figueroa ◽  
P Densen
Keyword(s):  
Infectious Diseases ◽  
Host Defense ◽  
Complement Activation ◽  
Immune Modulation ◽  
Alternative Pathway ◽  
Membrane Attack Complex ◽  
Host Cells ◽  
Microbial Pathogens ◽  
Classical Pathway ◽  
Cellular Effects

The complement system consists of both plasma and membrane proteins. The former influence the inflammatory response, immune modulation, and host defense. The latter are complement receptors, which mediate the cellular effects of complement activation, and regulatory proteins, which protect host cells from complement-mediated injury. Complement activation occurs via either the classical or the alternative pathway, which converge at the level of C3 and share a sequence of terminal components. Four aspects of the complement cascade are critical to its function and regulation: (i) activation of the classical pathway, (ii) activation of the alternative pathway, (iii) C3 convertase formation and C3 deposition, and (iv) membrane attack complex assembly and insertion. In general, mechanisms evolved by pathogenic microbes to resist the effects of complement are targeted to these four steps. Because individual complement proteins subserve unique functional activities and are activated in a sequential manner, complement deficiency states are associated with predictable defects in complement-dependent functions. These deficiency states can be grouped by which of the above four mechanisms they disrupt. They are distinguished by unique epidemiologic, clinical, and microbiologic features and are most prevalent in patients with certain rheumatologic and infectious diseases. Ethnic background and the incidence of infection are important cofactors determining this prevalence. Although complement undoubtedly plays a role in host defense against many microbial pathogens, it appears most important in protection against encapsulated bacteria, especially Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and, to a lesser extent, Neisseria gonorrhoeae. The availability of effective polysaccharide vaccines and antibiotics provides an immunologic and chemotherapeutic rationale for preventing and treating infection in patients with these deficiencies.

Role of complement and complement membrane attack complex in laser-induced choroidal neovascularization

2005 ◽  
Vol 139 (5) ◽  
pp. 957
Author(s):  
P.S. Bora ◽  
J.H. Sohn ◽  
J.M. Cruz ◽  
P. Jha ◽  
H. Nishihori ◽  
...  
Keyword(s):  
Choroidal Neovascularization ◽  
Membrane Attack Complex

Complement activation: the missing link between ADAMTS-13 deficiency and microvascular thrombosis of thrombotic microangiopathies

2005 ◽  
Vol 93 (03) ◽  
pp. 443-452 ◽  
Author(s):  
Maria Ruiz-Torres ◽  
Federica Casiraghi ◽  
Miriam Galbusera ◽  
Daniela Macconi ◽  
Sara Gastoldi ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Complement Activation ◽  
Ex Vivo ◽  
Membrane Attack Complex ◽  
Surface Expression ◽  
Endothelial Injury ◽  
Microvascular Endothelial Cell ◽  
Microvascular Damage ◽  
Microvascular Thrombosis ◽  
First Time

SummaryEndothelial injury is the central factor in the events leading to thrombotic microangiopathy (TMA); however, the mechanisms involved are not fully understood. Here we investigate the role of neutrophils (PMNs) and of complement activation in inducing microvascular damage and loss of thromboresistance in TMA associated with ADAMTS-13 deficiency. PMNs isolated during the acute phase of the disease released excessive amounts of reactive-oxygen species (ROS), N-derived oxidants and proteinases and induced damage and thromboresistance loss in human microvascular endothelial cell line (HMEC-1) ex vivo. Endothelial cytotoxicity and thromboresistance loss was also induced by TMA serum. Complement-derived products were responsible for the above effects: in fact, TMA serum caused C3 and Membrane Attack Complex (MAC) deposition on HMEC-1 and its cytotoxic effect was abolished by complement inhibition. TMA serum caused surface expression of P-selectin on HMEC-1 which may promote PMN adhesion and resulted in increased PMN cytotoxicity, indicating that complement may have a role in PMN activation. In addition, TMA serum stimulated control PMNs to release ROS and proteinases, and to cause endothelial cell cytotoxicity. All of the above effects were abrogated by complement inactivation. These data document for the first time that complement-initiated PMN activation and endothelial injury may have a crucial role in microvascular thrombosis of TMA associated with ADAMTS-13 deficiency.

scholarly journals Complement Activation Products in the Urine from Proteinuric Patients

2000 ◽  
Vol 11 (4) ◽  
pp. 700-707 ◽  
Author(s):  
YOSHIKI MORITA ◽  
HIROSHI IKEGUCHI ◽  
JIRO NAKAMURA ◽  
NIGISHI HOTTA ◽  
YUKIO YUZAWA ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Metabolic Acidosis ◽  
Sodium Bicarbonate ◽  
Complement Activation ◽  
Plasma Proteins ◽  
Excretion Rate ◽  
Membrane Attack Complex ◽  
Glomerular Sclerosis ◽  
Focal Glomerular Sclerosis ◽  
Activation Products

Abstract. The presence of plasma proteins in the tubular lumen has variety of adverse effects on the tubular cells. Among various plasma proteins filtered through glomerular barrier, complement has been proven as the possible candidate inducing tubulointerstitial injury. To study the role of intratubular complement activation in proteinuric patients, complement activation products (CAP) at C3 level (iC3b and Bb) and C9 level (membrane attack complex) were measured in both plasma and urine of patients with minimal change nephrotic syndrome (MCNS), focal glomerular sclerosis, IgA nephropathy, membranous nephropathy, and diabetic nephropathy. For evaluation of the effect of metabolic acidosis on the intratubular complement activation, urinary CAP were measured before and after sodium bicarbonate administration in patients with renal insufficiency. The following results were obtained: (1) Patients with focal glomerular sclerosis and diabetic nephropathy showed the highest level of urinary CAP excretion rate (unit/creatinine), while MCNS revealed no increase. (2) Patients with membranous nephropathy showed a unique finding,i.e., isolated increase of membrane attack complex excretion. (3) There was no significant correlation between urine and plasma levels of CAP. (4) Except for MCNS patients, the urinary excretion rate of CAP significantly increased when the level of proteinuria exceeded the nephrotic range, and it was significantly correlated with the serum creatinine level. (5) Urinary CAP excretion rate significantly decreased 2 wk after sodium bicarbonate administration without affecting the level of proteinuria or plasma CAP. These results suggest that the degree of intratubular complement activation correlates with the level of proteinuria, type of glomerular disease, impairment of renal function, and metabolic acidosis.

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