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The maternal immune system during pregnancy
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
DAF inhibits formation and accelerates decay of C3/C5 convertase, which inhibits the alternative pathway. MCP is an intrinsic-acting protein that binds efficiently to C3b attached to other molecules on the cell surface (13). MCP then cleaves the C3b or C4b components of complement to their inactive derivatives, which inhibits the classical complement pathway. Finally, CD59 inhibits the final common component of both complement pathways—the MAC. CD59 is expressed in greater amounts than either DAF or MCP, although the absence of CD59 is compatible with successful pregnancy, indicating that MCP and DAF are able to compensate for a lack of CD59.
Internalization of Lipopolysaccharide by Phagocytes
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Richard L. Kitchens, Robert S. Munford
Since large LPS aggregates can bind mCD14, another potential LPS internalization mechanism is phagocytosis. We (30) found that the internalization of [3H]LPS aggregates by THP-1 cells was only slightly (25–35%) inhibited by concentrations of cytochalasin D or cytochalasin H that completely inhibited mCD14-mediated phagocytosis of BODIPY-labeled E. coli. Phagocytosis is thus not required for internalization of LPS aggregates that bind to mCD14. Interestingly, the relatively weak inhibition by cytochalasins also suggests that the mechanism of LPS internalization mediated by GPI-anchored CD 14 differs from that of GPI-anchored CD59, which is internalized by a cytochalasin-inhibitable, non-clathrin-dependent pathway in T lymphocytes (47). Internalization of cross-linked CD59 appears to involve an actin-dependent capping mechanism that does not occur during LPS internalization. On the other hand, the fact that cytochalasins partially inhibit LPS internalization points to some role for the actin cytoskeleton in this process.
Host Defense I: Non-specific Immunity
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
Several membrane components act to protect cells from complement lysis. Decay accelerating factor (DAF) is anchored in the cell membranes of erythrocytes, leukocytes, platelets, and endothelial cells. This protein interacts with complement complexes deposited on the cell’s surface and, as its name suggests, hastens their dissociation. Membrane cofactor protein (MCP) is found on leukocytes and platelets. It binds to C3b and iC3b and appears to enhance the activity of factor I. Homologous restriction factor (HRF) has a distribution similar to that of DAF. This protein binds to C8 and C9 and inhibits formation of an effective lytic unit. CD59 (also known as membrane attack complex inhibition factor, or membrane inhibitor of reactive lysis) has activity similar to HRF.
Cytological and functional effect of complement 3a on Human Scleral Fibroblasts
Published in Cutaneous and Ocular Toxicology, 2023
Kang Xiao, Ying Jie, Mingyue Luo, Qin Long
The effect of C3a on levels of CD59 was analysed using western blot. Briefly, HSFs (5 × 105cells/well) were plated into 6-well plates using DMEM/F12 medium containing 10% FBS and were treated with or without 0.1 μM C3a. After 60 h of incubation, cells were then washed in ice-cold PBS and lysed using ice-cold RIPA lysis buffer and ultrasonic dispersion. Then the lysates were centrifuged at 12,000 rpm for 10 min at 4 °C and protein concentrations were determined with the BCA assay. Supernatant proteins were collected, denatured, separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) with 5% stacking gels and 12% separating gels, and transferred to polyvinylidene difluoride membranes. The membranes were blocked in 5% skim milk for 1 h and incubated with primary antibodies against CD59 (1: 500, Proteintech) and GAPDH (1: 10,000, Proteintech) at 4 °C overnight. Membranes were washed and then incubated with horseradish peroxidase (HRP)-conjugated goat anti-mouse secondary antibodies for 1 h. Then an Enhanced Chemiluminescence (ECL) Plus kit (Millipore, USA) was applied for visualisation and densitometry was analysed using Image J software.
The role of the alternative pathway in paroxysmal nocturnal hemoglobinuria and emerging treatments
Published in Expert Review of Clinical Pharmacology, 2022
Jong Wook Lee, Robert A. Brodsky, Jun-Ichi Nishimura, Austin G. Kulasekararaj
Under normal physiologic conditions, complement activity is tightly controlled by complement regulators that protect the host against complement-mediated injury [3,21,22]. Membrane-bound complement regulators include, among others, CD55 (decay accelerating factor) and CD59 (membrane inhibitor of reactive lysis). CD55 inhibits the formation and stability of C3 and C5 convertases and thus limits the ability of C3 convertases to promote further complement activation, whereas CD59 prevents assembly of the MAC (C5b-9). The Inab phenotype, which indicates a genetic defect in CD55 on the erythrocyte membrane, shows no hemolytic findings [26]. On the other hand, the genetic deficiency of CD59 has the same hemolytic findings and symptoms as PNH [27]. These results suggest that the deficiency of CD59 is particularly important for the hemolytic mechanism of PNH. PNH cells can be further subdivided into type 2 (mutation causing a partial GPI defect) and type 3 (mutation causing a complete GPI defect) GPI-deficient clones [28]. Type 3 cells have been associated with higher LDH levels and greater hemolytic activity [28].
Complement system network in cell physiology and in human diseases
Published in International Reviews of Immunology, 2021
Roberta Romano, Giuliana Giardino, Emilia Cirillo, Rosaria Prencipe, Claudio Pignata
Another major clinical disorder related to abnormalities of the regulatory network of the complement cascade is the Paroxysmal Nocturnal Hemoglobinuria. Paroxysmal Nocturnal Hemoglobinuria is a rare hematopoietic stem cell disease due to the clonal expansion of hematopoietic stem cells carrying a somatic mutation in the gene phosphatidylinositol glycan anchor biosynthesis, class A (PIG-A) located on X chromosome. This gene encodes for an enzyme involved in the biosynthesis of phosphatidylinositol glycan that serves as anchor for membrane proteins such as Decay Accelerating Factor and CD59, whose physiological function is to inhibit complement system activation. DAF inhibits C3 convertase while CD59 competes with the C9 for the binding to the C5b-C8 complex thus interfering with Membrane Attack Complex formation. When their regulatory effect on complement system is impaired, complement mediated lysis of cells occurs leading to profound intravascular hemolysis and hemoglobinuria, hallmarks of the disease. Patients affected with Paroxysmal Nocturnal Hemoglobinuria show moderate to severe anemia and are prone to thromboembolic events usually affecting hepatic or cerebral veins and representing the main cause of morbidity and mortality associated with the disease [56]. Intravascular hemolysis releases free hemoglobin, which causes typical symptoms like dysphagia and abdominal pain, due to smooth muscles dystonia consequent to nitric oxide (NO) depletion.