The complement system in health and disease
Gabriel Virella in Medical Immunology, 2019
CD59 is another membrane-bound complement inhibitor that is widely expressed on mammalian cells. It binds to C8 in the C5b-8 complex and blocks the binding and incorporation of C9 into the complex. Further, CD59 also binds directly to C9 stopping the addition of additional C9 to the complex, inhibiting its polymerization, and therefore stops the complex from forming a transmembrane pore. In addition to this membrane regulator of membrane attack complex formation, additional soluble proteins can inhibit assembly or membrane insertion. Clusterin and vitronectin are widely distributed intracellular matrix proteins that can incorporate into the C5b-7 complex rendering them nonmembrane-binding inactivated complexes. Finally, normal human cells have the ability to eliminate the membrane attack complex from their surface either by endocytosis or by direct emission/release of membrane vesicles (ectocytosis).
Myelodysplastic Syndromes
Wojciech Gorczyca in Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
PNH is a rare clonal stem disease of hematopoietic stem cells that causes intravascular hemolysis, venous thrombosis, and BM failure leading to anemia and/or pancytopenia. PNH may overlap to some degree with either aplastic anemia and/or MDS. Patients with MDS or aplastic anemia may have minute PNH clones detectable by FC (Figure 32.28). Subset of patients with PNH has preceding aplastic anemia [118,119]. The hallmark of PNH blood cells is a deficiency or absence of glycosylphosphatidylinositol (GPI)-anchored complement regulatory proteins, such as CD55 and CD59. PNH is characterized phenotypically by downregulation or complete lack of expression of CD55 and CD59 by granulocytes, erythroid cells, and often lymphoid cells [120–126]. There is a great degree of heterogeneity in the patterns and levels of expression of the GPI-linked proteins in the various cell types, as well as a possible heterogeneity in lineage involvement, and therefore, the different patterns of expression of GPI-linked proteins should be considered when using FC to diagnose PNH [126–128]. The sample preparation protocol has a significant impact on the quality of the staining obtained for the CD55 and CD59 antigens on the major blood leukocyte subsets [129]. FLAER (Alexa488-labeled inactive variant of aerolysin that does not cause lysis of cells) combined with multiparameter FC offers an improved assay for diagnosis and monitoring of PNH clones [130].
Helicobacter pylori
Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward in Case Studies in Infectious Disease, 2010
Even though the organism does not normally penetrate the gastric epithelium, damage caused by factors shown below result in an acute inflammatory reaction at first, followed by a more chronic inflammatory reaction. Initially there is a strong recruitment of granulocytes to the area but phagocytosis of H. pylori by both granulocytes and macrophages is inhibited in some way, not yet clearly understood. The acquired immune system is also activated with the production of both local (stomach) and systemic antibodies of IgM, IgG, and IgA class. It is supposed that IgA secreted into the stomach is unable to penetrate the mucus and presumably fails to block successfully the adhesins expressed by the organisms. H. pylori is susceptible to complement lysisin vitro, yet in vivo it is protected by natural complement inhibitors. These include coating of the organism with anti-complementary proteins such as CD59, which prevent lysis of the organism. Antibodies of the IgM and IgG class suggest that at least parts of the organism are taken up by dendritic cells leading to a systemic immune response. Thus, although a good antibody and cellular immune response is mounted, the organism is able to evade the immune defenses. An initial intense acute inflammatory response is invoked with infiltration of the lamina propria by granulocytes and as the inflammation becomes chronic a mononuclear cell infiltrate occurs and a chronic infection of the stomach ensues (Figure 7).
Dual functions of discoidinolysin, a cholesterol-dependent cytolysin with N-terminal discoidin domain produced from Streptococcus mitis strain Nm-76
Published in Journal of Oral Microbiology, 2022
Atsushi Tabata, Airi Matsumoto, Ai Fujimoto, Kazuto Ohkura, Takuya Ikeda, Hiroki Oda, Shuto Yokohata, Miho Kobayashi, Toshifumi Tomoyasu, Ayuko Takao, Hisashi Ohkuni, Hideaki Nagamune
We used recombinants of DLY (rDLY) from S. mitis strain Nm-76 and other reference CDCs (rSm-hPAF, rILY, and rSLY [40,50] for the assay. The minimal protein concentration of each recombinant CDC showing complete hemolysis was adopted in this assay and adjusted with PBS to the final concentration of 1.4 nM for both rDLY and rSm-hPAF, 0.53 nM for rILY, and 0.56 nM for rSLY. To inhibit the binding between recombinant CDC and human CD59 on erythrocytes, we pre-incubated anti-human CD59 monoclonal antibody (YTH53.1; DS Pharma Biomedical Co., Ltd., Suita, Osaka, Japan) with human erythrocytes at a final concentration of 50 μg/mL for 15 min at 37°C and then washed them with PBS. Human erythrocytes pre-incubated with or without anti-human CD59 monoclonal antibody were added to the reaction mixture at a final concentration of 0.5% (v/v) and incubated at 37°C for 1 h. To inhibit the binding of recombinant CDC to membrane cholesterol, each recombinant CDC was pre-incubated (37°C, 15 min) with cholesterol at a final concentration of 1 μM in PBS before the assay. A sample containing 0.1% (v/v) ethanol was used as control for the cholesterol solvent. Each reaction mixture was incubated at 37°C for 1 h for the hemolysis assay, and the hemolytic activity was calculated as previously described [50].
Complement inhibition as a therapeutic strategy in retinal disorders
Published in Expert Opinion on Biological Therapy, 2019
Enoch Kassa, Thomas A. Ciulla, Rehan M. Hussain, Pravin U. Dugel
As noted above, complement activation leads to cleavage of factor C5, into fragments (C5a and C5b). The C5a fragment, found in drusen of AMD patients, is an important inflammatory activator, recruiting inflammatory cells and inducing vascular endothelial growth factor (VEGF) expression from RPE cells [15]. C5b leads to the formation of MAC (C5b-9); in humans, deposition of MAC in Bruch’s membrane and choriocapillaris increases significantly with aging and with AMD [20]. When choroidal endothelial cells are exposed to MAC, cell lysis occurs, likely contributing to RPE atrophy, and the surviving cells express VEGF and matrix metalloproteases (MMP); thus, MAC deposition in the choriocapillaris may play a role in atrophic and neovascular AMD, respectively [21]. Of note, CD59 is a naturally occurring membrane-bound inhibitor of MAC formation, and functions by binding the terminal complement protein complex, thereby preventing the incorporation of C9 molecules required to complete the formation of a pore in the cell membrane [22].
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].
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