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Complement Activation: Challenges to Nanomedicine Development
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
Dennis E. Hourcade, Christine T. N. Pham, Gregory M. Lanza
Complement activation is mediated by three major pathways (Fig. 9.1) [3, 4]. Each pathway responds to a different set of activators, ensuring that a wide range of dangerous agents are recognized: The classical pathway (CP) is triggered by antibody: antigen complexes, and the lectin pathway (LP) responds to specific carbohydrate moieties. The alternative pathway (AP) operates spontaneously at low levels and is further activated by a range of microbial surfaces. Each activation pathway results in the assembly of the C3 convertases, the central enzymes of the C cascade, which cleave the fluid phase protein C3, producing C3a and C3b. Nascent C3b can bind covalently to the target surface and mediate clearance by the mononuclear phagocytic system (MPS). Target-bound C3b can amplify C activity by providing an assembly point for additional AP convertases (the amplification loop). C3b can also form a complex with preformed C3 convertase to generate C5 convertase, a protease that cleaves C5 into C5a and C5b. C5b initiates the complement terminal pathway, culminating in the assembly of the membrane attack complex (MAC) in the plasma membrane. The MAC promotes cell lysis by disrupting membrane integrity. C3a and C5a, the anaphylatoxins, recruit immune cells that promote further inflammatory reactions [5, 6]. C3d, a C3 derivative, in complex with antigen, provides an adjuvant effect leading to the generation of higher antibody titer [7].
Introduction to Host-Biomaterial Interactions
Published in Nina M. K. Lamba, Kimberly A. Woodhouse, Stuart L. Cooper, Polyurethanes in Biomedical Applications, 2017
Nina M. K. Lamba, Kimberly A. Woodhouse, Stuart L. Cooper
The classical pathway is usually initiated by the presence of an antigen-antibody complex containing IgM or IgG. The alternative pathway involves the direct activation of C3.90 Generally, complement activation by artificial surfaces is believed to occur through the alternative pathway, although this is not always the case. C3 is split into C3a and C3b, and in the presence of factor D, factor B is split into Ba and Bb. Bb binds onto the C3b fragment, which is stabilized by properdin (P). The C3bBbP complex is a C3 convertase, and fragments further C3 molecules. A further molecule of C3b can bind to the C3 convertase to produce the C5 convertase C3bBbP3b. However, if the C3b molecule associates with inhibitory factors H and I, formation of the C5a convertase is inhibited. Once C5 is cleaved; C5b binds to C6, C7, C8, and several C9 molecules to produce the terminal membrane attack complex (MAC). This can bind to cell walls resulting in cell destruction. Cleavage products C3a, C4a, and C5a are anaphylatoxins; C5a is the most potent. Anaphylatoxins are able to release histamine from mast cells and basophils, invoke contraction of smooth muscle and increase the permeability of capillaries. C5a also is involved in eliciting granulocyte responses, such as adhesion, aggregation, and the production of oxygen radicals, which can damage organ systems. It also can cause leukocytes to accumulate at sites of inflammation.91
Introduction to basic immunology and vaccine design
Published in Amine Kamen, Laura Cervera, Bioprocessing of Viral Vaccines, 2023
Alaka Mullick, Shantoshini Dash
One such effector function is the activation of a proteolytic cascade that is shown in Figure 3.9. Once an antibody recognizes its target on a pathogen surface, C1, a complement component recognizes the antigen-antibody complex and gets activated. This sets off a series of proteolytic events, which are amplified in successive steps. The activated C1 cleaves C2 into C2a and C2b, and cleaves C4 into C4a and C4b. C2b and C4b combine to form C3 convertase, a protease that cleaves C3 into C3a and C3b. C3b, also known as C5 convertase cleaves C5 into C5a and C5b. C5b reacts with other complement components, including C6, C7, C8, and C9 to form a membrane attack complex. The membrane attack complex forms a hole in the cell membrane, causing cells to lyse.
A human whole-blood model to study the activation of innate immunity system triggered by nanoparticles as a demonstrator for toxicity
Published in Science and Technology of Advanced Materials, 2019
Kristina N Ekdahl, Karin Fromell, Camilla Mohlin, Yuji Teramura, Bo Nilsson
The primary function of the complement system is to act as a purging system that removes agents that do not belong in the body such as pathogens, antigen-antibody complexes, and apoptotic cells. It consists of ≈50 proteins that are soluble in blood plasma or expressed on cells where they act as receptors and regulators that protect autologous tissue against complement attacks. Schematically, the system is divided into three activation pathways known as the classical, the alternative, and the lectin pathway. Each pathway is activated by proteins which recognize structures (often carbohydrates) expressed on pathogens, apoptotic or ischemic cells, but not on healthy autologous cells. This leads to the formation of two different enzyme complexes, so-called C3 convertases, both mediating proteolytic cleavage and activation of C3, which is the central and most abundant component of the system. It is an asymmetric cleavage that gives rise to the smaller anaphylatoxin C3a and the larger fragment C3b that can bind covalently to amino acids or carbohydrates on the target particle and thereby facilitates its phagocytosis. Further activation of the complement system leads to cleavage of C5 to the anaphylatoxin C5a (even more potent than C3a), and C5b which is the basis for the formation of the multi-molecular complex C5b-9 or membrane attack complex (MAC) which can perforate the membrane on sensitive cells or pathogens thereby destroying them. C5b-9 also exists in a soluble form (sC5b-9) that can activate endothelial cells (ECs). The main function of the anaphylatoxins is to recruit and activate PMNs and monocytes and thereby prepare them to perform efficient phagocytosis.