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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 can be rapid and robust: Antibody-initiated CP activation can mediate the deposition of 2 × 107 C3b molecules on a cellular target within 5 min [8]. The C cascade is normally held in check on host surfaces by the regulators of C activation (RCA) that inhibit convertase activity and MAC assembly [9]. These include fluid phase proteins Factor H (FH) and C4-binding protein (C4BP) as well as the membrane proteins CD46 (membrane cofactor protein, MCP), decay accelerating factor (DAF) and complement receptor 1 (CR1, CD35). These proteins inhibit C activation via two critical mechanisms: (1) They inhibit convertase activity directly by dissociating the convertase complexes (decay accelerating activity), and (2) they inhibit convertase formation by serving as cofactor for the cleavage of C3b and C4b by the fluid phase protease Factor I (FI) (cofactor activity). In addition, CD59, a membrane-bound non-RCA protein, protects host tissue by blocking the assembly of the MAC. These regulators, plus the intracellular pathways that respond to membrane perturbation [10], normally prevent the lysis of nucleated cells.
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
Autologous cells, but not pathogens or biomaterial or other non-biological surfaces, are protected against complement attack by a large number of membrane-bound regulatory proteins, e.g., decay accelerating factor (DAF), membrane co-factor protein (MCP) and complement receptor 1 (CR1). The protection can also be ‘topped up’ by recruitment of other protective proteins such as factor H and C4b-binding protein (C4BP) from the plasma. This binding is due to their affinity for heparan sulfate and other polymeric carbohydrates which are components of the glycocalyx which covers the ECs. Another important regulator is C1 inhibitor (C1INH) that acts in the plasma where it inhibits proteolytic enzymes which are generated early in the complement cascade (prior to activation of C3) as well as proteases within the contact system (see below).