Complement system. In the late 19th century Xxxxx Xxxxxx discovered “complementing” antibodies in the plasma that recognised and eliminated pathogens. He described a heat- labile activity in serum that could complement the ability of a specific antibody to cause lysis of bacteria. Today this heat-labile activity is known to comprise dozens of serum proteins and is known as the complement system. The complement system contributes to the defence against pathogens (e.g bacteria, virus-infected cells and parasites) through release of anaphylatoxins, opsonisation and lysis of pathogens, stimulation of leukocyte chemotaxis and activation of leucocytes releasing inflammatory molecules. Complement is known to function both in the defence against microbes and in the clean-up of tissues, e.g. in the disposal of immune complexes and apoptotic cells. To exert its biological activities, the complement system needs to be activated, after which it generates a variety of functional molecules. The complement system is composed of more than thirty plasma proteins, glycoproteins as well as soluble or membrane bound receptors (Xxx & Xxxx 2005). A number of complement proteins are proteolytic enzymes that also in themselves become activated by proteolytic cleavage. This protein system acts as an enzymatic cascade via various protein-protein interactions. The pattern of sequential activation produces an expanding cascade of activity, which means that the activation of a single molecule will lead to thousands of molecules being generated in the following steps. Thus, many regulatory mechanisms are needed to prevent uncontrolled complement activation and tissue damage. There are three recognised pathways of complement activation, those being the classical, alternative and lectin-binding pathways, which are activated in different
Complement system. It is a part of the immune system comprised of a biochemical proteolytic cascade that aids (complement) the antibodies and phagocytic cells to eliminate pathogens from the body (Xxxxxxxx and Xxxxxx 2013). MNMs and the immune system Since MNMs can interact with proteins, and proteins, including antibodies, are often used to target MNMs to specific cells and tissues, understanding the use of cytokines as biomarkers of undesirable immunostimulation associated with engineered MNMs is emerging as an essential component of MNM safety testing. Evaluation of the immunotoxicity of MNMs by measuring the levels of cytokines, in particular the proinflammatory cytokines can be useful tools in evaluating MNM immunotoxicity. High levels of cytokines upon treatment with MNMs are usually associated with toxicity, adverse reactions and low therapeutic efficacy, as will be discussed later. Hence, cytokines might be utilized to partially predict the MNM immunotoxicity (Xxxxxxxx and Xxxxxx 2013). The ability of MNMs to induce an immune response (immunogenicity) is a product of the MNMs’ physicochemical properties (size, charge, hydrophobicity, synthesis). It is also influenced by other factors such as the surface targeting moieties and therapeutic payload, the animal model, and the route of administration. MNMs can reach the systemic circulation via different sites, where the route of administration plays a pivotal role in dictating the fate of the MNMs and their immunotoxicity. The immune system may recognize many of the components of MNMs (e.g. shell, core, surface decorating moieties, and cargoes) as foreign, and initiates an immune response through a complex process. There are several markers and measures, which can be utilized to study and predict the immune response of biomaterials, such as, lymphocyte proliferation, cell surface markers, morphological and histopathological examination. Soluble mediators, such as, antibodies (e.g. IgG, IgE, IgM), complement proteins (e.g. C3a, C5a), and cytokines (e.g. TH1 and TH2 cytokines) have also been exploited to evaluate the immunogenicity of various therapeutics (Xxxxxxxx and Xxxxxx 2013). However, there is still a fundamental lack of biomarker specific for the safety screening of nanoproducts (Bergamaschi et al, NANOTODAY 2015). Proper design of MNMs has been always a subject of interest to improve their in vitro and in vivo characteristics, mainly to impart greater stability to their cargoes and to prolong blood circulation tim...
Complement system. In the placenta, the complement system helps to protect the mother and fetus against the invasion of pathogens. The fetus is protected by the maternal immune system by the expression of complement inhibitors. Trophoblast cells express complement regulatory proteins, which are important to protect the fetal cells because complement activation leads to destruction of the immunologic target [40]. Uncontrolled complement activation is prevented by decay accelerating factor (DAF), membrane cofactor protein (MCP), and CD59 [41]. Furthermore, tumor necrosis factor (TNF) α, Fas ligand (CD95L), TNF related apoptosis inducing ligand (TRAIL) are ligands identified in or on human trophoblast cells which are able to support the pregnancy host defense by supporting the maternal or fetal antibody production [42-44]. The various strategies of immune evasion may result in the acceptance of the fetus. However, despite these mechanisms the maternal immune system is aware of paternal antigens. Microchimerism is the persistence of a small population of foreign cells in another individual. Microchimerism is present between mother and fetus [45]. Therefore, other additional mechanisms are necessary to tolerate allogeneic cells by the maternal immune system. The microparticles which are shed from the syncytiotrophoblast layer lack HLA expression and therefore they will not be attacked by alloreactive T cells. However, the microparticles are able to bind to monocytes and stimulate the production of inflammatory cytokines, making them potential contributors to altered systemic inflammatory responsiveness in pregnancy [46].
