Antibody Effector Mechanisms and the Activation of the Complement System

The binding of antibodies to antigens triggers several functions of the immune system, usually referred to as "effector mechanisms,” which depends on the isotype of the antibody. These mechanisms comprise the ability to (1) neutralize function of intruding microorganisms or other foreign bodies, [2] facilitate the uptake of foreign bodies through receptors on the surface leukocytes that bind antibodies, or (3) activation of the complement system as discussed below in this section.

Antibodies are able to neutralize functions of infectious microbial organisms by simple binding to key molecules of these organisms. Several studies have demonstrated that nanoparticle formulations of various antigens enhance the immune response, i.e., antibody synthesis, compared with the response of the naked antigen [14-16]. It is unclear, however, if nanomaterials enhance the immune response compared with particulate formulations with larger particles, which routinely are used as adjuvants in vaccines. While the particle-enhanced immune response may serve certain purposes in vaccine formulations, it is likely that the strong response could generate antibodies that would interfere with other functions of nanoparticles, e.g., the targeting to specific tissues and drug release. Similarly, binding of antibodies to these or other types of nanomaterials may also be speculated to alter chemical properties of surfaces with regard to hydrophilicity, surface roughness, and the presentation of cues for cell adhesion. Since the function of many nanomaterials critically depends on these properties, such antibody "biofouling" could potentially incapacitate the function of the material [17]. However, the current insight into such processes is limited.

A significant effector mechanism of antibodies involves a processes referred to as "opsonization” derived from an ancient Greek word meaning "preparing for food." A group of leukocytes that includes monocytes, macrophages, dendritic cells, and neutrophil granulocytes is capable of phagocytosis (literally meaning "eating") of particulate material. The same process also plays a role in the interaction between these cells and solid materials where phagocytes may enable restructuring or degradation of the material. Binding of antibodies to particles greatly facilitates the uptake of these particles by phagocytes and stimulates the production of cytokines. Following the contact between the phagocyte and the antibody-coated particle, receptors for the Fc part of antibodies mediate the uptake of the particles in membrane-clad vesicles into phagocyte cytoplasm. Here, the vesicles are fused with lipid vesicles with enzymes, typically esterases, which may degrade not only protein species but also other polymers. In processes where phagocytes interact with surfaces or objects vastly larger than the cell itself, the cells show signs of incomplete, or frustrated, phagocytosis, which releases enzymes and oxygen radicals to the extracellular environment [18, 19]. The enzymes may eventually affect the successful integration of the nanomaterial in the body.

A third effector mechanism of antibody binding is comprised by the activation of the complement system [20, 21]. The complement system consists of approximately 30 soluble components in human plasma andreceptorsexpressedonthecellsurface.Followingantibody binding to target surfaces, the Cl complexes bind the antibodies and through its enzymatic components activate complement factors C2 and C4 through cleavage of these proteins into the fragments C2a and C2b as well as C4a and C4b. The C2a and C4b fragments form an enzyme that cleaves C3 into C3a and C3b. Since C3b together with the b fragment of complement factor В (Bb) also is an enzyme that may cleave C3, a positive amplification loop is established, which rapidly covers a target surface with C3b fragments. The C3 and C4 proteins are structurally similar and both of these proteins forms a covalent adduct with hydroxyl or amine groups on the activating surface. The process is controlled by Factor I that inactivates the СЗЬВЬ complex by cleavage of C3b into iC3b. Both the C3b and iC3b fragments are facilitators of receptor-mediated phagocytosis and appropriate receptors are expressed on all phagocytes. C3a, the small fragment of C3 following cleavage during activation, together with other small fragments of complement factors (usually referred to as anaphylatoxins), is a potent mediator of inflammation, notably with an influence on the endothelial barrier. Strong activation of the complement system may consequently cause a breakdown in the function of vascular system leading to a rapid and life-threatening drop in blood pressure (shock) and disseminated intravascular coagulation.

While the above-mentioned activation pathway with antibody as the initiating event is referred to as the "classical" pathway, other antibody independent pathways of complement activation also exist. These include the "alternative pathway” where a spontaneous deposition of autoactivated C3 on surfaces catalyzes further deposition of C3b through formation of the СЗЬВЬ convertase.

On host cell, such deposition is avoided by cell surface-expressed molecules that catalyzes the proteolytic degradation of C3. During the past 20 years of research, it has become evident that certain lectins,

1. e., carbohydrate-binding proteins that are not antibodies, also may contribute to the activation of the complement system through the "lectin pathway" in plasma [22]. Mannan-binding lectin (MBL) binds glycans with terminal mannose, /V-acetylglucose, or glucose residues. These are typically exposed on the surfaces of viruses, bacteria, and fungi and the opsonization of these microorganisms via complement deposition is clearly important to avoid infections.

MBL mediates complement deposition through the associated MBL- associated serine proteases (MASP), notably through the activation of C4 and C2 by MASP-2. More recently, the group of ficolins has also attracted attention [23]. While ficolins also associate with MASP-

2, their ligands are not primarily carbohydrates but acetylated compounds, including acetylated sugars, e.g., N-acetylglucosamine.

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