Effector functions of Antibodies: Neutralization, Opsonization, and ADCC (Part 6- Antibody Basics)
Welcome to the 6th part of the 13-part series on Antibody basics.
Previous parts: Part 1, Part 2, Part 3, Part 4, and Part 5
Neutralization of infectivity
Pathogens or toxins cause disease by binding to the specific receptors on the host cells to gain entry into the cells. But when the specific antibodies bind to the pathogens or toxins, they block their entry into the host cells. In other words, antibodies neutralize the pathogens’ infectivity.
For instance, the Human Immunodeficiency Virus (HIV) weakens the immune system by infecting immune cells, i.e., CD4 T cells, eventually depleting them. The glycoproteins gp120 and gp41, present on the envelope, allow HIV to lock onto the CD4 receptor present on CD4 T cells to gain entry into the cells. The neutralizing antibodies raised by the immune system bind to the gp120 proteins, which block the attachment of the virus to the T cells, thus preventing its entry into the T cells.
Once a pathogen has been neutralized by the neutralizing antibodies, the pathogen-antibody complex is eventually taken up and degraded by the macrophages.
Opsonization
Opsonization is the process by which pathogens, immune complexes, tumor cells, apoptotic cells, etc., are marked for ingestion and then eliminated by the phagocytes like macrophages and neutrophils. The molecules that promote opsonization are called opsonins. The complement protein C3b (discussed in Part 5) and the antibody are two main opsonins.
Additionally, the phagocytes have receptors (Fc receptors) for binding to the antigen-coated opsonins on their membranes. The Fab region of the antibody binds to the target antigen, whereas the Fc region of the antibody binds to the Fc receptor on the phagocyte. Once bound, phagocytosis of Ab bound Ag occurs by the phagocytic cells. This process is called opsonization.
During the phagocytosis process, the membrane of the phagocyte cell induces membrane protrusions, called pseudopodia, to extend around the attached Ag-Ab complex. The fusion of the pseudopodia encloses the Ag-Ab complex within a membrane-bounded structure called a phagosome, which then enters the endocytic processing pathway. In this pathway, a phagosome fuses with a lysosome to form a phagolysosome. Lysosomes contain lysozyme and a variety of other hydrolytic enzymes that digest the ingested antigen. In this way, through phagocytosis, the internalized antigen is neutralized.
Antibody-dependent cell-mediated cytotoxicity (ADCC)
ADCC pathway is activated when
· there is an intracellular infection (e.g., tumor cell or if the virus has infected the cell)
· or when the invading pathogen is too large, e.g., parasitic worms.
In both cases, phagocytosis cannot eliminate the infected cell or parasites as it is challenging to internalize them by phagocytic cells. In such cases, the immune system activates the ADCC pathway.
Activation of ADCC involves the binding of antibodies to specific proteins (antigens) on the infected cell, tumor cell, or parasite. The Fc region of the bound antibodies then binds to the Fc receptors present on the effector cells of the immune system that have the cytotoxic function, like natural killer (NK) cells and eosinophils. Once bound, degranulation of the cytotoxic cells occurs. The released cytotoxic chemicals disrupt the cell membrane of the target cell, resulting in its lysis. For instance,
Natural killer (NK) cells: NK cells are generally involved in killing tumor cells and cells infected by viruses. Tumor cells and cells infected by viruses display antigens that are recognized as foreign by the immune system, against which the immune system generates antibodies, specifically IgG. The IgG antibodies then bind to the antigens displayed by tumor and virus-infected cells. NK cells express CD16, a membrane Fc receptor that binds to the Fc region of the bound IgG molecule. Once the Fc receptor binds to the Fc region of the bound antibodies, NK cells release cytotoxic factors like granzyme and perforin proteins, which cause the lysis of the target cells, thereby killing them.
Eosinophils: Eosinophils are generally involved in recognizing parasites and killing them by releasing toxic substances. The IgE antibodies coat the surface of the parasitic worm by binding to its surface antigens. These bound IgE antibodies are then recognized by the eosinophils. This recognition is mediated by specific Fcε receptors present on the eosinophils, which bind to the Fc region of IgE bound to worms. Once bound, the eosinophils undergo translocation of their granules to the plasma membrane, followed by the release of contents of the granules to the extracellular environment. The release of granular content is known as degranulation. The granule content is a source of various cytokines, chemokines, enzymes, cationic proteins, etc., that, when released, destroy the parasitic worms.
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