Antibody-dependent cell-mediated cytotoxicity: Type II hypersensitivity reaction
During a hypersensitivity reaction, the body can also respond to its own components that
are usually ignored.
In a type two reaction, this response is caused by the presence of certain antibodies.
Under normal conditions, antibodies are produced during an adaptive immune response to fight
off pathogens. In type two hypersensitivity, the antigen is located on the cell surface
or is part of the connective tissue. This leads to an antibody-mediated immune response
to the body’s own cells. The antibodies initiate a cascade of events that can lead
to cell lysis, phagocytosis, or apoptosis. Therefore, a type two hypersensitivity reaction
is also called an antibody-dependent cell-mediated cytotoxic response.
Let’s take a more detailed look at the mechanisms involved.
Antibody-binding to the antigen primarily activates the complement system. This system
comprises specific plasma proteins that act as a cascade, mediating further activation
of immune cells and heightening the intensity of the response.
The complement cascade is triggered by a complement protein that binds to the antigen-antibody
complex on the cell. This leads to the activation of further complement proteins through cleavage
of small fragments. These fragments are chemotactic, meaning they attract immune cells such as
neutrophils, which bind to the antibody via Fc receptors present on the surface. These
Fc receptors can detect and bind to the Fc portion of an antibody. After binding, neutrophils
generate aggressive substances such as radical oxygen species. These substances cause cellular
damage, inflammation, and eventually cell death.
In addition, activated complement proteins can bind to the target cell surface, marking
it for a process called opsonization. These marked cells can be recognized by phagocytes,
notably macrophages, which also use Fc receptors to bind to the antibody. After binding, macrophages
start to engulf the target cell and break it down.
Furthermore, activation of the complement system also leads to the formation of a membrane
attack complex, in short MAC. This complex can insert into the plasma membrane, resulting
in an influx of extracellular fluid. As a result, the cell swells and eventually lyses.
Bound IgG antibodies can also be recognized by natural killer cells, often referred to
as NK cells. These lymphocytes also possess Fc receptors on their surface, which bind
to the antibody leading to natural killer cell activation.
The natural killer cell releases perforin, a protein similar to the membrane attack complex,
that inserts into the plasma membrane and causes target cell lysis.
Natural killer cells also release granzymes, a group of proteins that initiate apoptosis.
In some diseases caused by type two hypersensitivity reactions, antibodies may be directed towards
cell surface receptors, thereby disrupting normal cell function. There are two cases
that can be distinguished:
First, the antibody blocks the receptor and prevents signals from being transmitted. Second,
the antibody binds to a receptor, activating it in the process, and acts as a transmitter.
Both can have severe physiological consequences. As we've just seen, type two hypersensitivity
reactions usually cause cell death.
This can either be complement-mediated or complement-independent. However, for most
type two hypersensitivity reactions, multiple mechanisms contribute to the autoimmune reaction
to varying degrees. It’s important to note here that cell death
via lysis most enhances inflammation through the release of cell components.