Type III hypersensitivity (immune complex mediated) – causes, symptoms & pathology
What is Type III hypersensitivity? Type III hypersensitivity describes when antigen-antibody complexes deposit in the blood vessels and cause subsequent inflammation and tissue damage.
This video covers the pathophysiology, as well as several important clinical examples of type III hypersensitivity.
Hypersensitivity occurs when an immune reaction harms the body instead of protecting or healing it. There are four types of hypersensitive reactions. During a type three reaction, antigen-antibody complexes attach to the walls of the blood vessels, causing inflammation and damage to the tissues.
Immune complexes are responsible for type three hypersensitive reactions. Immune complexes are composed of two parts: an antigen and an antibody. Antibodies involved in type three reactions are made by plasma cells, which are differential B cells that have fully matured.
Plasma cells create IgM antibodies. Some of the antibodies bind to the cell surface of the plasma cell, where they act as cell receptors. Others are secreted. When cross linking of two IgMs occurs, the B cell presents the antigen to receptors on T helper cells. B cells work with co-stimulatory molecule CD4 and trigger the T cells to release cytokines. In type three hypersensitive reactions, isotope switching is triggered and B cells that previously made IgM antibodies start making IgG antibodies. Because antibodies are specific to their antigens, isotope switching makes it more difficult for the body to fight the antigen.
Some antigens are soluble and move through the blood, others bind to cell surfaces. The immune complexes responsible for type three hypersensitive reactions are antibodies bound to soluble antigens. This is a notable difference between type three and type two reactions, which occur when antibodies bind with antigens on cell surfaces.
Systemic Lupus Erythematosus is an excellent example of a type three hypersensitive reaction. Lupus is an autoimmune disease in which IgG antibodies are self-reactive and target the body’s DNA and nuclear proteins.
Healthy immune systems will only react to a foreign molecule. This is achieved through a process called tolerance, in which self-reactive antibodies, or auto antigens, are destroyed or deactivated. The process is flawed and sometimes self-reactive antibodies escape and damage the body.
Let’s follow the cycle of self-reactive antibodies within the immune system of a Lupus patient. DNA auto antigens are released into the body, then bound by B cells, creating IgG DNA auto antigen complexes. Nearby T helper cells activate the B cells to create IgG antibodies specific to the auto antigens. Typically, the antibodies are drastically outnumbered by the auto antigens. When the antibodies bind to the auto antigens, they form small antigen-antibody complexes that don’t draw much attention from macrophages and, therefore, aren’t removed from the blood stream as quickly as larger antigen-antibody complexes. The positively charged DNA within the IgG DNA auto antigen complexes are attracted to the negatively charged basement membrane layers of blood vessels, and the complexes attach themselves there, activating the compliment system.
The compliment system is comprised of nine proteins, called C1 through C9. The proteins clear infections from the body through an enzymatic cascade.
In the above example, C1 would bind with the IgG DNA auto antigen complex, activating C2 through C9. The proteins are activated by cleaving, which results in protein fragments. C3A, C4A, and C5A fragments work as anaphylatoxins, which increase the permeability of blood vessels. This allows fluid to move easily through the vessel and causes swelling.
The process of the compliment system is another distinction between types two and three hypersensitive reactions. In type two reactions, only small numbers of compliment proteins are activated. In type three reactions, the large amounts of compliment proteins are activated. Because of this, testing compliment levels in the blood can help track disease activity.
The anaphylatoxins that increase vessel permeability also act as chemokines, which attract neutrophils to the site of reaction. The neutrophils attempt to destroy the immune complex, but can’t. They degranulate, causing inflammation and tissue death. The inflammation triggers the release of more auto antigens, and the destructive cycle continues.
The cycle of inflammation and damage typically occurs in the kidneys, where blood is filtered, and the joints, where plasma is filtered. This is another distinction between type two and type three hypersensitivity. Type two reactions typically occur where immune complexes are made. Type three reactions occur where immune complexes are deposited.
Another example of a type three hypersensitivity reaction is serum sickness, in which a patient has an antibody response to foreign antigens present in donated blood. For instance, someone with a snake bite may be given blood that contains antivenom antibodies. The body would then create antibodies against the antivenom antibodies. If venom is introduced into the body again, the antibodies created upon first exposure will form immune complexes with the antivenom antibodies the body believes to be antigens. In turn, the immune complexes bind to vessel walls and cause tissue damage.