TYPE III HYPERSENSITIVITY
Author: Sanketh DS, MDS
The immune system protects the human body against disease by dispatching a bunch of immune cells whenever the body encounters foreign material or antigens. These immune cells elicit an inflammatory response in order to remove or eliminate the foreign antigen without causing much damage to the host. However, under certain conditions, the host may elicit an exaggerated or an inappropriate immune response to a foreign antigen causing much damage to host tissues. This exaggerated or inappropriate immune response is termed hypersensitivity. There are four types of hypersensitivity reactions them being Type I, Type II, Type III and Type IV.
Type III hypersensitivity is an immune complex disease, where the tissue damage is a result of the inflammation induced by antigen-antibody complexes also called immune complexes. These immune-complexes deposit in blood vessel walls or other tissues and organs inducing complement and leukocyte mediated tissue damage.
One of the numerous ways the body removes antigens from the system is by forming antibodies specifically against the particular antigens. Once formed, antibodies react with the antigens forming antigen-antibody complexes, also called immune complexes. Hence immune complex formation is a normal phenomenon and these complexes are eventually removed by phagocytic cells. The problem arises when these immune complexes are formed in excess. In such cases, factors responsible for removal of immune complexes are overloaded and complexes are not effectively removed. These non-cleared circulating complexes hence circulate in blood for longer durations and begin to deposit in vessel walls and other tissues and organs causing their damage eventually. Though these complexes can be deposited in any tissue or organ, they are known to be frequently deposited in blood vessel walls, basement membrane of kidneys and the synovial membrane of the joints.
The antigens in Type III hypersensitivity could possibly arise from three sources.
1. Microbial antigens from a chronic or persistent microbial infection like leprosy or viral hepatitis could lead to excessive immune complex formation.
2. In autoimmune diseases like systemic lupus erythematosus, self-reactive immune cells recognize the body’s own nuclear antigens (DNA, RNA, histones) as foreign and produce auto-antibodies against these antigens, forming immune complexes.
3. Farmer’s lung, a form of allergic alveolitis occurs due to prolonged or repeated inhalation of actinomycetes in moldy hay, causing immune complex mediated damage to the lungs.
So, how do immune complexes damage tissues?
Immune complex mediated tissue damage begins when complement proteins are activated by circulating complexes. Complement proteins are a bunch of nine proteins, C1 – C9, which when activated, trigger a cascade of enzymatic reactions. This is triggered when complement protein C1 attaches to the antibody (a subclass of IgG) of the immune complex. During the enzymatic cascade of reactions, certain complement proteins like C3, C4 and C5 are cleaved or split. The cleaved or split proteins C3a, C4a and C5a, called anaphylatoxins stimulate mast cells to degranulate and release histamine. Histamine increases vascular permeability, which further helps immune complexes to deposit and attach to the basement membrane of the blood vessels. Complement cleaved products C3a and C5a are also chemotactic factors, which help attract neutrophils to the site. Once in the site, the neutrophils try to phagocytize immune complexes but are impeded due to the complexes being attached to the blood vessel wall. The neutrophils however in the process, release a bunch of lytic enzymes and free radicals causing tissue necrosis and inflammation. Also the neutrophils produce a bunch of inflammatory mediators which help in recruiting more leukocytes, thereby amplifying damage. In addition to the damage, complement can also stimulate platelet aggregation, and subsequent stimulation of clotting factors resulting in formation of thrombi!
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