Type II hypersensitivity (cytotoxic hypersensitivity) – causes, symptoms, & pathology
What is type II hypersensitivity? Type II hypersensitivity is an immune response in which host cells are damaged due to antibodies binding to the cell surface.
This video discusses five mechanisms of cellular damage, including via the complement pathway, opsonization and phagocytosis, and antibody-mediated cellular dysfunction.
Hypersensitivity occurs when the immune system reacts in a way that damages the body instead of healing or protecting it. There are four types of hypersensitive reactions.
Type two hypersensitivity reactions commonly involve healthy cell destruction mediated by antibodies. Because of this, it is sometimes referred to as cytotoxic hypersensitivity. The antibodies, as well as the disorders they cause, are usually tissue or organ specific.
The immune system is designed to fight anything that’s foreign to the body, but protect healthy body cells. This balance occurs through a process called central tolerance, in which self-reactive immune cells are inactivated or destroyed. The destruction or inactivation occurs within the cell developing lymphoid organs, the thymus for T cells and bone marrow for B cells. Sometimes, self-reactive T and B cells escape the process and attack healthy body tissue, which results in an autoimmune disease.
Antigens involved in type two hypersensitive reactions may be intrinsic, or natural to the body, or extrinsic, or foreign to the body. Extrinsic antigens may be from infections or medications. For example, when penicillin binds to a red blood cell, it becomes an extrinsic antigen. If an immunoglobulin antibody binds to the penicillin molecule, an antigen antibody complex is formed. These complexes may form during the course of a normal infection, but problems will occur when complexes against host tissue are formed.
Most of the mechanisms of type two hypersensitivity are cytotoxic, or lead to cell death. The first of these is the activation of the compliment system, a group of small proteins that work together and fight infection through an enzymatic cascade. IgG or IgM antibodies activate the compliment system, which will in turn kill the antigen antibody complex. Using the example of penicillin, we can see that the first complement protein, C1, binds to the Fc portion of the antibody, then triggers C2 through C9. Activation of some compliment proteins is achieved by enzymatic cleaving. The cleaved fragments attract neutrophils, which degranulate and generate oxygen radicals, which then cause tissue damage. Type two hypersensitive reactions triggered by drugs may result in hemolytic anemia, neutropenia, or thrombocytopenia.
The same cytotoxic process may occur with intrinsic antigens as well. For example, Goodpasture’s syndrome occurs when antibodies bind to intrinsic on collagen in the kidneys or lungs.
The second cytotoxic mechanism of type two hypersensitivity also involves the compliment system. C5b, a cleaved fragment of compliment protein 5, joins forces with C6, C7, C8, and C9 to form the membrane attack complex, also referred to as MAC. The MAC inserts itself into the cell membrane and allows molecules to flow through the cell. Due to osmosis, fluid rushes into the cell and it bursts, then dies.
Hemolytic anemia may be detected using a Coomb’s test, in which the red blood cells are removed from the plasma and missed with Coomb’s reagent, an antibody against human antibodies. If the red blood cells clump, antibodies were likely present.
Blood group incompatibility can be tested using an indirect Coomb’s test, in which blood serum is mixed with laboratory acquired red blood cells with previously identified antigens on their surface. The Coomb’s reagent is then added; if the red blood cells clump, antibodies or compliment proteins are in the serum.
The third cytotoxic mechanism of type two hypersensitivity occurs when IgG antibodies clot with blood cells that have been bound by C3b, a fragment of the compliment three protein. When this occurs, the cell is opsonized, or targeted for phagocytosis. Once the cell is opsonized, the antibody antigen complex is carried to the spleen, where it is ingested and destroyed by phagocytes.
The fourth cytotoxic mechanism of type two hypersensitivity is referred to as ADCC, short of antibody dependent cell mediated cytotoxicity. In this mechanism, bound antigen antibody complexes are recognized by the natural killer cells of the immune system. These cells recognize the tail of the antibody and release granules toxic to it. The granules compromise the cell membrane and allow destructive enzymes called granzymes into the cell. The granzymes kill the cell without triggering surrounding inflammation.
Antibody mediated cellular dysfunction is a mechanism of type two hypersensitivity that does not lead to cell death. During this process, an antibody binds to an antigen and disrupts its function. An example of this is myasthenia gravis, an autoimmune disease in which specific antibodies block acetylcholine from binding to its receptors in muscles. This prevents muscle stimulation and leads to muscle weakness.
This mechanism also occurs in Grave’s disease. The antibodies target the receptors that stimulate hormone production in the thyroid. With Grave’s disease, the antibodies themselves trigger the receptors, causing overproduction of hormones and hyperthyroidism.