B Cell–Mediated Hypersensitivity

The antigens that cause type I reactions are often environmental—for example, pollen and food—and are otherwise harmless. Antigens causing type I hypersensitivity are considered allergens, and the reaction is considered allergic. During initial exposures to the antigen, B cells (B lymphocytes) bind the antigen and secrete immunoglobulin E (IgE) specific to it. In most cases a person requires repeated exposure to the allergen to build up sufficient IgE to become sensitized and cause an allergic reaction upon subsequent exposures. The IgE that builds up during sensitization binds to cell membrane receptors on the surface of two granulocyte white blood cell types: mast cells and basophils. When the antigen is reintroduced, a reaction happens rapidly, as it can readily bind to IgE antibodies on the surfaces of mast cells or basophils. The IgE antibodies can become cross-linked and activate a signaling pathway inside the cell. Secretory vesicles are transported to the mast cell and basophil cell membranes, and their contents are released in the process of degranulation. Chemicals, primarily histamine, prostaglandin, and leukotriene, are released during degranulation and mediate the allergic response. Histamine is a small, organic, inflammation-mediating molecule that increases blood flow by causing vasodilation and promotes swelling by increasing local capillary permeability. It is responsible for most symptoms of the allergic hypersensitivity response, including vasodilation leading to lowered blood pressure, increased vessel permeability, fluid accumulation in tissues, the secretion of mucus, and development of skin itchiness and rashes. A prostaglandin is any of a family of pro-inflammatory lipids released by granulocytic leukocytes, causing pain by promoting vasodilation. A leukotriene is any of a family of related inflammation-mediating molecules released by phagocytes, basophils, and injured cells to attract neutrophils from the blood to sites of infection. Prostaglandins and leukotrienes are primarily responsible for the inflammatory response of many allergies. Allergic rhinitis, also called hay fever, is a type I hypersensitivity response in which plant pollen acts as the allergen. Pollen binds IgE on mast cells in the nasal cavities. The resultant histamine causes local vasodilation that increases local blood flow and increases vascular permeability, resulting in fluid loss from the blood into tissues. The inflow of blood and loss of fluid from the blood in the nasal cavities causes the typical watery eyes and runny nose symptomatic of pollen allergies. Reactions in other type I hypersensitivities range from mild to severe, as in anaphylaxis, a severe, life-threatening allergic reaction that can cause death. In mild type I hypersensitivities, symptoms in response to allergens such as pollen and pet dander include itching, rash, and fluid buildup in tissues. Symptoms of bloating, diarrhea, and vomiting can occur in response to food allergies.

Some antigens are only found on the surfaces of cells of specific tissues. For example, a red blood cell in a person with type A blood has A antigens on the surface of the red blood cells. This makes A antigens "tissue specific." Similarly, some drugs, their metabolites, or antigens released by pathogens bind to the surfaces of cells in a tissue-specific manner, where they can act as antigens that instigate a type II reaction. In both cases the variable region of an immunoglobulin G (IgG) or immunoglobulin M (IgM) antibody will recognize these antigens and elicit further immune response against the cells to which they are bound. Type II hypersensitivity reactions are also known as cytotoxic hypersensitivity reactions because the cells targeted in these immune responses are typically destroyed. This may be accomplished through complement activation; phagocytosis, or ingestion by phagocytes; or cellular destruction from cytotoxic T cells.

Autoimmune hemolytic anemia is an example of a type II hypersensitivity reaction. Individuals with this condition produce antibodies to their own red blood cells, which are then destroyed. Antigens binding the cell membranes of the red blood cells can come from various precursors.

The catabolism of some antibiotics—for example, penicillin—produces compounds that attach to the surface of red blood cells. In an individual with a susceptible hypersensitive immune system, IgG or IgM antibodies can develop that recognize these antibiotic metabolites as antigens. Once antibodies bind to antigens on the red blood cells, the complement system is activated, the cells are lysed, and ultimately the individual develops anemia.

Mismatched blood transfusions represent a type II hypersensitivity reaction. If a person with type A blood is transfused with type B blood, anti-B antibodies bind to the B antigen, causing agglutination (clotting of the blood) and complement-mediated cell lysis. The person experiences fever, nausea, and chills, and within hours free hemoglobin is detected in the blood plasma. Some of this hemoglobin is converted to bilirubin, which in high enough levels is toxic to the brain. Blood then clots within the vessels. Treatment consists of stopping the transfusion and maintaining urine output.

Hemolytic disease of the newborn, also called erythroblastosis fetalis, is marked by an antigenic difference between a mother and the fetus. The mother's IgG antibodies specific for fetal blood-group antigens cross the placenta and destroy fetal red cells. This occurs commonly in a mother who is Rh-negative, or D antigen negative, and carrying a fetus who is Rh-positive, or has D antigens present on red blood cells. At delivery, a large amount of fetal umbilical cord blood enters maternal blood circulation, allowing for the activation of the mother's D antigen–specific B cells. This results in the production of anti–D antigen antibodies and memory B cells.

If this mother becomes pregnant with another Rh-positive fetus, fetal red blood cells will cross the placenta and activate the mother's memory B cells. This results in the production of IgG antibodies that cross the placenta, bind the fetal D antigen, and lyse the fetal red blood cells. Often, this condition is fatal to the fetus.

There are several mechanisms through which a cell with attached antigen and antibody might be destroyed. One mechanism is lysis following antibody activation of the classic complement cascade and the formation of membrane attack complexes. Another mechanism is phagocytosis following recognition of the IgG-bound antigen and cell by a macrophage.

In situations that involve antigens on cells of endothelial walls, or cells that line the walls of blood vessels or organs, other aspects of the complement system are activated and recruit neutrophils to the cell, where they release enzymes and reactive oxygen species that damage the tissue. Finally, the IgG or IgM bound to the antigen can bind a cytotoxic T cell with a receptor specific to the constant end of the antibody. The cytotoxic T cell induces cell death in the target cell by releasing cytolytic enzymes into it.

In type III hypersensitivity, the antigens are soluble and free in circulation. IG and IgM antibodies may sensitize to the antigens and bind with them in circulation. Normally, immune complexes formed are easily cleared by the phagocytic cells of the immune system and removed from circulation by the kidneys. However, when antigen-antibody complexes are present in excess, they are deposited in extravascular tissue or on the walls of vessels.

Once deposited, a complement cascade is initiated that recruits neutrophils, mast cells, and other granulocyte white blood cells that attempt to remove the complexes by phagocytosis. Due to the size of the complexes and their adherence to tissues, phagocytosis is unsuccessful, and degranulation of the granulocytes occurs. The released enzymes and reactive oxygen species can damage tissues directly, while the released cytokine recruits inflammatory cells and initiates an inflammatory response.

Type III hypersensitivity is not tissue specific, though antibody-antigen complex deposition is more prevalent in some tissues, particularly the kidneys, joints, and vessel walls. An example of a kidney-specific type III hypersensitivity reaction is poststreptococcal glomerulonephritis. A person with a streptococcal throat infection develops antibodies against the streptococcal organism. However, these antibodies can cross-react with antigens in the glomerulus of the kidney. Antibody-antigen immune complexes then lodge in the kidney and cause nephritis, or inflammation of the kidney.

Before the advent of antibiotics, it was regular practice to treat patients suffering from certain infections with serum from other animals, notably horses, that had developed antibodies to the infectious pathogen. Over the course of a week, the patient would develop antibodies to antigens in the foreign serum and immune complexes formed in circulation. Subsequent deposition of these complexes led to a type III hypersensitivity reaction known as serum sickness. Serum sickness is a type III hypersensitivity reaction forming antigen-antibody complexes with proteins in medicines or antisera, thus causing fever, malaise, hives, itching, joint pain, rash, or lymph node swelling. Antibody-antigen deposits commonly form in the joints, blood vessels, and kidneys.

Foreign serum is no longer administered as an infection treatment, but a host of drugs and their metabolic products can lead to similar pathology. The end result typically involves joint pain, fever, rashes, swollen lymph nodes, and inflammation with pain localized to the sites of inflammation.