Hypersensitivity Reactions

Immune and hypersensitivity (allergy) reactions involve the same mechanisms, and the differences between them are not clear. Both require exposure to an antigen and subsequent stimulation of antibody-mediated immunity and/or cell-mediated immunity. If immunity to the antigen is established, later exposure to the antigen results in an immune system response that eliminates the antigen, and no symptoms appear. In hypersensitivity reactions the antigen is called the allergen, and later exposure to the allergen stimulates much the same process that occurs during the normal immune system response. However, the processes that eliminate the allergen also produce undesirable side effects such as a very strong inflammatory reaction. This immune system response can be more harmful than beneficial and can produce many unpleasant symptoms. Hypersensitivity reactions are categorized as immediate or delayed.

Immediate Hypersensitivities

Immediate hypersensitivities are accused by antibodies interacting with the allergen, and symptoms appear within a few minutes of exposure to the allergen. Immediate hypersensitivity reactions include atopy, anaphylaxis, cytotoxic reactions, and immune complex disease.

Atopy (at'-o-pe) is a localized IgE-mediated hypersensitivity reaction. For example, plant pollens can be allergens that cause hay fever when they are inhaled and absorbed through the respiratory mucosa. The resulting localized inflammatory response produces swelling and excess mucus production. In asthma patients, allergens can stimulate the release of leukotrienes and histamine in the bronchioles of the lung, causing constriction of the smooth muscles of the bronchioles and difficulty in breathing. Hives (urticaria) is an allergic reaction that results in a skin rash or localized swellings and is usually caused by an ingested allergen.

Anaphylaxis (an-a-fi-lak'is) is a systemic IgE-medicated reaction and can be life threatening. Introduction of allergens such as drugs (for example, penicillin) and insect stings is the most common cause. The chemicals released from mast cells and basophils causes systemic vasodilation, a drop in blood pressure, and cardiac failure. Symptoms of hay fever, asthma, and hives may also be observed.

In cytotoxic reactions, IgG or IgM combines with the antigen on the surface of a cell, resulting in the activation of complement and subsequent lysis of the cell. Transfusion reactions caused by incompatible blood types, hemolytic disease of the newborn, and some types of autoimmune disease are examples.

Immune complex disease occurs when too many immune complexes are formed. Immune complexes are combinations of soluble antigens and lgG or lgM. When there are too many immune complexes, too much complement is activated, and an acute inflammatory response develops. Complement attracts neutrophils to the area of inflammation and stimulates the release of lysosomal enzymes. This release causes tissue damage, especially in small blood vessels, where the immune complexes tend to lodge: and lack of blood supply causes tissue necrosis. Arthus reactions, serum sickness, some autoimmune diseases, and chronic graft rejection are examples of immune complex diseases.

An Arthus reaction is a localized immune complex reaction. For example, if an individual has been sensitized to antigens in the tetanus toxoid vaccine because of repeated vaccinations and if that individual were vaccinated again, at the injection site there would be large amounts of antigen with which the antibody could complex, causing a localized inflammatory response, neutrophil infiltration, and tissue necrosis.

Serum sickness is a systemic Arthus reaction in which the antibody-antigen complexes circulate and lodge in many different tissues. Serum sickness can develop from prolonged exposure to an antigen that provides enough time for an antibody response and the formation of many immune complexes. Examples of antigens include long-lasting drugs and passive artificial immunity. Symptoms include fever, swollen lymph nodes and spleen, and arthritis. Symptoms of anaphylaxis such as hives may also be present because IgE involvement is a part of serum sickness. If large numbers of the circulating antibody-antigen complexes are removed from the blood by the kidney, immune complex glomerulonephritis can develop, in which kidney blood vessels are destroyed and the kidneys fail to function.

Delayed Hypersensitivity

Delayed hypersensitivity is mediated by T cells, and symptoms usually take several hours or days to develop. Like immediate hypersensitivity, delayed hypersensitivity is an acute extension of the normal operation of the immune system. Exposure to the allergen causes activation of T cells and the production of cytokines. The cytokines attract basophils and monocytes, which differentiate into macrophages. The activities of these cells result in progressive tissue destruction, loss of function, and scarring.

Delayed hypersensitivity can develop as allergy of infection and contact hypersensitivity. Allergy of infection is a side effect of cell-mediated efforts to eliminate intracellular microorganisms, and the amount of tissue destroyed is determined by the persistence and distribution of the antigen. The minor rash of measles results from tissue damage as cell-mediated immunity destroys virus-infected cells. In patients with chronic infections with long-term antigenic stimulation, the allergy-of-infection response can cause extensive tissue damage. The destruction of lung tissue in tuberculosis is an example.

Contact hypersensitivity is a delayed hypersensitivity reaction to allergens that contact the skin or mucous membranes. Poison ivy, poison oak, soaps, cosmetics, drugs, and a variety of chemicals can induce contact hypersensitivity, usually after prolonged exposure. The allergen is absorbed by epithelial cells, and T cells invade the affected area, causing inflammation and tissue destruction. Although itching can be intense, scratching is harmful because it damages tissues and causes additional inflammation.

Autoimmune Diseases

In autoimmune disease the immune system fails to differentiate between self-antigens and foreign antigens. Consequently, an immune system response is produced, resulting in tissue destruction. In many instances, autoimmunity probably results from breakdown of tolerance, which normally prevents an immune system response to self-antigens. In molecular mimicry a foreign antigen that is very similar to a self antigen stimulates an immune system response. After the foreign antigen is eliminated, the immune system continues to act against the self antigen. It is hypothesized that type 1 diabetes develops in this fashion. In susceptible people a foreign antigen can stimulate adaptive immunity, especially cell-mediated immunity, which destroys the insulin-producing beta cells of the pancreas. Other autoimmune disease that involve antibodies are rheumatoid arthritis, rheumatic fever, Grave's disease, systemic lupus erythematosus, and myasthenia gravis.

Immunodeficiencies

Immunodeficiency is a failure of some part of the immune system to function properly. A deficient immune system is not uncommon because it can have many causes. Inadequate protein in the diet inhibits protein synthesis, and anti-body levels will decrease. Stress can depress the immune system, and fighting an infection can deplete lymphocyte and granulocyte reserves, making a person more susceptible to further infection. Diseases that cause proliferation of lymphocytes, such as mononucleosis, leukemias, and myelomas, can result in an abundance of lymphocytes that do not function properly. Finally, the immune system can purposefully be suppressed by drugs to prevent graft rejection.

Congenital (present at birth) immunodeficiencies can involve inadequate B cell formation, inadequate T cell formation, or both. Severe combined immunodeficiency disease (SCID) in which both B and T cells fail to differentiate is probably the best known. Unless the person suffering from SCID is kept in a sterile environment or is provided with a compatible bone marrow transplant, death from infection results.

Tumor Control

Tumor cells have tumor antigens that distinguish them from normal cells. According to the concept of immune surveillance, the immune system detects tumor cells and destroys them before a tumor can form. T cells, NK cells, and macrophages are involved in the destruction of tumor cells. Immune surveillance may exist for some forms of cancer caused by viruses. However, the immune response appears to be directed more against the viruses than against tumors in general. Only a few cancers are known to be caused by viruses in humans. For most tumors the response of the immune system may be ineffective and too late.

An effective approach to treating cancer would be to destroy only cells displaying tumor antigens. The use of monoclonal antibodies, administering cytokines, and injection tumor-specific cytotoxic T cells that have been isolated and stimulated outside the body are examples. To date such attempts have had only limited success and often produce undesirable side effects.

Transplantation

The genes that code for the production of the MHC antigens are generally called the major histocompatibility complex genes. Histocompatibility refers to the ability of tissues (Gr. Histo) to get along (compatibility) when tissues are transplanted from one individual to another. In humans, the major histocompatibility complex genes are often referred to as human leukocyte antigen (HLA) genes because they were first identified in leukocytes. There are millions of different possible combinations of the HLA genes, and it is very rare for two individuals (except identical twins) to have the same set of HLA genes. Because they are genetically determined, however, the closer the relationship between two individuals, the greater the likelihood of sharing the same HLA genes.

Acute rejection of a graft occurs several weeks after transplantation and results from delayed hypersensitivity reaction and cell lysis. Lymphocytes and macrophages infiltrate the area, a strong inflammatory response occurs, and the foreign tissue is destroyed. If acute rejection does not develop, chronic rejection may occur at a later time. In chronic rejection, immune complexes form in the arteries supplying the graft, blood supply fails, and the graft is rejected.

Graft rejection can occur into different directions. In host vs. graft rejection, the recipient's immune system recognizes the donor's tissue as foreign and rejects the transplant. In a graft vs. host rejection, the donor tissue recognizes the recipient's tissue as foreign, and the transplant rejects the recipient, causing destruction of the recipient's tissues and death.

To reduce graft rejection, a tissue match is performed. Only tissues with HLAs similar to the recipient's have a chance of acceptance. Even when the match is close, immunosuppressive drugs must be administered throughout the patient's life to prevent rejection. An exact match is possible only for a graft from one part to another part of the same person's body or between identical twins.

The HLA genes control the production of human leukocyte antigens (HLAs), also called MHC antigens, which are inserted onto the surface of cells. The immune system can distinguish between self- and foreign cells because they are both marked with HLAs. Rejection of a transplanted tissue is caused by normal immune system response to the foreign HLAs.

HLAs are important in ways in addition to organ transplants. Because they are genetically determined, HLAs help resolve paternity suits. In forensic medicine, the HLAs in blood, semen, and other tissues help identify the person from whom the tissue came.

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