14th lecture
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After initial exposure to amount of antigen, the immune system produces large quantities of antibodies that circulate in the fluid compartments. When this antigen enters the system a second time, it reacts with the antibodies to form antigen-antibody complexes. These complexes summon various inflammatory components such as complement and neutrophils, which would ordinarily eliminate Ag-Ab complexes as part of the normal immune response. In an immune complex disease, however, these complexes are so abundant that they deposit in the basement membranes of epithelial tissues and become inaccessible. In response to these events, neutrophils release lysosomal granules that digest tissues and cause a destructive inflammatory condition. The symptoms of type III hypersensitivities are due in great measure to this pathologic state.* 14th lecture
Arthus reaction and serum sickness, are associated with certain types of passive immunization (especially with animal serum). Serum sickness and the Arthus reaction are like anaphylaxis in requiring sensitization and preformed antibodies. Characteristics that set them apart are: They depend upon IgG, IgM, or IgA (precipitating antibodies) rather than IgE. They require large doses of antigen (not a miniscule dose as in anaphylaxis). They have delayed symptoms (a few hours to days).
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The Arthus reaction is usually an acute response to a second injection of vaccines (boosters) or drugs at the same site as the first injection due to inflamed blood vessels in the vicinity of any injected antigen. In a few hours, the area becomes red, hot to the touch, swollen, and very painful. These symptoms are mainly due to the destruction of tissues in and around the blood vessels and the release of histamine from mast cells and basophils. Although the reaction is usually self-limiting and rapidly cleared, intravascular blood clotting can occasionally cause necrosis and loss of tissue.
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Serum sickness was named for a condition that appeared in soldiers after repeated injections of horse serum to treat tetanus. It can also be caused by injections of animal hormones and drugs. Serum sickness is a systemic injury initiated by antigen-antibody complexes that circulate in the blood and settle into membranes at various sites, eventually deposited in blood vessels of the kidney, heart, skin, and joints. The condition can become chronic, causing symptoms such as enlarged lymph nodes, rashes, painful joints, swelling, fever, and renal dysfunction.
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The background of immune complex disease. In general, circulating immune complexes become lodged in the basement membrane of the epithelia and cause vascular damage and organ malfunction.
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In the case of autoimmunity, an individual actually develops hypersensitivity to himself. This pathologic process accounts for autoimmune diseases, in which autoantibodies and, in certain cases, T cells mount an abnormal attack against self antigens. The scope of autoimmune diseases is extremely varied. In general, they can be differentiated as systemic, involving several major organs, or organ-specific, involving only one organ or tissue. They usually fall into the categories of type II or type III hypersensitivity, depending upon how the autoantibodies bring about injury.
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*In most cases, the precipitating cause of autoimmune disease remains obscure, but we do know that susceptibility is determined by genetics and influenced by gender. More direct evidence comes from studies of the MHC. Particular genes in the class I and II major histocompatibility complex coincide with certain autoimmune diseases. For example: Autoimmune joint diseases such as rheumatoid arthritis and ankylosing spondylitis are more common in persons with the B-27 HLA type. Systemic lupus erythematosus, Graves disease, and myasthenia gravis are associated with the B-8 HLA antigen.
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Attempts to explain the origin of autoimmunity include the following theories. The sequestered antigen theory explains that during embryonic growth, some tissues are immunologically privileged; that is, they are sequestered behind anatomical barriers and cannot be scanned by the immune system. Regions of the central nervous system, which are shielded by the meninges and blood-brain barrier. The lens of the eye, which is enclosed by a thick sheath; Antigens in the thyroid and testes, which are sequestered behind an epithelial barrier. Eventually the antigen becomes exposed by means of infection, trauma, or deterioration, and is perceived by the immune system as a foreign substance.
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Possible explanations for autoimmunity.
(a) Self antigens are sequestered and later incorrectly identified as a foreign antigen by B lymphocytes.(b) Self antigens are altered by viral infection, which causes an immune response against the perceived foreign antigens.
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The clonal selection theory, the immune system of a fetus develops tolerance by eradicating all self-reacting lymphocyte clones, called forbidden clones, while retaining only those clones that react to foreign antigens. Some of these clones may survive; they can attack tissues with self antigens. The theory of immune deficiency proposes that mutations in the receptor genes of some lymphocytes render them reactive to self or that a general breakdown in the normal T-suppressor function sets the scene for inappropriate immune responses. Some autoimmune diseases appear to be caused by molecular mimicry, in which microbial antigens bear molecular determinants similar to normal human cells. An infection could cause formation of antibodies that can cross-react with tissues. This is one purported explanation for the pathology of rheumatic fever.
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lupus erythematosus: (SLE, or lupus). One of the severest chronic autoimmune diseases. This name originated from the characteristic rash that spreads across the nose and cheeks in a pattern suggesting the appearance of a wolf. The patients produce autoantibodies against a great variety of organs and tissues (kidneys, bone marrow, skin, nervous system, joints, muscles, heart, and GIT). Antibodies to intracellular materials such as the nucleoprotein of the nucleus and mitochondria are also common. In SLE, autoantibody-autoantigen complexes appear to be deposited in the basement membranes of various organs. Kidney failure, blood abnormalities, lung inflammation, myocarditis, and skin lesions are the predominant symptoms. It is not known how such a generalized loss of self-tolerance arises, though viral infection or loss of T-cell suppressor function are suspected. The fact that women of childbearing years account for 90% of cases indicates that hormones may be involved. The diagnosis of SLE can usually be made with blood tests. Antibodies against the nucleus (ANA) and various tissues are common, and a positive test for the lupus factor (an antinuclear factor) is also very indicative of the disease.
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Common autoimmune diseases. (a) Systemic lupus erythematosus. One symptom is a prominent rash across the bridge of the nose and on the cheeks. These papules and blotches can also occur on the chest and limbs. (b) Rheumatoid arthritis commonly targets the synovial membrane of joints. Over time, chronic inflammation causes thickening of this membrane, erosion of the articular cartilage, and fusion of the joint. These effects severely limit motion and can eventually swell and distort the joints
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Systemic autoimmune disease, damage to the joints. In some patients, the lung, eye, skin, and nervous system are also involved. In the joint form of the disease, autoantibodies form immune complexes that bind to the synovial membrane of the joints and activate phagocytes and stimulate release of cytokines. Chronic inflammation leads to scar tissue and joint destruction. The joints in the hands and feet are affected first, followed by the knee and hip joints, though infectious agents such as Epstein-Barr virus have been suspected. The most common feature of the disease is the presence of an IgM antibody, called rheumatoid factor (RF), directed against other antibodies. This does not cause the disease but is used mainly in diagnosis.
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Thyroid gland: The underlying cause of Graves disease is the attachment of autoantibodies to receptors on the follicle cells that secrete the hormone thyroxin. The abnormal stimulation of these cells causes the overproduction of this hormone and the symptoms of hyperthyroidism. In Hashimoto thyroiditis, both autoantibodies and T cells are reactive to the thyroid gland, but in this instance, they reduce the levels of thyroxin by destroying follicle cells and by inactivating the hormone. As a result of these reactions, the patient suffers from hypothyroidism.
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The pancreas: and its hormone, insulin, are other Auto immune targets. Insulin, secreted by the beta cells in the pancreas, regulates and is essential to the utilization of glucose by cells. Diabetes mellitusis caused by a dysfunction in insulin production or utilization. Type I diabetes (also termed insulin dependent diabetes) is associated with autoantibodies and sensitized T cells that damage the beta cells. A complex inflammatory reaction leading to lysis of these cells greatly reduces the amount of insulin secreted
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*is named for the pronounced muscle weakness that is its principal symptom. The first effects are usually felt in the muscles of the eyes and throat. Eventually, it can progress to complete loss of muscle function and death. The classic syndrome is caused by autoantibodies binding to the receptors for acetylcholine, a chemical required to transmit a nerve impulse across the synaptic junction to a muscle. The immune attack so severely damages the muscle cell membrane that transmission is blocked and paralysis ensues.
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*is a paralyzing neuromuscular disease associated with lesions in the insulating myelin sheath that surrounds neurons in the white matter of the central nervous system by both T cells and autoantibodies that severely compromises the capacity of neurons to send impulses. The principal motor and sensory symptoms are muscular weakness and tremors, difficulties in speech and vision, and some degree of paralysis. Convincing evidence from studies of the brain tissue of MS patients points to a strong connection between the disease and infection with human herpesvirus.
* 14th lecture
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