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The immune system is essential for survival, providing recovery from disease and long-lasting protective immunity. Under normal circumstances the immune system responds to foreign organisms by the production of antibodies and the stimulation of antigen- specific lymphocytes, leading to killing of the organisms and neutralization of their toxic products (toxins). A major function of the immune system is surveillance of the cells of the body to ensure that they are not abnormal. Cells infected with viruses, malignant cells, or cells from another individual of the same species have protein markers on their outer membrane that act as a signal to the immune system to destroy them. The system to which these proteins belong is called the major histocompatibility complex (MHC).
Immune responses are not always beneficial. They can contribute directly to pathological processes during infections and autoimmunity. The terms hypersensitivity or allergy are used when immune reactions produce tissue damage and harm the host; such reactions to an otherwise-harmless foreign substance may have severe effects and even lead to anaphylactic SHOCK and death. In some cases, for reasons that are not clear, normal cells may be wrongly identified as foreign or abnormal. The immune system may develop antibodies and activate lymphocytes against them, producing autoimmune diseases including systemic LUPUS ERYTHEMATOSUS, MYASTHENIA GRAVIS, DIABETES, and Graves' disease.
Cells And Tissues In The Immune Response
The immune system has two general types of responses, antibody and cell-mediated responses. The cells of the immune system that respond to antigens are the lymphocytes. There are two types of lymphocytes that develop in the primary lymphoid organs: B lymphocytes, or B cells, develop in the bone marrow, while T lymphocytes, or T cells, develop in the thymus. B cells are responsible for antibody production. Plasma cells, derived from B lymphocytes, secrete antibodies that circulate in the bloodstream or are secreted onto mucosal surfaces of the gut and respiratory tract. Antibodies cause neutralization or lysis of extracellular organisms, such as bacteria, free viruses and parasites, or aid their phagocytosis and destruction by neutrophils and macrophages.
T cells are responsible for cell-mediated immunity (CMI). There are two classes of T cells: helper and cytotoxic T cells. Helper T cells activate other lymphocytes, including B cells and cytotoxic T cells, and macrophages, by releasing soluble protein mediators called cytokines (the term lymphokine is also used). Cytotoxic T cells kill targets such as virally infected cells or tumor cells. The two T cell types can be identified by surface markers called CD4 (helper cells) and CD8 (cytotoxic cells). The CD4 molecule is also important as the receptor for the human immunodeficiency virus (HIV), which causes AIDS by infecting helper T cells. Both helper and cytotoxic T cells take part in cell-mediated immunity. This is the means for destroying intracellular organisms, such as viruses within infected cells and bacteria that can survive within macrophages. It involves T cell killing of virus-infected cells or activation of macrophages to increase their bactericidal potential.
Mature T and B lymphocytes are found in secondary, or peripheral, lymphoid organs and tissues--lymph nodes, mucosal lymphoid tissues, spleen--where immune responses are induced; they also circulate in the bloodstream. Mobility is an important aspect of lymphocyte behavior, enabling effector and memory cells to seek out antigenic invading organisms in tissues. Many lymphocytes recirculate between the lymphoid tissues and the blood and back again; from the blood they also enter areas of inflammation and react locally with the antigens of infecting microbes. The presence of lymphocytes in nonlymphoid tissues in elevated numbers is an indication of a local immune response, as in infected lesions and sites of autoimmune reactions.
A third small group of lymphocytes, which are neither T nor B cells, is called natural killer, or NK, cells. They are large lymphocytes with numerous cytoplasmic granules found in the circulation and especially in the spleen. Their origins are uncertain. NK cells kill certain tumor cells and virus-infected cells spontaneously, apparently without specific induction. They also kill cells precoated with a specific antibody.
To activate lymphocytes, antigens must be recognized by specific cell surface receptors. The receptors on B cells are antibodies, while the T cell receptors are similar, but nonidentical, to antibodies. Unlike antibodies, T cell receptors exist only in the membrane-bound form and are not secreted. Another group of cell surface proteins that interact with antigen are the MHC molecules, encoded by MHC genes. MHC proteins bind peptides, derived from protein antigens, in a specialized binding "groove." MHC proteins come in two types, called class I and class II molecules. Whereas B cells recognize intact antigens in any physical state, T cells only recognize antigens on the surfaces of other cells in the form of peptides bound to MHC molecules. Helper T cells recognize peptides on class II MHC molecules, while cytotoxic T cells recognize peptides on class I molecules.
The steps by which protein antigens are degraded into peptides that become bound to MHC molecules for T cell recognition are called antigen processing and presentation. During the induction phase of immune responses, specialized antigen- presenting cells ingest and partially digest foreign proteins, expressing peptide fragments of the antigen on their surface in the grooves of MHC class II molecules. The peptide/MHC complexes are then recognized by the receptors of helper T cells. In a similar fashion, cytotoxic T cells recognize peptide fragments of viruses presented in association with class I MHC molecules on the surface of virally infected cells.
Antibodies are the molecules in the plasma responsible for recognizing and binding to foreign antigens. Antibodies are members of a related group of proteins known as immunoglobulins (Ig). Five classes of immunoglobulins exist, based on structural differences, and are called IgG, IgM, IgA, IgD, and IgE. Each has different biological and functional properties. Considerable use in medicine and research is made of monoclonal antibodies. These are pure, homogeneous antibodies made by hybrid cells created by the fusion of B cells and tumor cells in culture. Monoclonal antibodies can be used as diagnostics and therapeutics, as in the neutralization of toxins in the circulation and targeting of drugs or radioisotopes onto cancer cells.
Antibodies
Antibodies combat infection in several ways. Organisms and their toxins can be neutralized by antibodies that prevent them from binding to cells. Antibodies assist phagocytic scavenger cells (macrophages, neutrophils) in taking up bacteria and cause lysis of organisms or infected cells by acting together with the complement proteins in the blood or NK cells.
IgG, the most abundant immunoglobulin, occurs primarily in serum, as well as throughout the internal body fluids. Produced in response to bacteria, viruses, and fungi that have gained access to the body, IgG is a major line of defense against such organisms. In humans it is the only immunoglobulin that can cross the placenta and thus is important in the defense of newborns against bacterial and viral infections. IgM, the largest immunoglobulin, is made of five sets of IgG-like units joined together. It is the earliest antibody class to be made in the primary response. IgM is a powerful activator of complement, a set of plasma protein molecules that, when activated in proper sequence, can produce holes in cell membranes resulting in death of the cell. IgM and complement are efficient in destroying gram-negative BACTERIA or protozoal parasites that have gained access to the blood. Complement also causes inflammatory reactions when activated.
IgA acts as a barrier against pathogenic organisms in the intestinal, respiratory, and urogenital tracts. Antibody- forming B cells located in these areas produce dimeric IgA molecules, which are transported across the epithelial lining and secreted onto the mucosal surfaces. Secretory IgA prevents bacteria and viruses from binding to the epithelium and causing local disease or gaining access to the rest of the body. IgA is the most plentiful antibody class in the body as a whole.
IgE triggers fast allergic reactions such as hay fever and asthma. It binds to the surface of mast cells that occur near blood vessels. These cells contain granules of stored histamine and other inflammatory mediators, which are immediately released when particles such as pollen, cat or dog dander, or house dust mite proteins bind to the surface-bound IgE molecules. The histamine and other mediators released by the mast cells cause the symptoms of allergic reactions. IgD operates with IgM as an antigen receptor on the surface of B cells. Very little IgD is secreted.
An input from helper T cells is generally required for B cells to develop into antibody-producing plasma cells. The helper T cells produce soluble proteins, or cytokines, called interleukins 4, 5, and 6 (IL-4, IL-5, and IL-6), which cause B cells to divide and differentiate after making contact with antigen. The requirement for helper T cells explains why antibody production is reduced in AIDS, where helper T cells are killed by infection with HIV.
The body has a very complex set of defenses which allow it to defend itself against pathogens. There are two sets of defenses-nonspecific and specific defenses. Nonspecific defenses act the same way against every disease-causing organisms no matter what its nature. This kind of defense includes the skin, nucous membrane, phagocytes, fever, interferon. These defenses act as mechanical and chemical barriers. The skin consists of a layer of dead cells on the surface which prevent pathogens from entering the body. If the skin has a break in it then pathogens can enter the body. Blood clots form a barrier until new skin seals the wound. Sweat, oils, and waxes that are produced by the skin contain chemical substances that are harmful to bacteria. Some bacteria however, are helpful because they cover the skin and inhibit the growth of pathogens. Mucous membranes and tiny hairs trap microorganisms that enter through the nose and mouth. If the pathogens reach body organs they are usually destroyed by other defenses such as gastric juice in the stomach. An inflammatory response is one in which white blood cells engulf foreign substances and the body tempature rises. These white blood cells are called phagocytes. There are two kinds of phagocytes-neutrophils and macrophages. Neutrophils are small white blood cells that engulf only a small number of bacteria. Macrophages on the other hand are large white blood cells that can engulf hundreds of bacteria.. The action of phagocytes is usually accomponied by fever. If the fever id high enough then it can kill pathogens. A fever is not a disease but a symptom that the body is reacting to an infection.
If the fever is to high it means that the fever is to severe and that death can result. Cells respond to an infection by a virus by producing a protien called interferon. This protein inhibits viral reproduction and triggers an enzyme which allows a cell to recognize a virus as a foreign substance. all types of viruses are affected by an interferon. Specific defenses are when one or more components of the immune system attack a specific pathogen. The immune system detects certain chemicals on the surface of the pathogen and targets it for destruction. Anything that causes a specific immune response to be triggered is called a antigen. There are two kinds of specific defenses, one uses cells, and the other uses proteins. Both of the defenses involve lymphocytes, which are special white blood cells. They exist in two forms T and B cells. Their response to an antigen is either primary or secondary. A primary response is a specific defense which envolves both T and B cells. While the T cells attack the antigens directly, the B cells produce chemicals that render the antigens harmless. Both types of lymphocytes form in bone marrow, but B cells differentiate in bone marrow and the T cells travel to the thymus to differentiate. A cell mediated response is a response by T cells. Helper cells, specialized T cells, initiate a cell mediated response. Each T cell recognizes between other lymphocytes and foreign substances.. When T cells recognize an antigen they multiply into many cells. Some of these cells attack the antigen while others called memory cells, stay in the blood. If that same antigen ever shows up again then it is the memory cells job to recognize and destroy it. B cells produce antibodies, Y shaped protiens that bind to and destroy specific antigens. Each B cell produces an antibody that functions only against a specific type of antigen. When B cells bind to invading antigens, they are stimulated to divide. Each cell, called a clone, produces the same antibody as the original B cell and thus they all destroy the same type of pathogen. In the secondary immune response T cells regulate the actions of B cells. A secondary immune response is one in which the same pathogen attacks again. When the pathogen dissapears from the blood, T cells called supressor cells stop the B cells from producing more antibodies. Even though the B cells stop manufactoring antibodies, several clones called memory B cells remain in circulation. The T cells have also form memory T cells. Therefore, when the body is attacked by the same pathogen in the furure, the memory cells quickly multiply and destroy the pathogen before ir does serious damage to the body. The AIDS virus difies this by taking over and not being harmed. When the virud enters the blood stream, its recognized as an antigen. First a phagocyte engulfs the virus but is unharmed. Then a type of T cell, called a T4 cell, attacks the virus but the virus enters the T4 cells unharmed. B cell antibodies also don't harm the AIDS virus. After some time, about 8 to 10 years, the virus starts reproducing and creates many new viruses within the T4 cells. When these viruses are released they infect other T4 cells and eventually destroy the ability of the T4 cells to fight disease. Once the T4 cells are gone the immune system can fight diseases no longer. This makes the body succeptible to many diseases and it is from these diseases and not the AIDS virus that the patiently usually dies from. The only known way to cure AIDS is through prevenion of it.
Paradoxically, a person's immunity system can backfire and develop autoantibodies against his own body tissue. In many diseases of unknown cause, doctors have found many unusual antibodies in the blood serum of patients.
Doctors think the patients become sensitive to something made by their own bodies. Only a slight change in certain proteins in normal body tissue is necessary for them to become antigens. Most diseases marked by the production of autoantibodies cannot be traced to infection or drug allergy. In rheumatoid arthritis, for example, the rheumatoid factor is the presence of autoantibodies in the victim's blood. These autoantibodies may stick to the membranes lining the bone joints and cause a reaction that destroys tissue in the joints. In other disorders associated with reversed immunity, autoantibodies strike red blood cells, tissues surrounding small blood vessels, or other target areas. Ulcerative colitis, a disorder marked by an inflamed portion of the intestine, often with ulcers, is also believed to be an autoimmune disease.
In some cases, lymphocyte defects or discrepancies in antibody production lead to an immune deficiency. The victim is then helpless against recurring infections. A simple head cold can soon become pneumonia. Antibiotics or serums with antibody-rich gamma globulin offer temporary relief in such cases.
