Immunology

Immunology is the study of how the body responds to foreign substances and fights off infection and other disease. Immunologists study the molecules, cells, and organs of the human body that participate in this response.

The beginnings of our understanding of immunity date to 1798, when the English physician Edward Jenner (1749–1823) published a report that people could be protected from deadly smallpox by sticking them with a needle dipped in the material from a cowpox boil. The French biologist and chemist Louis Pasteur (1822–1895) theorized that such immunization protects people against disease by exposing them to a version of a microbe that is harmless but is enough like the disease-causing organism, or pathogen, that the immune system learns to fight it. Modern vaccines against diseases such as measles , polio, and chicken pox are based on this principle.

In the late nineteenth century, a scientific debate was waged between the German physician Paul Ehrlich (1854–1915) and the Russian zoologist Élie Metchnikoff (1845–1916). Ehrlich and his followers believed that proteins in the blood, called antibodies, eliminated pathogens by sticking to them; this phenomenon became known as humoral immunity. Metchnikoff and his students, on the other hand, noted that certain white blood cells could engulf and digest foreign materials: this cellular immunity, they claimed, was the real way the body fought infection.

Modern immunologists have shown that both the humoral and cellular responses play a role in fighting disease. They have also identified many of the actors and processes that form the immune response.

The immune response recognizes and responds to pathogens via a network of cells that communicate with each other about what they have "seen" and whether it "belongs." These cells patrol throughout the body for infection, carried by both the blood stream and the lymph ducts, a series of vessels carrying a clear fluid rich in immune cells.

The antigen presenting cells are the first line of the body's defense, the scouts of the immune army. They engulf foreign material or microorganisms and digest them, displaying bits and pieces of the invaders—called antigens—for other immune cells to identify. These other immune cells, called T lymphocytes, can then begin the immune response that attacks the pathogen.

The body's other cells can also present antigens, although in a slightly different way. Cells always display antigens from their everyday proteins on their surface. When a cell is infected with a virus, or when it becomes cancerous, it will often make unusual proteins whose antigens can then be identified by any of a variety of cytotoxic T lymphocytes. These "killer cells" then destroy the infected or cancerous cell to protect the rest of the body. Other T lymphocytes generate chemical or other signals that encourage multiplication of other infection-fighting cells. Various types of T lymphocytes are a central part of the cellular immune response; they are also involved in the humoral response, encouraging B lymphocytes to turn into antibody-producing plasma cells.

The body cannot know in advance what a pathogen will look like and how to fight it, so it creates millions and millions of different lymphocytes that recognize random antigens. When, by chance, a B or T lymphocyte recognizes an antigen being displayed by an antigen presenting cell, the lymphocyte divides and produces many offspring that can also identify and attack this antigen. The way the immune system expands cells that by chance can attack an invading microbe is called clonal selection .

Some researchers believe that while some B and T lymphocytes recognize a pathogen and begin to mature and fight an infection, others stick around in the bloodstream for months or even years in a primed condition. Such memory cells may be the basis for the immunity noted by the ancient Chinese and by Thucydides. Other immunologists believe instead that trace amounts of a pathogen persist in the body, and their continued presence keeps the immune response strong over time.

Substances foreign to the body, such as disease-causing bacteria , viruses , and other infectious agents (known as antigens), are recognized by the body's immune system as invaders. The body's natural defenses against these infectious agents are antibodies—proteins that seek out the antigens and help destroy them. Antibodies have two very useful characteristics. First, they are extremely specific; that is, each antibody binds to and attacks one particular antigen. Second, some antibodies, once activated by the occurrence of a disease, continue to confer resistance against that disease; classic examples are the antibodies to the childhood diseases chickenpox and measles.

The second characteristic of antibodies makes it possible to develop vaccines. A vaccine is a preparation of killed or weakened bacteria or viruses that, when introduced into the body, stimulates the production of antibodies against the antigens it contains.

It is the first trait of antibodies, their specificity, that makes monoclonal antibody technology so valuable. Not only can antibodies be used therapeutically, to protect against disease; they can also help to diagnose a wide variety of illnesses, and can detect the presence of drugs, viral and bacterial products, and other unusual or abnormal substances in the blood.

Given such a diversity of uses for these disease-fighting substances, their production in pure quantities has long been the focus of scientific investigation. The conventional method was to inject a laboratory animal with an antigen and then, after antibodies had been formed, collect those antibodies from the blood serum (antibody-containing blood serum is called antiserum ). There are two problems with this method: It yields antiserum that contains undesired substances, and it provides a very small amount of usable antibody.

Monoclonal antibody technology allows the production of large amounts of pure antibodies in the following way. Cells that produce antibodies naturally are obtained along with a class of cells that can grow continually in cell culture . The hybrid resulting from combining cells with the characteristic of "immortality" and those with the ability to produce the desired substance, creates, in effect, a factory to produce antibodies that work around the clock.

A myeloma is a tumor of the bone marrow that can be adapted to grow permanently in cell culture. Fusing myeloma cells with antibody-producing mammalian spleen cells, results in hybrid cells, or hybridomas, producing large amounts of monoclonal antibodies. This product of cell fusion combined the desired qualities of the two different types of cells, the ability to grow continually, and the ability to produce large amounts of pure antibody. Because selected hybrid cells produce only one specific antibody, they are more pure than the polyclonal antibodies produced by conventional techniques. They are potentially more effective than conventional drugs in fighting disease, because drugs attack not only the foreign substance but also the body's own cells as well, sometimes producing undesirable side effects such as nausea and allergic reactions. Monoclonal antibodies attack the target molecule and only the target molecule, with no or greatly diminished side effects.

While researchers have made great gains in understanding immunity, many big questions remain. Future research will need to identify how the immune response is coordinated. Other researchers are studying the immune systems of nonmammals, trying to learn how our immune response evolved. Insects, for instance, lack antibodies, and are protected only by cellular immunity and chemical defenses not known to be present in higher organisms.

Immunologists do not yet know the details behind allergy, where antigens like those from pollen, poison ivy, or certain kinds of food make the body start an uncomfortable, unnecessary, and occasionally life-threatening immune response. Likewise, no one knows exactly why the immune system can suddenly attack the body's tissues—as in autoimmune diseases like rheumatoid arthritis, juvenile diabetes, systemic lupus erythematosus, or multiple sclerosis.

The hunt continues for new vaccines, especially against parasitic organisms like the malaria microbe that trick the immune system by changing their antigens. Some researchers are seeking ways to start an immune response that prevents or kills cancers. A big goal of immunologists is the search for a vaccine for HIV , the virus that causes AIDS . HIV knocks out the immune system—causing immunodeficiency—by infecting crucial T lymphocytes. Some immunologists have suggested that the chiefly humoral response raised by conventional vaccines may be unable to stop HIV from getting to lymphocytes, and that a new kind of vaccine that encourages a cellular response may be more effective.

Researchers have shown that transplant rejection is just another kind of immune response, with the immune system attacking antigens in the transplanted organ that are different from its own. Drugs that suppress the immune system are now used to prevent rejection, but they also make the patient vulnerable to infection. Immunologists are using their increased understanding of the immune system to develop more subtle ways of deceiving the immune system into accepting transplants.

See also AIDS, recent advances in research and treatment; Antibody, monoclonal; Biochemical analysis techniques; BSE, scrapie and CJD: recent advances in research; History of immunology; Immunochemistry; Immunodeficiency disease syndromes; Immunodeficiency diseases; Immunodeficiency; Immunogenetics; Immunological analysis techniques; Immunology, nutritional aspects; Immunosuppressant drugs; Infection and resistance; Laboratory techniques in immunology; Reproductive immunology; Transplantation genetics and immunology

Immunochemistry

Immunochemistry is the study of the chemistry of immune responses.

An immune response is a reaction caused by the invasion of the body by an antigen . An antigen is a foreign substance that enters the body and stimulates various defensive responses. The cells mainly involved in this response are macrophages and T and B lymphocytes . A macrophage is a large, modified white blood cell. Before an antigen can stimulate an immune response, it must first interact with a macrophage. The macrophage engulfs the antigen and transports it to the surface of the lymphocytes. The macrophage (or neutrophil) is attracted to the antigen by chemicals that the antigen releases. The macrophage recognizes these chemicals as alien to the host body. The local cells around the infection will also release chemicals to attract the macrophages; this is a process known as chemotaxis. These chemicals are a response to the infection. This process of engulfing the foreign body is called phagocytosis , and it leads directly to painful swelling and inflammation of the infected area.

Lymphocytes are also cells that have been derived from white blood cells (leucocytes). Lymphocytes are found in lymph nodes, the spleen, the thymus, bone marrow, and circulating in the blood plasma. Those lymphocytes that mature inside mammalian bone marrow are called B cells . Once B cells have come into contact with an antigen, they proliferate and differentiate into antibody secreting cells. An antibody is any protein that is released in the body in direct response to infection by an antigen. Those lymphocytes that are formed inside the thymus are called T lymphocytes or T cells . After contact with an antigen, T cells secrete lymphokines—a group of proteins that do not interact with the antigens themselves, instead they stimulate the activity of other cells. Lymphokines are able to gather uncommitted T cells to the site of infection. They are also responsible for keeping T cells and macrophages at the site of infection. Lymphokines also amplify the number of activated T cells, stimulate the production of more lymphokines, and kill infected cells. There are several types of T cells. These other types include T helper cells that help B cells mature into antibody-secreting cells, T suppresser cells that halt the action of B and T cells, T cytotoxic cells that attack infected or abnormal cells, and T delayed hypersensitivity cells that react to any problems caused by the initial infection once it has disappeared. This latter group of cells are long lived and will rapidly attack any remaining antigens that have not been destroyed in the major first stages of infection.

Once the antibodies are released by the B and T cells, they interact with the antigen to attempt to neutralize it. Some antibodies act by causing the antigens to stick together; this is a process known as agglutination. Antibodies may also cause the antigens to fall apart, a process known as cell lysis. Lysis is caused by enzymes known as lytic enzymes that are secreted by the antibodies. Once an antigen has been lysed, the remains of the antigen are removed by phagocytosis. Some antigens are still able to elicit a response even if only a small part of the antigen remains intact. Sometimes the same antibody will cause agglutination and then lysis. Some antibodies are antitoxins, which directly neutralize any toxins secreted by the antigens. There are several different forms of antibody that carry out this process depending upon the type of toxin that is produced.

Once antibodies have been produced for a particular antigen they tend to remain in the body. This provides immunity . Sometimes immunity is long term and once exposed to a disease we will never catch the disease again. At other times, immunity may only be short lived. The process of active immunity is when the body produces its own antibodies to confer immunity. Active immunity occurs after an initial exposure to the antigen. Passive immunity is where antibodies are passed form mother to child through the placenta. This form of immunity is short lived. Artificial immunity can be conferred by the action of immunization . With immunization, a vaccine is injected into the body. The vaccine may be a small quantity of antigen, it may be a related antigen that causes a less serious form of the disease, it may be a fragment of the antigen, or it may be the whole antigen after it has been inactivated. If a fragment of antigen is used as a vaccine, it must be sufficient to elicit an appropriate response from the body. Quite often viral coat proteins are used for this. The first vaccine was developed by Edward Jenner (1749–1823) in 1796 to inoculate against smallpox . Jenner used the mild disease cowpox to confer immunity for the potentially fatal but biochemically similar smallpox.

Within the blood there are a group of blood serum proteins called complement . These proteins become activated by antigen antibody reactions. Immunoglobulin is an antibody secreted by lymphoid cells called plasma cells. Immunoglobulins are made of two long polypeptide chains and two short polypeptide chains. These chains are bound together in a Y-shaped arrangement, with the short chains forming the inner parts of the Y. Each arm of the Y has specific antigen binding properties. There are five different classes of immunoglobulin that are based on their antigen-binding properties. Different classes of immunoglobulins come into play at different stages of infection. Immunoglobulins have specific binding sites with antigens.

One class of compounds in animals has antigens that can be problematical. This is the group called the histocompatibility complex. This is the group of usually surface proteins that are responsible for rejections and incompatibilities in organ transplants. These antigens are genetically encoded and they are present on the surface of cells. If the cells or tissues are transferred from one organism to another or the body does not recognize the antigens, it will elicit a response to try to rid the body of the foreign tissue. A body is not interested where foreign proteins come from. It is interested in the fact that they are there when they should not be. Even if an organ is human in origin, it must be genetically similar to the host body or it will be rejected. Because an organ is much larger than a small infection of an antigen when it elicits an immune response, it can be a greater problem. With an organ transplant, there can be a massive cascade reaction of antibody production. This will include all of the immune responses of which the body is capable. Such a massive response can overload the system and it can cause death. Thus, tissue matching in organ transplants is vitally important. Often, a large range of immunosuppressor drugs are employed until the body integrates a particular organ. In some cases, this may necessitate a course of drugs for the rest of the individuals life. Histocompatibility problems also exist with blood. Fortunately, the proteins in blood are less specific and blood transfusions are a lot easier to perform than organ transplants. The blood-typing systems that are in use are indications of the proteins that are present. If blood is mixed from the wrong types, it can cause lethal clotting. The main blood types are A, B, O, and AB. Group O individuals are universal donors, they can give blood to anyone. Group AB are universal recipients because they can accept blood from anyone. Type A blood has A antigens on the blood cells and B antibodies in the plasma. The combination of B antibodies and B antigens will cause agglutination. There are also subsidiary blood proteins such as the rhesus factor (rh) that can be positive (present) or negative (absent). If only small amounts of blood are transfused, it is not a problem due to the dilution factor.

Immunochemistry is the chemistry of the immune system . Most of the chemicals involved in immune responses are proteins. Some chemicals inactivate invading proteins, others facilitate this response. The histocompatibility complex is a series of surface proteins on organs and tissues that elicit an immune response when placed in a genetically different individual.

See also Biochemistry; History of immunology; Immune stimulation, as a vaccine; Immunity, active, passive and delayed; Immunity, cell mediated; Immunity, humoral regulation; Immunization; Immunological analysis techniques; Laboratory techniques in immunology; Major histocompatibility complex (MHC)