Immunity, Natural and Acquired

As long ago as the 5th century B.C., Greek physicians noted that people who had recovered from the plague would never get it again-they had acquired immunity. This is because, whenever T cells and B cells are activated, some of the cells become "memory" cells. Then, the next time that an individual encounters that same antigen, the immune system is primed to destroy it quickly.

The degree and duration of immunity depend on the kind of antigen, its amount, and how it enters the body. An immune response is also dictated by heredity; some individuals respond strongly to a given antigen, others weakly, and some not at all.

Infants are born with relatively weak immune responses. They have, however, a natural "passive" immunity; they are protected during the first months of life by means of antibodies they receive from their mothers. The antibody IgG, which travels across the placenta, makes them immune to the same microbes to which their mothers are immune. Children who are nursed also receive IgA from breast milk; it protects the digestive tract.

Passive immunity can also be conveyed by antibody-containing serum obtained from individuals who are immune to a specific infectious agent. Immune serum globulin or "gamma globulin" is sometimes given to protect travelers to countries where hepatitis is widespread. Passive immunity typically lasts only a few weeks.

"Active" immunity-mounting an immune response-can be triggered by both infection and vaccination. Vaccines contain microorganisms that have been altered so they will produce an immune response but will not be able to induce full-blown disease. Some vaccines are made from microbes that have been killed. Others use microbes that have been changed slightly so they can no longer produce infection. They may, for instance, be unable to multiply. Some vaccines are made from a live virus that has been weakened, or attenuated, by growing it for many cycles in animals or cell cultures.

Recent research, benefiting from the biotechnology revolution, has focused on developing vaccines that use only part of the infectious agent. Such subunit vaccines , which are now available for meningitis, pneumonia, and hepatitis B, produce the desired immunity without stirring up separate and potentially harmful immune reactions to the many antigens carried, for instance, on a single bacterium.

Vaccines Through Biotechnology

Through genetic engineering, scientists can isolate specific genes and insert them into DNA of certain microbes or mammalian cells; the microbes or cells become living factories, mass producing the desired antigen. Then, using another product of biotechnology, a monoclonal antibody that recognizes the antigen, the scientists can separate the antigen from all the other material produced by the microbe or cell. This technique has been used to produce immunogenic but safe segments of the hepatitis B virus and the malaria parasite.

In another approach, scientists have inserted genes for desired antigens into the DNA of the vaccinia virus, the large cowpox virus familiar for its role in smallpox immunization. When the reengineered vaccinia virus is inoculated, it stimulates an immune reaction to both the vaccinia and the products of its passenger genes. These have included, in animal experiments, genes from the viruses that cause hepatitis B, influenza, rabies, and AIDS.

Instead of adding a gene, some scientists have snipped a key gene out of an infectious organism. Thus crippled, the microbe can produce immunity but not disease. This technique has been tried with a bacterium that causes the severe diarrheal disease cholera; such a vaccine is commercially available against a virus disease of pigs.

A totally different approach to vaccine development lies in chemical synthesis. Once scientists have isolated the gene that encodes an antigen, they are able to determine the precise sequence of amino acids that make up the antigen. They then pinpoint small key areas on the large protein molecule, and assemble it chemical by chemical. Wholly synthetic vaccines are being explored for malaria and for the major diarrheal diseases that are so devastating in developing countries.

Another pioneering vaccine strategy exploits antiidiotype antibodies (see A Web of Idiotypes). The original antibody (or idiotype) provokes an antiantibody (or antiidiotype) that resembles the original antigen on the disease-causing organism. The antiidiotype will not itself cause disease, but it can serve as a mock antigen, inducing the formation of antibodies that recognize and block the original antigen. To make such a vaccine, scientists inject animals with a monoclonal antibody (idiotype) against a disease-causing microorganism, then harvest the antiidiotypes produced in response.

Disorders of the Immune System: Allergy

The most common types of allergic reactions-hay fever, some kinds of asthma, and hives-are produced when the immune system response to a false alarm. In a susceptible person, a normally harmless substance-grass pollen or house dust, for example-is perceived as a threat and is attacked.

Such allergic reactions are related to the antibody known as immunoglobulin E. Like other antibodies, each IgE antibody is specific; one reacts against oak pollen, another against ragweed. The role of IgE in the natural order is not known, although some scientists suspect that it developed as a defense against infection by parasitic worms.

The first time an allergy-prone person is exposed to an allergen, he or she makes large amounts of the corresponding IgE antibody. These IgE molecules attach to the surfaces of mast cells (in tissue) or basophils (in the circulation). Mast cells are plentiful in the lungs, skin, tongue, and linings of the nose and intestinal tract.

When an IgE antibody siting on a mast cell or basophil encounters its specific allergen, the IgE antibody signals the mast cell or basophil to release the powerful chemicals stored within its granules. These chemicals include histamine, heparin, and substances that activate blood platelets and attract secondary cells such as eosinophils and neutrophils. The activated mast cell or basophil also synthesizes new mediators, including prostaglandins and leukotrienes, on the spot.

It is such chemical mediators that cause the symptoms of allergy, including wheezing, sneezing, runny eyes and itching. They can also produce anaphylactic shock, a life-threatening allergic reaction characterized by swelling of body tissues, including the throat, and a sudden fall in blood pressure.
 

Autoimmune Diseases

Sometimes the immune system's recognition apparatus breaks down, and the body begins to manufacture antibodies and T cells directed against the body's own constituents-cells, cell components, or specific organs. Such antibodies are known as autoantibodies, and the diseases they produce are called autoimmune diseases. (Not all autoantibodies are harmful; some types appear to be integral to the immune system's regulatory scheme.)

Autoimmune reactions contribute to many enigmatic diseases. For instance, autoantibodies to red blood cells can cause anemia, autoantibodies to pancreas cells contribute to juvenile diabetes, and autoantibodies to nerve and muscle cells are found in patients with the chronic muscle weakness known as myasthenia gravis. Autoantibody known as rheumatoid factor is common in persons with rheumatoid arthritis.

Persons with systemic lupus erythematosus (SLE), whose symptoms encompass many systems, have antibodies to many types of cells and cellular components. These include antibodies directed against substances found in the cell's nucleus-DNA, RNA, or proteins-which are known as antinuclear antibodies, or ANAs. These antibodies can cause serious damage when they link up with self antigens to form circulating immune complexes, which become lodged in body tissue and set off inflammatory reactions (Immune Complex Diseases).

Autoimmune diseases affect the immune system at several levels. In patients with SLE, for instance, B cells are hyperactive while suppressor cells are underactive; it is not clear which defect comes first. Moreover, production of IL-2 is low, while levels of gamma interferon are high. Patients with rheumatoid arthritis, who have a defective suppressor T cell system, continue to make antibodies to a common virus, whereas the response normally shuts down after about a dozen days.

No one knows just what causes an autoimmune disease, but several factors are likely to be involved. These may include viruses and environmental factors such as exposure to sunlight, certain chemicals, and some drugs, all of which may damage or alter body cells so that they are no longer recognizable as self. Sex hormones may be important, too, since most autoimmune diseases are far more common in women than in men.

Heredity also appears to play a role. Autoimmune reactions, like many other immune responses, are influenced by the genes of the MHC. A high proportion of human patients with autoimmune disease have particular histocompatibility types. For example, many persons with rheumatoid arthritis display the self marker known as HLA-DR4.

Many types of therapies are being used to combat autoimmune diseases. These include corticosteroids, immunosuppressive drugs developed as anticancer agents, radiation of the lymph nodes, and plasmapheresis, a sort of "blood washing" that removes diseased cells and harmful molecules from the circulation.

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