The Immune System

The immune system is a bodywide network of cells and organs that has evolved to defend the body against attacks by "foreign" invaders.

The proper targets of the immune defenses are infectious organisms -- bacteria such as these streptococci;

Fungi (this one happens to be the mold from which penicillin is made);

Parasites, including these worm-like microbes that cause schistosomiasis; and

Viruses such as this herpes virus.

Markers of Self

At the heart of the immune response is the ability to distinguish between self and nonself.

Every body cell carries distinctive molecules that distinguish it as "self." Normally the body's defenses do not attack tissues that carry a self marker; rather, immune cells coexist peaceably with other body cells in a state known as self-tolerance.

Markers of Non-Self

Foreign molecules, too, carry distinctive markers, characteristic shapes called epitopes that protrude from their surfaces.

One of the remarkable things about the immune system is its ability to recognize many millions of distinctive non-self molecules, and to respond by producing molecules such as these antibodies -- and also cells -- that can match and counteract each one of the non-self molecules.

Any substance capable of triggering an immune response is known as an antigen. An antigen can be a bacterium or a virus, or even a portion or product of one of these organisms. Tissues or cells from another individual also act as antigens; that's why transplanted tissues are rejected as foreign.

Organs of the Immune System

The organs of the immune system are stationed throughout the body.

They are known as lymphoid organs because they are concerned with the growth, development, and deployment of lymphocytes -- white blood cells that are key operatives of the immune system.

Lymphatic System

The organs of the immune system are connected with one another and with other organs of the body by a network of lymphatic vessels similar to blood vessels.

Immune cells and foreign particles are conveyed through the lymphatics in lymph, a clear fluid that bathes the body's tissues.

Lymph Node

Lymph nodes are small, bean-shaped structures that are laced throughout the body along the lymphatic routes.

Lymph nodes contain specialized compartments where immune cells congregate, and where they can encounter antigens.

Cells of the Immune System

Cells destined to become immune cells, like all blood cells, arise in the bone marrow from so-called stem cells.

Some develop into myeloid cells, a group typified by the large, cell- and particle-devouring white blood cells known as phagocytes; phagocytes include monocytes, macrophages, and neutrophils. Other myeloid descendants become granule-containing inflammatory cells such as eosinophils and basophils. Lymphoid precursors develop into the small white blood cells called lymphocytes. The two major classes of lymphocytes are B cells and T cells.

B Cells

B cells work chiefly by secreting soluble substances known as antibodies.

Each B cell is programmed to make one specific antibody. When a B cell encounters its triggering antigen (along with various accessory cells), it gives rise to many large plasma cells. Each plasma cell is essentially a factory for producing that one specific antibody.

Antibody

Each antibody is made up of two identical heavy chains and two identical light chains, shaped to form a Y.

The sections that make up the tips of the Y's arms vary greatly from one antibody to another; this is called the variable region. It is these unique contours in the antigen-binding site that allow the antibody to recognize a matching antigen, much as a lock matches a key.

The stem of the Y links the antibody to other participants in the immune defenses. This area is identical in all antibodies of the same class -- for instance, all IgEs -- and it's called the constant region.

IgG, IgD, and IgE

Antibodies belong to a family of large protein molecules known as immunoglobulins.

Scientists have identified nine chemically distinct classes of human immunoglobulins, four kinds of IgG and two kinds of IgA, plus IgM, IgE, and IgD.

Immunoglobulins G, D, and E are similar in appearance. IgG, the major immunoglobulin in the blood, is also able to enter tissue spaces; it works efficiently to coat microorganisms, speeding their uptake by other cells in the immune system. IgD is almost exclusively found inserted into the membrane of B cells, where it somehow regulates the cell's activation. IgE is normally present in only trace amounts, but it is responsible for the symptoms of allergy.

IgA and IgM

IgA -- a doublet -- concentrates in body fluids such as tears, saliva, and the secretions of the respiratory and gastrointestinal tracts.

It is, thus, in a position to guard the entrances to the body.

IgM usually combines in star-shaped clusters. It tends to remain in the bloodstream, where it is very effective in killing bacteria.

Antibody Genes

Scientists long wondered how all the genetic information needed to make millions of different antibodies could fit in a limited number of genes.

The answer is that antibody genes are pieced together from widely scattered bits of DNA, and the possible combinations are nearly endless. As this gene forms, it assembles segments that will determine the variable-V, diversity-D, joining-J, and constant-C segments of this antibody molecule, a typical IgM heavy chain.

T Cells

T cells contribute to the immune defenses in two major ways. Some help regulate the complex workings of the immune system, while others are cytotoxic and directly contact infected cells and destroy them.

Chief among the regulatory T cells are "helper/inducer" T cells. They are needed to activate many immune cells, including B cells and other T cells. Another subset of regulatory T cells acts to turn off or suppress immune cells.

Cytotoxic T cells help rid the body of cells that have been infected by viruses as well as cells that have been transformed by cancer. They are also responsible for the rejection of tissue and organ grafts.

Cytokines

Cytokines are diverse and potent chemical messengers secreted by the cells of the immune system -- and the chief tool of T cells.

Lymphocytes, including both T cells and B cells, secrete lymphokines, while monocytes and macrophages secrete monokines.

Binding to specific receptors on target cells, cytokines recruit many other cells and substances to the field of action. Cytokines encourage cell growth, promote cell activation, direct cellular traffic, and destroy target cells -- including cancer cells. Because they serve as a messenger between white cells, or leukocytes, many cytokines are also known as interleukins.

Natural Killer Cells

At least two types of lymphocytes are killer cells -- cytotoxic T cells and natural killer cells.

To attack, cytotoxic T cells need to recognize a specific antigen, whereas natural killer or NK cells do not. Both types contain granules filled with potent chemicals, and both types kill on contact. The killer binds to its target, aims its weapons, and delivers a burst of lethal chemicals.

Phagocytes and Granulocytes

Phagocytes are large white cells that can engulf and digest foreign invaders.

They include monocytes, which circulate in the blood, and macrophages, which are found in tissues throughout the body, as well as neutrophils, cells that circulate in the blood but move into tissues where they are needed. Macrophages are versatile cells; they act as scavengers, they secrete a wide variety of powerful chemicals, and they play an essential role in activating T cells.

Neutrophils are not only phagocytes but also granulocytes: they contain granules filled with potent chemicals. These chemicals, in addition to destroying microorganisms, play a key role in acute inflammatory reactions. Other types of granulocytes are eosinophils and basophils. Mast cells are granule-containing cells in tissue.

Phagocytes in the Body

Specialized phagocytes are found in organs throughout the body.

Complement

The complement system consists of a series of proteins that work to "complement" the work of antibodies in destroying bacteria.

Complement proteins circulate in the blood in an inactive form. The so-called "complement cascade" is set off when the first complement molecule, C1, encounters antibody bound to antigen in an antigen-antibody complex. Each of the complement proteins performs its specialized job in turn, acting on the molecule next in line. The end product is a cylinder that punctures the cell membrane and, by allowing fluids and molecules to flow in and out, dooms the target cell.

Mounting an Immune Response

Microbes attempting to get into the body must first get past the skin and mucous membranes, which not only pose a physical barrier but are rich in scavenger cells and IgA antibodies.

Next, they must elude a series of nonspecific defenses -- cells and substances that attack all invaders regardless of the epitopes they carry. These include patrolling scavenger cells, complement, and various other enzymes and chemicals.

Infectious agents that get past the nonspecific barriers must confront specific weapons tailored just for them. These include both antibodies and cells. Almost all antigens trigger both nonspecific and specific responses.

Antigen Receptors

Both B cells and T cells carry customized receptor molecules that allow them to recognize and respond to their specific targets.

The B cell's antigen-specific receptor is a sample of the antibody it is prepared to manufacture; it recognizes antigen in its natural state.

The T cell receptor system is more complex. A T cell can recognize an antigen only after the antigen is processed and presented to it by a so-called antigen-presenting cell, in combination with a special type of cell marker.

The T4 T cell's receptor looks for an antigen that has been broken down by an immune system cell such as a macrophage or a B cell and combined with a marker, known as a class II protein, carried by immune cells. The T8 T cell's receptor recognizes an antigen fragment produced within the cell, combined with a class I protein; class I proteins are found on virtually all body cells.

This complicated arrangement assures that T cells act only on precise targets and at close range.

Activation of B Cells to Make Antibody

The B cell uses its receptor to bind a matching antigen, which it proceeds to engulf and process.

Then it combines a fragment of antigen with its special marker, the class II protein. This combination of antigen and marker is recognized and bound by a T cell carrying a matching receptor. The binding activates the T cell, which then releases lymphokines -- interleukins -- that transform the B cell into an antibody-secreting plasma cell.

Activation of T Cells: Helper and Cytotoxic

After an antigen-presenting cell such as a macrophage has ingested and processed an antigen, it presents the antigen fragment, along with a class II marker protein, to a matching helper T cell with a T4 receptor.

The binding prompts the macrophage to release interleukins that allow the T cell to mature.

A cytotoxic T cell recognizes antigens such as virus proteins,which are produced within a cell, in combination with a class I self-marker protein. With the cooperation of a helper T cell, the cytotoxic T cell matures. Then, when the mature cytotoxic T cell encounters its specific target antigen combined with a class I marker protein -- for instance, on a body cell that has been infected with a virus -- it is ready to attack and kill the target cell.

Immunity: Short- and Long-Term Cell Memory

Whenever T cells and B cells are activated, some become "memory" cells.

The next time that an individual encounters that same antigen, the immune system is primed to destroy it quickly. Long-term immunity can be stimulated not only by infection but also by vaccines made from infectious agents that have been inactivated or, more commonly, from minute portions of the microbe.

Short-term immunity can be transferred passively from one individual to another via antibody-containing serum; similarly, infants are protected by antibodies they receive from their mothers (primarily before birth).

Disorders of the Immune System: Allergy

When the immune system malfunctions, it can unleash a torrent of disorders and diseases.

One of the most familiar is allergy. Allergies such as hay fever and hives are related to the antibody known as IgE. The first time an allergy-prone person is exposed to an allergen -- for instance, grass pollen -- the individual's B cells make large amounts of grass pollen IgE antibody. These IgE molecules attach to granule-containing cells known as mast cells, which are plentiful in the lungs, skin, tongue, and linings of the nose and gastrointestinal tract. The next time that person encounters grass pollen, the IgE-primed mast cell releases powerful chemicals that cause the wheezing, sneezing, and other symptoms of allergy.

Disorders of the Immune System: Autoimmune Disease

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 cells and organs.

Such cells and autoantibodies, as they are known, contribute to many diseases. For instance, T cells that attack pancreas cells contribute to diabetes, while an autoantibody known as rheumatoid factor is common in persons with rheumatoid arthritis.

Disorders of the Immune System: Immune Complex Disease

Immune complexes are clusters of interlocking antigens and antibodies.

Normally they are rapidly removed from the bloodstream. In some circumstances, however, they continue to circulate, and eventually they become trapped in and damage the tissues of the kidneys, as seen here, or in the lungs, skin, joints, or blood vessels.

Disorders of the Immune System: AIDS

When the immune system is lacking one or more of its components, the result is an immunodeficiency disorder.

These can be inherited, acquired through infection, or produced as an inadvertent side effect of drugs such as those used to treat cancer or transplant patients.

AIDS is an immunodeficiency disorder caused by a virus that destroys helper T cells and that is harbored in macrophages as well as helper (T4) T cells. The AIDS virus splices its DNA into the DNA of the cell it infects; the cell is thereafter directed to churn out new viruses.

Human Tissue Typing for Organ Transplants

For an organ transplant to "take," it is necessary to minimize the body's drive to rid itself of foreign tissue.

One way is to make sure that the markers of self on the donor's tissue are as similar as possible to those of the recipient. Because tissue typing is usually done on white blood cells, or leukocytes, the markers are referred to as human leukocyte antigens, or HLA. Each cell has a double set of six major antigens, HLA-A, B, and C, and three types of HLA-D. Since each of the antigens exists, in different individuals, in as many as 20 varieties, the number of possible HLA types is about 10,000. The genes that encode the HLA antigens, located on chromosome 6, are the subject of intense research.

"Privileged" Immunity

A child in the womb carries foreign antigens from the father as well as immunologically compatible self antigens from the mother.

One might expect this condition to trigger a graft rejection, but it does not because the uterus is an "immunologically privileged" site where immune responses are subdued.

Immunity and Cancer

When normal cells turn into cancer cells, some of the antigens on their surface change.

These new or altered antigens flag immune defenders, including cytotoxic T cells, natural killer cells, and macrophages. According to one theory, patrolling cells of the immune system provide continuing bodywide surveillance, spying out and eliminating cells that undergo malignant transformation. Tumors develop when the surveillance system breaks down or is overwhelmed.

Immunotherapy

A new approach to cancer therapy uses antibodies that have been specially made to recognize specific cancer.

When coupled with natural toxins, drugs, or radioactive substances, the antibodies seek out their target cancer cells and deliver their lethal load. Alternatively, toxins can be linked to a lymphokine and routed to cells equipped with receptors for the lymphokine.

The Immune System and the Nervous System

Biological links between the immune system and the central nervous system exist at several levels.

Hormones and other chemicals such as neuropeptides, which convey messages among nerve cells, have been found also to "speak" to cells of the immune system -- and some immune cells even manufacture typical neuropeptides. In addition, networks of nerve fibers have been found to connect directly to the lymphoid organs.

The picture that is emerging is of closely interlocked systems facilitating a two-way flow of information. Immune cells, it has been suggested, may function in a sensory capacity, detecting the arrival of foreign invaders and relaying chemical signals to alert the brain. The brain, for its part, may send signals that guide the traffic of cells through the lymphoid organs.

Hybridoma Technology

Thanks to a technique known as hybridoma technology, scientists are now able to make quantities of specific antibodies.

A hybridoma can be produced by injecting a specific antigen into a mouse, collecting antibody-producing cells from the mouse's spleen, and fusing them with long-lived cancerous immune cells. Individual hybridoma cells are cloned and tested to find those that produce the desired antibody. Their many identical daughter clones will secrete, over a long period of time, the made-to-order "monoclonal" antibody.

Genetic Engineering

Genetic engineering allows scientists to pluck genes -- segments of DNA -- from one type of organism and combine them with genes of a second organism.

In this way relatively simple organisms such as bacteria or yeast can be induced to make quantities of human proteins, including interferons and interleukins. They can also manufacture proteins from infectious agents such as the hepatitis virus or the AIDS virus, for use in vaccines.

The SCID-hu Mouse

The SCID mouse, which lacks a functioning immune system of its own, is helpless to fight infection or reject transplanted tissue.

By transplanting immature human immune tissues and/or immune cells into these mice, scientists have created an in vivo model that promises to be of immense value in advancing our understanding of the immune system.