A Web of Idiotypes

The unique and characteristic pocket on an antibody that recognizes a specific antigen-its variable region-can itself act as an antigen. More precisely, the variable region contains a number of antigen-like segments, and these are known collectively as an idiotype. Like any other antigen, an idiotype can trigger complementary antibody. This second-round antibody is known as an antiidiotype. An antiidiotype, in turn, can trigger an antiantiidiotype. Like a series of mirrored reflections, the process can go on and on.

Interactions between idiotypes and antiidiotypes, it has been proposed, constitute a mechanism whereby the immune system regulates itself. According to the "network theory," not only antibodies but B cells and T cells carry-in their unique antigen-receptors-idiotypes. The B cells and T cells that proliferate in response to a certain antigen carry a complementary idiotype. Antiidiotype B cells secrete antiidiotype antibodies, which may neutralize the original idiotypes (antibodies), or bind to idiotypes on regulatory T cells. Alternatively, antiidiotypes may trigger antiantiidiotypes, creating a spiraling response within the network-turning on, amplifying, and shutting down immune responses.

The concept of the idiotype is being put to practical use today in the development of experimental antigen-free vaccines (Vaccines Through Biotechnology).

Microbes that breach the nonspecific barriers are confronted by specific weapons tailored to fit each one. These may be cellular responses directed both by cells, primarily T lymphocytes and their secretions (lymphokines), and against cells that have been infected. Or they may be humoral responses, the work of antibodies secreted by B lymphocytes into the body's fluids or humors.

Most antigens are recognized by a limited number of specific immune cells ( and their offspring). A few antigens, however, are capable of rousing large classes of T cells, setting off an immune response so massive that it is harmful. Dubbed "superantigens," these substances include bacterial toxins such as those responsible for the toxic shock syndrome.

Although immunologists traditionally distinguished between cellular and humoral immunity, it has become increasingly clear that the two arms of the immune response are closely intertwined. Almost all antigens evoke both a humoral response and a cellular response-and most B cell responses require T cell help. In practice, however, one arm is usually more effective than the other, and regulatory mechanisms end up skewing the response toward either the cellular or the humoral side.

The cell-mediated response is initiated by a macrophage or other antigen-presenting cell. The antigen-presenting cell takes in the antigen, digests it, and then displays antigen fragments on its own surface. Bound to the antigen fragment is an MHC molecule. It takes both of these structures, together, to capture the T cell's attention.

A T cell whose receptor fits this antigen-MHC complex binds to it. The binding stimulates the antigen-presenting cell to secrete interleukins required for T cell activation and performance.

Before activated T cells can set to work, however, they need a second go-ahead signal. In a maneuver known as co-stimulation, the antigen-presenting cell displays a special molecule that engages specific receptor molecules on the T cell, including one known as CD28. Without co-stimulation, activated T cells fall into a state of unresponsiveness known as anergy. Anergy arrests T cell growth by blocking its ability to produce or respond to signals to proliferate.

Once up and going, some subsets of T cells synthesize and secrete lymphokines. Interleukin-2, for instance, spurs the growth of more T cells. Other lymphokines attract other immune cells-fresh macrophages, granulocytes, and other lymphocytes-to the site of the infection. Yet others direct the cells' activities once they arrive on the scene. Some subsets of T cells become killer (or cytotoxic) cells, and set out to track down body cells infected by viruses. And when the infection has been brought under control, suppressor T cells draw the immune response to a close.

Receptors for Recognizing Antigen

In order to recognize and respond to the antigens that are their specific targets, both B cells and T cells carry special receptor molecules on their surface. For the B cell, this receptor is a prototype of the antibody the B cell is prepared to manufacture, anchored in its surface. When a B cell encounters a matching antigen in the blood or other body fluid, this antibody-like receptor allows the B cell to interact with it very efficiently.

The T cell receptor is more complex. Structurally, it is somewhat similar to an antibody, made of a pair of chemically linked chains with variable and constant regions. (But to work, it needs the help of an associated set of signaling and anchoring cell surface molecules called T3.) Unlike a B cell, however, a T cell cannot recognize antigen in its natural state; the antigen must first be broken down, and the fragments bound to an MHC molecule, by an antigen-presenting cell.

Helper T cells (T4 cells) look for antigen bound to a class II MHC molecule-a combination displayed by macrophages and B cells. Most cytotoxic T cells (T8), on the other hand, respond to antigen bound to MHC class I molecules, which are found on almost all body cells.

The T cell receptor molecule thus forms a three-way complex with its specific foreign antigen and an MHC protein. This complicated arrangement assures that T cells-which affect other cells through either direct contact or bursts of secretions-act only on precise targets and at close range.

The major antigen receptor, name alpha/beta for its two chains, is found on most T4 and T8 cells. A second, more recently discovered antigen receptor also has two chains and is known as gamma/delta; it is found on a distinct subset of mature T cells. Like the alpha/beta receptor, the more primitive gamma/delta receptor works in conjunction with T3. The function of T cells that carry gamma/delta receptors is not known.

Humoral immunity chiefly involves B cells, although the cooperation of helper T cells is almost always necessary. B cells, like macrophages, take in and process circulating antigen. Unlike macrophages, however a B cell can bind only that antigen that specifically fits its antibody-like receptor.

To enlist the help of a T cell, the B cell exhibits antigen fragments bound to its class II MHC molecules. This display attracts mature helper T cells (which may have been already activated by macrophages presenting the same antigen). The B cell and T cell interact, and the helper T cell secretes several lymphokines. These lymphokines set the B cell to multiplying, and soon there is a clone of identical B cells. The B cells differentiate into plasma cells and begin producing vast quantities of identical antigen-specific antibodies.

Released into the bloodstream, the antibodies lock onto matching antigens. The antigen-antibody complexes trigger the complement cascade or are removed from the circulation by clearing mechanisms in the liver and the spleen. The infection is overcome and, in response to suppressor influences wielded by yet other subsets of T cells, antibody production wanes.

Clinically, infections manifest themselves through the five classic symptoms of the inflammatory response-redness, warmth, swelling, pain, and loss of function. Redness and warmth develop when, under the influence of lymphokines and complement components, small blood vessels in the vicinity of the infection become dilated and carry more blood. Swelling results when the vessels, made leaky by yet other immune secretions, allow fluid and soluble immune substances to seep into the surrounding tissue, and immune cells to converge on the site.

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