The Body's Army Its Immune System

Gary A. Sputter, associate professor, Department of Veterinary Science, University of Wisconsin-Madison.

Daily warfare rages between invaders and defenders within our bodies. The body's army its immune system patrols for unfamiliar shapes using special troops immune cells whose origin is in the bone marrow but whose final maturation may occur elsewhere in the body. A system of communication and specialization of duties allows these cells to act most effectively.

The immune system's purpose is to recognize itself from everything else, especially bacteria, viruses, and parasites. It helps that each cell in the body has a distinct shape on its surface that distinguishes it from foreign invaders. And every foreign invader has hundreds of components, termed antigens, that can be recognized by immune cells as foreign. The two branches of the immune system--cell-mediated and humoral immunity work together in responding to invaders.

Cell-mediated immunity refers to the direct response of immune cells to the foreign antigen.

Humoral immunity refers to the production by immune cells of antibodies that circulate in the blood in response to the foreign antigen.

Principal Cells

Principal cells of the immune system are T and B lymphocytes and macrophages. These cells reside in organized tissues and organs, including the lymph nodes, spleen, tonsils, thymus, and bone marrow. In addition, a substantial fraction of the lymphocytes and macrophages comprise a recirculating pool of cells found in the blood and the lymph. Lymphocytes in both lymphoid organs and in the circulation provide the body's immune army with fortified garrisons and patrol missions to seek out foreign invaders.

Individual lymphocytes are committed to respond to a limited group of structurally related antigens. This commitment, which exists before the first contact of the immune system with a given antigen, is expressed by the presence on the lymphocyte membrane of receptors specific for the antigen. Characterizing these antigen specific receptors at the genetic level and determining the mechanisms of cell stimulation and activation of these receptors are areas of intense present study. One set, or clone, of lymphocytes will differ from another set, or clone, in the structure of the antigen-combining region of its receptors and, thus, the range of antigenic substances that may stimulate it to respond. A large number of separate sets of lymphocytes, each bearing receptors specific for distinct antigens, enables the body to respond to virtually any antigen.

As a result, lymphocytes are an enormously heterogeneous collection of cells. Although exact figures are not available, the number of distinct antigen-combining sites of lymphocyte receptors present in an adult animal exceeds one million. That is, over a million different lymphocytes, each specific for a different antigen, exist. In actuality, there are more lymphocytes because many of them have already recognized their specific antigen either through vaccination or natural exposure and produced multiple daughters.

T and B Lymphocytes. Lymphocytes differ from one another not only in the specificity of their receptors but also in their functional properties. Two broad classes of lymphocytes are recognized: T, or thymus-dependent lymphocytes and B lymphocytes, which are precursors of antibody-secreting cells.

T lymphocytes consist of a series of subtypes. Some mediate important regulatory functions, such as the ability to help the development of immune responses. Other T lymphocytes suppress the development of immune responses. Both helper and suppressor T cells regulate antibody production. Additional T lymphocytes (cytotoxic T cells) are involved in producing soluble products that start a variety of inflammatory responses, or directly destroy agents bearing antigenic substances (killer function).

Precursors of T lymphocytes originate in the bone marrow but are required to travel to the thymus for final maturation. On completion of intrathymic maturation under the influence of thymic hormones and education of self-recognition, thymic lymphocytes join the peripheral pool of T lymphocytes.

Several distinct peripheral T lymphocyte groups can be identified because they express characteristic molecules on their membranes. These molecules that distinguish different T lymphocyte groups have only recently begun to be characterized in domestic animals. To date, molecules on helper and cytotoxic lymphocytes have been described, but those that characterize suppressor lymphocytes have not been identified.

Identifying and characterizing molecules specific for each lymphocyte group will provide methods to isolate different cell groups and to study the response of each cell group to different bacteria, viruses, and parasites. Also, the relationships that different cell groups have to pathologic lesions in infectious diseases can be identified in diseased animals. Knowing the types of cells that respond to infectious agents, it may be possible to augment the function of cells with biological response-modifying factors produced by similar kinds of cells grown in the laboratory.

A recent advance has been the production of monoclonal antibodies to the immune cells of domestic animals. Monoclonal antibodies produced specifically for the molecules for each of the body's army cells have helped in identifying the cells of the immune system. In the future, the role of all of the different cell populations in the animal's response to disease-producing agents will be defined.

Killer Cells. In addition to the major T and B lymphocyte classes, lymphocytes that are large, possess cytoplasmic granules, and mediate certain nonspecific cytotoxic responses have been identified. These include natural killer (NK) cells that kill certain tumor cells using recognition systems which may be quite different from those used by T or B lymphocytes. Another type of nonspecific killing of target cells is antibody-dependent cellular cytotoxicity (ADCC), where a lymphocyte or macrophage is capable of killing antibody-coated cells after recognizing the constant portion of the antibody bound to that cell. The role of these types of immune cells in response to bacterial and viral infections in domestic animals has not been well defined. But the response to herpes virus infections by these immune cells in cattle has been shown in the laboratory.

Macrophages. Macrophages are the third type of cell involved in the development and expression of humoral and cell-mediated immune responses. These cells, which function in a nonspecific manner to remove foreign matter, are located throughout the body at fixed sites as well as wandering freely through blood and lymph. When a bacterium or virus enters the body, it is usually first ingested by a macrophage. Macrophages participate in the immune response by 1) killing micro-organisms, particularly intracellular microorganisms, by the release of toxic chemicals; 2) functioning as scavengers to remove damaged or dying cells and sequestering nonmetabolizable inorganic materials; 3) functioning in bidirectional cellular interactions with lymphocytes; 4) serving as an important secretory cell in the production of bioactive materials (cytokines) that regulate other cellular functions; and 5) playing an important cytocidal role in the control of cancer.

Cell-Cell Interaction in Response to Viruses or Bacteria

An immune response to Brucella abortus illustrates the interaction of macrophages with T lymphocytes. Macrophages engulf foreign material and process the bacterium. Processing involves digesting the complex bacterium into small fragments that are more easily recognized by lymphocytes bearing receptors specific for antigens on these fragments. The actual processing events are not fully understood, but most of the bacteria are destroyed inside the macrophage, and only a few are processed into an immunogenic form recognized by lymphocytes.

The many bacterial antigens are expressed on the surface of the macrophage in association with a self-molecule. The self-molecule is a product of the macrophage's genes located in the major histocompatibility complex (MHC). This complex is a genetic region found in all mammals whose products are primarily responsible for the rapid rejection of grafts between individuals, and which function in signaling between lymphocytes and cells expressing antigen. The MHC segment responsible for this function is termed the class II region. This complex of genes has not been thoroughly characterized at the molecular or functional levels in domestic animals. In mice and humans, the MHC consists of a tightly clustered series of genes that code for protein molecules on the cell surface called MHC class I and II molecules. MHC class I molecules are present on all cells of the body, while MHC class II molecules are found on only select cells such as macrophages. T lymphocytes with receptors for both the bacterial antigen and the self-molecule interact with the macrophage expressing this complex.

This complex of bacterial antigen associated with the MHC class II self-molecule constitutes the first signal of activation of the T lymphocyte. Animals possessing different MHC genes have different levels of immune response to a number of foreign antigens. Ultimate survival of an animal may depend on its particular MHC genes and how well antigens are associated with MHC self-molecules. Characterization of the MHC in domestic animals is a promising area in investigating the contribution of these genes to an immune response.

A second signal is provided by the macrophage in the form of a soluble cytokine termed interleukin 1. After the T lymphocyte receives this second signal, the lymphocyte undergoes cell division. Classically, these T lymphocytes are helper T cells and secrete a variety of soluble products, termed cytokines or more specifically lymphokines. These lymphokines have specific functions that affect selected cell groups. However, in domestic animals lymphokines have only been studied recently. Examples of lymphokines are: interleukin 2, T cell replacing factor, B cell growth factor, and gamma interferon.