Immunology, the study of the body's immune system. It was originally the branch of medical science dealing with defence or resistance against infections, but the term has broadened over the past four decades to encompass all processes and mechanisms which discriminate between "self"-that is, the body's own innate mechanisms, molecules, cells, and tissues, and everything that belongs to it-and "non-self"-anything which comes from outside the body; that which is alien to it. The latter term includes infectious micro-organisms (protozoa, fungi, bacteria, mycoplasmas, and viruses); parasites; toxins and poisons of sufficient size and appropriate composition, tumours and neoplastic cells; transplants; and transfused cells or molecules from genetically non-identical animals.
THE IMMUNE RESPONSE
Most animals are capable of mounting a defensive response against non-self substances; this is known as the immune response. The study of the natural development of mechanisms involved in the immune response is the main feature of immunology and immunological research. Immune responses can be classified as innate (meaning those which occur without prior exposure to the foreign substance, organism, or tissue) or acquired (meaning those which require exposure to the non-self material).
° Innate Immunity
Animals have natural barriers and substances which help to prevent infections with micro-organisms and parasites. The skin and mucus-containing secretions act as barriers, and proteolytic enzymes (digestive enzymes which break down protein) present in body fluids have the ability to destroy some invading organisms. In addition to this, cells with specific innate immune functions rapidly respond to invading organisms to destroy them. These cells are primarily of two types: monocytes (especially macrophages) and polymorphonuclear leucocytes. Both of these can ingest micro-organisms by a process known as "phagocytosis" and destroy them. They also synthesize and secrete many substances, including cytokines and enzymes, which protect against infections and promote the development of the immune response.
Polymorphonuclear leucocytes circulate in the blood, but can migrate rapidly into tissues in response to stimuli provoked by unwanted foreign bodies and substances. Circulating monocytes also migrate from blood into tissues, while macrophages are usually present in all body tissues.
Primitive animals as well as higher species can produce innate immune responses; early work by the Russian immunologist Metchnikoff showed that starfish larvae can respond to foreign material by macrophage-mediated processes.
The inflammatory response that often accompanies the immune response is also important in defence against infection or protection against unwanted materials; this inflammation is induced by cells of the immune and other systems.
The complement system is also important in protection against some micro-organisms and can play a part in innate immunity.
Innate immunity is relatively non-specific, although normally it clearly discriminates between self and non-self. It reacts rapidly and provides a quick first-line defence against unwanted invasion and infection.
° Acquired Immunity
The ability to respond specifically to non-self is acquired after interaction with antigens (foreign substances potentially dangerous to the body) present in such organisms. Non-vertebrate animals show little if any ability to respond in a genuinely specific manner; acquired immunity is most developed in mammals and birds. Amphibians and fish show some acquired immunity and primitive vertebrates such as lampreys and hagfish are able to respond to some antigens, although their response is usually weak and relatively simple.
Acquired immunity relies on the activity of two systems: humoral immunity and cell-mediated immunity. Humoral immunity is mediated by soluble proteins called immunoglobulins or antibodies. Mammals produce five different classes of immunoglobulin molecules known as immunoglobulins G, M, A, D, and E. Parts of the structure of these relatively large globular proteins consist of short sequences which are positioned closely together on the surface of the molecule and interact specifically with the antigen. Other parts of the antibody molecules mediate immunobiological functions such as complement activation interaction with macrophages and other cells.
All classes of immunoglobulins are present in blood but immunoglobulin G (IgG) is the predominant class and is a major serum protein (serum from normal human beings contains 8 to 16 mg/ml IgG). IgM antibodies are induced in blood early in the immune response and IgA is secreted in gastric and lung fluids, sweat, and saliva. IgE mediates anaphylactic (histamine-releasing) and allergic responses and can be important for protection against parasites. The function of circulating IgD is unclear. Immunoglobulins are produced and secreted by B-lymphocytes.
Antibodies bind specifically to non-self organisms and substances. This often results in inactivation of undesired properties. Antigen-antibody complexes are removed from the body by various processes and antibody-coated micro-organisms are particularly susceptible to phagocytosis by macrophages and other cells. After interacting with an antigen, antibodies trigger a range of immunobiological mechanisms which protect against infections and other undesirable effects.
Cell-mediated immunity is mediated by T-lymphocytes. Antigen-specific T-cells are produced, which interact with antigens to mediate a number of immunobiological functions. One example of this is the production of cytotoxic cells that specifically "kill" unwanted micro-organisms or cells. A third class of lymphocyte, known as large granular lymphocytes or natural killer (NK) cells, also destroy non-self cells and micro-organisms. The acquired immune response complements the innate response to provide a specific, very efficient defence system.
CONTROLLING THE DEVELOPMENT OF ACQUIRED IMMUNITY
The acquired immune system is tightly controlled. B-lymphocytes that secrete antibodies are strongly influenced by T-cells which can either "help" the response or suppress it. Such T-cells secrete cytokines and other potent, biologically active molecules which enhance or inhibit B-cell activation, maturation, and ability to secrete appropriate immunoglobulin. B-cells (and other cell types) also secrete cytokines which modulate immunity. In particular, Interleukins 1,2,4,6,10,12,13,14,15, and 16, •interferon-, and transforming growth factor â influence the development and modulation of the acquired immune response. IL-12 is a potent stimulator of NK cells.
The acquired immune system is capable of producing antibodies and T-cells which recognize a very large number of different molecules with remarkable specificity. It has been estimated that mammals can produce about a million different antibodies, and the mechanism able to achieve this generation of diversity has been a primary field of immunological research. It is also known that antibodies can be produced against synthetic substances which do not occur in nature. Early theories seeking to explain this diversity considered that an "instructive" process, involving the "induced fit" of antibody with antigens was the basis of specificity.
This theory has been largely abandoned as no convincing biological basis for its action has been conceived or discovered. It is now known that immunoglobulins are produced by reorganization and joining of several genes, and that somatic mutation of genetic material occurs during the development of acquired immunity. This especially affects the highly variable portions of the immunoglobulin protein that make up the antigen recognition site.
Such processes play a significant role in the generation of diversity and specificity of the immune system. Development of humoral immunity involves interaction of antigens with IgM or IgD molecules present on the B-cell surface. This triggers B-cell activation which (if sufficient help from T-cells and other systems is available) results in maturation of the response and secretion of appropriate antibodies. This concept was put forward by the pioneering German immunologist Paul Ehrlich decades before it was proven by experimentation. T-cells interact with antigens via T-cell receptors, which show structural similarities with immunoglobulins.
DISCRIMINATION BETWEEN SELF AND NON-SELF
The discrimination between self and non-self is fundamental to immunology. Clones of cells which have the capacity to recognize self antigens are eliminated early (usually neonatally) in an animal's development. This "clonal deletion", which occurs possibly by processes involving programmed cell death (apoptosis), is not yet fully understood, but is known to produce tolerance to self antigens. Tumour cells can be destroyed by immune processes if they express antigens that are not present on normal cells (the so-called "tumour associated antigens"). The magnitude of the immune response against an antigen is often considerably affected by the difference between its structure and that of host antigens, and by the extent of recruitment of "help" (largely mediated by T-cells) for the antigen.
ANTIGEN PRESENTATION AND THE MAJOR HISTOCOMPATIBILITY COMPLEX ANTIGENS
Most animal cells (except mammalian erythrocytes) express molecules on their surfaces which are strongly recognized as non-self by other, genetically non-identical, individuals. These major histocompatibility antigens show considerable similarity in structure to the immunoglobulins and T-cell receptor proteins. They play an important (though not exclusive) role in transplant rejection and some transfusion reactions. They are also fundamentally involved in the "presentation" of processed antigens to T-lymphocytes, which is especially important in the development of immune responses. Antigen-presenting cells such as macrophages, dendritic cells, and B-lymphocytes process antigens by degradation (which is mediated by enzymes) and present the resulting peptides, bound in grooves on the major histocompatibility complex (MHC) molecules, to responding T-cells (see Histocompatibility Groups). The type of the MHC molecules and their ability to present antigen influences significantly the strength and nature of the resulting immune response.
MMUNITY AND DISEASE
Immunological processes are normally beneficial. However, development of inappropriate immunity can cause disease or at least adverse clinical effects. The breakdown of tolerance to self can result in autoimmune diseases, such as rheumatoid arthritis, primary biliary cirrhosis, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, and insulin-dependent diabetes mellitus. Production of antibodies against sperm can result in a woman's inability to conceive. Excessive aggressive immune reactivity (hypersensitivity) can result in conditions like anaphylaxis, allergy, and asthma.
An impaired immune response occurs in a group of pathological conditions known as immunodeficiencies. Such conditions can affect innate or acquired immunity and may involve humoral or cellular responses. They vary in severity. Bruton's congenital agammaglobulinaemia results in a grossly impaired ability to produce immunoglobulins. Common variable immunodeficiency is the most frequently occurring immunodeficiency disease and involves a defect in B-cell function such that the cells cannot secrete antibodies. DiGeorge and Nezelof syndromes involve defects in T-cell development. Severe combined immunodeficiency results in total lack of ability to mount humoral and cellular immune responses. The underlying basis for such conditions is often genetic, but in several cases is unclear.
Other immunodeficiencies are caused by viruses. The acquired immune deficiency syndrome (AIDS) results from infection with the human immunodeficiency virus (HIV); this virus destroys CD4-positive T-cells, causing dramatic immunosuppression. Immunosuppressive disorders result in an inability to cope with infections and, in some cases, the spontaneous growth of tumours. Severe illness or death often results.
Immunochemistry is a branch of immunology which encompasses the use of biochemical and biophysical procedures for the study and use of antibodies. Immunochemical procedures, particularly those using monoclonal antibodies, are widely used for research in many branches of biology and medicine.
Research in immunology has had a fundamental impact on the understanding of many important aspects of biology and medicine. This impact has been acknowledged by the award of the Nobel Prize to several immunologists. As early as 1901, von Behring received the Nobel Prize for his work on immunotherapy; this was followed by awards to Paul Ehrlich and Élie Metchnikoff in 1908. Other Nobel laureates include Karl Landsteiner for discovery of the blood groups; Sir Frank Macfarlane Burnet and Peter Medawar for work on tolerance; Rodney Porter and Edelman for the discovery of the biochemical structure of antibodies; Rosalyn Yalow for the development of radioimmunoassay technology; Georges Köhler and César Milstein for development of monoclonal antibody technology; Niels Jerne for work on immune system function; and Tonegawa Susumu for discovering the genetic basis of antibody diversity.
Current research is diverse but includes examination of the roles of cytokines and their receptors in modulating the immune response, and classification of the functions of the various leucocyte types in this process. Identification of subtypes of T-lymphocytes (for example, the so-called TH1 and TH2 populations of "helper" T-cells) which direct the humoral and cellular immune response to mature in different ways by secreting different cytokines and other substances, has initiated a greater understanding of control of the immune system. Refinement of procedures for production of monoclonal antibodies, including the use of recombinant DNA technology, has increased the potential of immunochemical methods. It is hoped that intense activity in the area of vaccine design and production, including the development of DNA vaccines, will lead to better and safer vaccines for the prevention of a wide range of infectious and other diseases.