Biomedicine and Health: Immunity and the Immune System

Introduction

The immune system is a complex system of cells, tissues, organs, and processes in the body that differentiates the self from foreign bodies, fights infections, and develops immunity against future attack. The immune system identifies pathogens of all types and destroys them by various means, including engulfment of invaders (phagocytosis), manufacturing of toxins (cytotoxicity) and biochemical neutralization (antibody production).

Bacteria, viruses, fungi, parasites, cancerous cells, and single-celled organisms such as amoebas can multiply in the body and cause disease. The immune system must recognize and act on these pathogens without attacking its own healthy tissues, which could also cause illness (autoimmune disease). The immune system also prevents dangerous pathogens from entering the body. This is an important function of the skin and mucous membranes, which resist, trap, and kill microorganisms, preventing them from causing disease.

A fundamental task of the immune system is to differentiate the “self” from the “nonself.” Almost all the cells of the body have specific proteins on their surfaces that identify them as self. This is the major histocompatibility complex (MHC). Foreign bodies, like bacteria, viruses, or cells that belong to another organism lack the appropriate MHC proteins and are thus identified as nonself. A healthy immune system reacts to things identified as nonself and not to things identified as self. The history of the science of immunology is the ongoing discovery of the cellular (and ultimately molecular) foundations of the immune system's ability to distinguish between the self and nonself, and to react appropriately to prevent harm to the self.

At the cellular level, the immune system is comprised of lymphocytes, also known as white blood cells, which are produced in the bone marrow and travel in the bloodstream. Certain lymphocytes, known as T cells, travel from the bone marrow to the thymus, where they mature. Lymphocytes also circulate through the body in the lymphatic system. Two major types of lymphocytes react to specific pathogens. B cells create antibodies, while T cells destroy invaders and coordinate the overall immune response. Antibodies are special markers that lock onto antigens and alert the T cells to destroy them. Somatic (body) cells use proteins called cytokines to communicate that they are injured and to marshal the immune cells.

Historical Background and Scientific Foundations

The concept of immunity (from the Latin immunis, meaning “free from”) has ancient roots and was used by the Greek historian Thucydides (c.460–c.404 BC) in the fifth century BC when he wrote of individuals recovering from an epidemic of the plague in Athens. It was already widely understood by then that individuals who had contracted an infectious disease and recovered were somehow “immune” or exempt from contracting it again.

The first recorded attempt to use the immunity of recovered individuals to prevent further illness comes from China in the tenth century AD, where smallpox was endemic. The Chinese developed the procedure of “variolation,” in which matter from the lesions of patients with a mild case of smallpox was inserted under the skin or, more frequently, dried into a powder and blown into the nose. This produced another mild case of the disease, and immunity to smallpox along with it. This practice spread westward through Central Asia; traders introduced it to the Ottoman Turks in the Middle East and Eastern Europe around 1670.

Lady Mary Wortley Montagu (1689–1762), wife of the British ambassador to the Ottoman Empire and a recovered smallpox victim herself, observed the practice in Istanbul and directed the Embassy surgeon Charles Maitland to learn the technique and variolate her children in 1718. Maitland established the efficacy of the practice using human volunteers and condemned prisoners. However, variability in the practice and the amount of inoculum used during the procedure contributed to variable outcomes, causing some disfigurement and even a few deaths from smallpox. Acceptance of variolation in England and later in America became more widespread when the procedure and inoculum were standardized to produce more consistently beneficial outcomes.

A crucial step toward greater safety was the substitution matter from cowpox (vaccinia) lesions for the smallpox inoculum. Cowpox, a mild disease carried by farm animals, is caused by a virus closely related to

smallpox (variola). In the first recorded use of cowpox inoculum in 1774, farmer Benjamin Jesty (1736–1836) inoculated his wife with vaccinia material obtained from another farmer, known to history as “farmer Elford of Chittenhall.”

In 1796 British surgeon Dr. Edward Jenner (1740–1823) inoculated eight-year-old James Phipps (1788–1853) with material from a dairymaid's cowpox lesion. Six weeks later he inoculated James with smallpox without producing disease. Jenner confirmed the positive results of this justifiably uncontrolled experiment with further studies that established the efficacy of the procedure.

The Germ Theory of Disease

In the late nineteenth century German physician Robert Koch (1843–1910) in Germany inoculated a rabbit with the blood of an animal that had died from anthrax. When the rabbit died the next day, Koch isolated bacteria from its infected lymph nodes. He then showed that these bacteria could transfer anthrax to other animals. He invented and refined techniques such as agar growth medium to culture bacteria and later identified the bacterium responsible for tuberculosis.

At this time French chemist Louis Pasteur (1822–1895) independently pursued studies of the chicken cholera bacillus. He serendipitously left a flask of the bacillus on a workbench for several months, then used this “old but viable” stock to inoculate eight chickens. The chickens did not become ill, and Pasteur speculated that the virulent chicken cholera bacillus had become attenuated by being left out on the bench through the summer months. He recognized the similarity of his results and Jenner's with the vaccinia virus, realizing that a weakened form of the bacillus could also prevent disease. Pasteur developed inoculum consisting of weakened infectious agent; he called this new method “vaccination” in Jenner's honor.

Koch and Pasteur became intensely and bitterly competitive, but together their discoveries firmly established the germ theory of disease by providing the biological basis for both the cause of infectious disease and the efficacy of variolation, now called vaccination.

Cellular and Humoral Immunity

Russian biologist Élie Metchnikoff (1845–1916) of the Pasteur Institute proved that phagocytes, amoeba-like cells found in blood, provided the first line of defense against infection by engulfing foreign bodies and infectious organisms. Metchnikoff became a leading proponent of the “cellularists,” who held that phagocytes played the leading role in immunity. Opposed to the them were the “humoralists,” led by German medical researcher Paul Ehrlich (1854–1915), who believed that an as-yet unknown substance dissolved in the body was responsible for immunity. Ehrlich believed that research would prove the existence of immune bodies (antibodies), a prediction he based on an earlier discovery that immunity to diphtheria could be transferred from one animal to another by a soluble antitoxin. These antibodies interact with foreign bodies that have particular stimulatory substances (antigens). This interaction causes the proliferation of the receptors or antibodies.

During this scientific debate between cellularists and humoralists, Ehrlich raised the concept of immunological self/not-self discrimination. He noted that the immune system included a highly adapted mechanism that prevents the production of antibodies against an organism's own tissues.

The humoralists dominated the scientific debate between 1900 and 1942, mainly because immunity could, in fact, be transferred via soluble factors that were later shown to be antibodies. In addition, many immunological dysfunctions such as anaphylaxis, serum sickness, and hemolytic anemia were associated with particular antibodies. Unlike phagocytosis, which appeared to be a very broad and nonspecific type of defense against all foreign organisms and particles, antibodies provided a basis for immunity to specific pathogens. The advent of immunochemistry further strengthened the case for antibodies as the basis of immunity.

Nevertheless, experimental observations such as delayed type hypersensitivity, (as seen in the common tuberculin test), first recognized by Koch in 1883, as well as graft rejection raised doubts that antibodies alone accounted for specific immunity. Proof that cells played a role in immunity came from experiments by Austrian biologist Karl Landsteiner (1868–1943) and immunologist Merrill Chase (1905–2004) in 1942 in which cells from guinea pigs immunized with tuberculosis bacteria were transferred into non-immunized guinea pigs. When the non-immunized guinea pigs were exposed to the antigen, they exhibited immunity “recall” that was not present in control animals. However it was not observed when just the serum fraction was transferred. A dichotomy of immediate (antibody-mediated) and delayed-type (cell-mediated) hypersensitivity was established by the 1940s, although the kind of cell that conferred the delayed-type response was not known until 1962, when James Gowans discovered that lymphocytes were essential to immunity (eliciting the immune response).

The Genetic Basis for the Immune Response

Early theories in immunology assumed that since antibodies were so diverse, they could not be preformed. Instead theories suggested that the antibodies were synthesized on demand following exposure to an antigen. During the 1950s scientists developed the clonal selection theory, based on the idea that every animal had a large set of natural immunoglobulins that diversified over time through evolution.

According to this theory, an antigen combines with an immunoglobulin and then encounters an antibody-producing cell, which would then make many copies of the immunoglobulin presented to it. Researchers hypothesized that the unit that actually multiplied was the antibody-producing cell itself; thus the proliferation of antibodies was partly due to the multiplication of clones of the antibody producing cell that had originally encountered the antigen-globulin complex.

Australian virologist Frank Macfarlane Burnet (1899–1985) elaborated the clonal selection theory as follows: a) animals contain numerous lymphocytes; 2) each lymphocyte responds to a particular antigen because of an affinity to particular surface receptor molecules; 3) the lymphocyte proliferates (clonal expansion) and differentiates into antibody secreting cells; 4) the expanded clone produces more cells (the secondary response) while the differentiated cells produce antibodies. The clonal selection theory was subsequently proven correct, and Burnet was awarded the Nobel Prize for physiology or medicine in 1960.

Major Histocompatibility Complex

Immunologists could still not explain how lymphocytes actually recognize antigens. In his work on tumor genetics, American immunogeneticist George Davis Snell (1903–1996) observed that tumor grafts were accepted between inbred mice, but not between mice of different genetic strains. He hypothesized that so-called histocompatibility genes varied between animals with different genotypes, and organisms' immune systems were able to discriminate and react against tissues from other animals. The location (locus) in the mouse chromosomes of these histocompatibility genes was identical to the genetic locus encoding antigen II (a large group of genes coded for cell surface antigens), which was renamed locus histocompatibility 2 or H2.

Around this same time doctors noticed that patients who received blood from many different donors produced antibodies that could agglutinate (clump together) the donors' white blood cells—but not their own. Subsequent family studies indicated the existence of a genetically determined system, HLA, which was found to be the human analogue of H2. Across species this system has been named the major histocompatibility complex (MHC), now known to be a set of molecules or antigens displayed on cell surfaces responsible for lymphocyte recognition and “antigen presentation.”

MHC Restriction and the Genetic Basis of Self-Nonself Recognition

In the course of investigating the role of T-lymphocytes (T cells) in the immune response to viral meningitis in mice, scientists found that T cells destroyed virus-infected cells from the host, but not those injected from other mice unless they were genetically identical. T cells actually ignored virus-infected cells from other mice strains. This established the principle of MHC restriction: T cells recognize an antigen only in the context of MHC molecules. It also demonstrated that the cells must recognize two signals: a fragment of the invading virus that the infected cell displays on its surface and a self-identifying tag from the cell's MHC antigens. Thus the identity of the molecular structure that constitutes immunological “self” is the MHC molecule. A virus-infected cell bearing MHC molecules and surface viral fragment constitutes “altered-self,” and the immune system responds to this combination.

Immunological Diversity

The immune system's ability to respond to a multitude of environmental insults requires an efficient way to ensure that it maintains a repertoire of responses. In 1978 evidence was found for somatic (as opposed to germ cell or gamete) rearrangement of immunoglobulin genes. This was a radical departure from one of the fundamental tenets of molecular genetics, which held that the genetic makeup of an organism remained unchanged throughout development (unless altered by pathological states, such as cancer). Scientists now understand that immunoglobulin genes and those that make up the T cell antigen receptor are the only genes that have been shown to undergo somatic rearrangements. The various combinations of genetic elements within these loci (sets of genes, in this case for antigen receptors) account for much of the diversity of the T and B cell “repertoire” or set of clones, although other mechanisms, such as somatic hypermutation (fast genetic change within mature immune cells), would later be discovered to generate even more diversity.

The Combination of Cellular and Molecular Immunology

Much of the knowledge of how antigens are recognized by the immune system has been gained in the past three decades, using complementary molecular and cellular research approaches. A type of phagocyte called the “dendritic cell,” so named because of the many narrow processes that radiate from it, was identified as the principal antigen-presenting cell of the immune system, expanding the phagocyte's role in engulfing foreign particles, as originally envisioned by Metchnikoff.

Investigators discovered a major dichotomy in helper T cell subsets: TH1 cells produce interferon-ϒ and activate macrophages and the lymphocytes that take part in delayed-type hypersensitivity. TH2 cells produce certain types of immunoglobulins and are involved in the development of allergic reactions and immediate hypersensitivity. These T cell subsets produce soluble substances that influence the behavior of other cells called cytokines. The first cytokine to be discovered was interferon in 1957; identifying cytokine properties remains one of the major areas of contemporary immunological research.

Lymphocyte Activation

Metchnikoff's discovery of the importance of phagocytes in immunity inaugurated the field of cellular immunology, although he mistakenly believed that the phagocyte was responsible for antibody production. A half century later scientists showed that lymphocytes, not antibodies, produced immunity to specific pathogens. This led to the discovery that the thymus fosters the development of lymphocytes from the bone marrow to maturity. It also explained the distinction between T cells, which provide toxins against pathogens (cytotoxicity), and B cells, which produce antibodies, as well as the nature of the collaboration between T and B cells in the immune response.

Another critical piece of the immune system puzzle was put in place with the realization that two distinct signals were necessary to activate an immune response. This hypothesis states that the immune cell (usually a dendritic cell) not only has to present antigen to a T cell, but must also simultaneously provide a costimulatory signal or molecule (e.g., a protein now identified as CD28). When both antigen and costimulation are presented by a dendritic cell, the T cell becomes activated, leading to proliferation and differentiation to an effector cell.

The Role of Innate Immunity in the Acquired Immune Response

“Acquired” or adaptive immunity, based on the complex interactions of lymphocytes, immunoglobulins, MHC molecules, and antigen receptors described above, appeared suddenly in the evolution of lower vertebrates. Still, higher vertebrates maintain the capabilities of “innate” immunity, based on macrophages, dendritic cells, etc. In 1989 American immunologist Charles A. Janeway, Jr. (1943–2003), suggested that the immune system recognizes “infectious nonself” in addition to recognizing the “self” as described above. The innate immune system becomes activated early in an immune response. Antigen-presenting dendritic cells are stimulated to respond, and in turn stimulate the acquired immune response. It was discovered that so-called “pattern recognition receptors” recognize products of microbial pathogens such as repetitive structures (e.g., components of bacterial cell walls) that are not present in higher organisms. Thus, rather than sensing pathogen signals directly, the immune system senses “danger” that results from infection such as debris from injured or dying cells.

Modern Cultural Connections

Further advances in the cell biology of the immune system will likely lead to new vaccines for infectious as well as noninfectious diseases, such as cancer and diseases of aging. New receptor- or cytokine-modifying therapies (e.g., antitumor necrosis factor-alpha or anti-TNF-a for rheumatoid arthritis) will be developed based on these accumulating insights. The human genome project will also identify new targets for drug therapies, while high-throughput screens and combinatorial chemistry will speed up the pace of drug discovery. Also, new aspects of the immune system will be uncovered using gene and protein microarray techniques and proteomics (branch of biotechnology that studies the structures and functions of proteins) that will increase knowledge of how the immune system works, and this knowledge will be exploited to alter the course of currently intractable diseases.

See Also Biomedicine and Health: Antibiotics and Antiseptics; Biomedicine and Health: Bacteriology; Biomedicine and Health: Prions and Koch's Postulates; Biomedicine and Health: The Germ Theory of Disease; Biomedicine and Health: Virology.

Books

Mazumdar, Pauline, ed. Immunology 1930–1980: Essays on the History of Immunology. Toronto: Wall and Thompson, 1989.

Periodicals

Brown, Kelly L., Céline Cosseau, Jennifer L. Gardy, Robert E. Hancock. “Complexities of Targeting Innate Immunity to Treat Infection.” Trends in Immunology (April 27, 2007).

Dempsey, P.W., S.A. Vaidya, and G. Cheng. “The Art of War: Innate and Adaptive Immune Responses.” Cellular and Molecular Life Sciences 60, no. 12 (December 2003): 2,604–2,621.

Du Pasquier, L. “Speculations on the Origin of the Vertebrate Immune System.” Immunology Letters 92, nos. 1–2 (March 29, 2004): 3–9.

Janeway Charles A., Jr. “The Immune System Evolved to Discriminate Infectious Nonself from Noninfectious Self.” Immunology Today 13, no. 1 (January 1992): 11–16.

Medzhitov, Ruslan, and Charles A. Janeway, Jr. “Innate Immune Recognition: Mechanisms and Pathways.” Immunological Reviews 173, no. 1 (February 2000): 89–97.

Tupin, Emmanuel, Yuki Kinjo, and Mitchell Kronenberg. “The Unique Role of Natural Killer T Cells in the Response to Microorganisms.” Nature Reviews Microbiology (May 8, 2007).

Villadangos Jose A. “Hold on, the Monocytes Are Coming!” Immunity 26, no. 4 (April 2007): 390–392.

Yang K.D., and H.R. Hill. “Immune Responses to Infectious Diseases: An Evolutionary Perspective.” Paediatric Infectious Disease Journal 15, no. 4 (April 1996): 355–364.

Kenneth T. LaPensee