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In
immunology Immunology is a branch of medicineImmunology for Medical Students, Roderick Nairn, Matthew Helbert, Mosby, 2007 and biology that covers the medical study of immune systems in humans, animals, plants and sapient species. In such we can see ther ...
, clonal selection theory explains the functions of cells of the
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
(
lymphocytes A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ada ...
) in response to specific
antigens In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
invading the body. The concept was introduced by Australian doctor Frank Macfarlane Burnet in 1957, in an attempt to explain the great diversity of
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of ...
formed during initiation of the
immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which coul ...
. The theory has become the widely accepted model for how the human
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
responds to
infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable di ...
and how certain types of B and T lymphocytes are selected for destruction of specific
antigens In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
. The theory states that in a pre-existing group of lymphocytes (specifically B cells), a specific antigen activates (i.e. selects) only its counter-specific cell, which then induces that particular cell to multiply, producing identical clones for antibody production. This activation occurs in secondary lymphoid organs such as the
spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .
and the
lymph node A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...
s. In short, the theory is an explanation of the mechanism for the generation of diversity of antibody specificity. The first experimental evidence came in 1958, when Gustav Nossal and Joshua Lederberg showed that one B cell always produces only one antibody. The idea turned out to be the foundation of molecular immunology, especially in
adaptive immunity The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...
.


Postulates

The clonal selection theory can be summarised with the following four tenets: * Each lymphocyte bears a single type of receptor with a unique specificity (generated by
V(D)J recombination V(D)J recombination is the mechanism of somatic recombination that occurs only in developing lymphocytes during the early stages of T and B cell maturation. It results in the highly diverse repertoire of antibodies/immunoglobulins and T cell re ...
). * Receptor occupation is required for cell activation. * The differentiated
effector cell In cell biology, an effector cell is any of various types of cell that actively responds to a stimulus and effects some change (brings it about). Examples of effector cells include: * The muscle, gland or organ cell capable of responding to ...
s derived from an activated lymphocyte bear receptors of identical specificity as the parent cell. * Those lymphocytes bearing receptors for self molecules (i.e.,
endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, ...
antigens produced within the body) are destroyed at an early stage.


Early work

In 1900,
Paul Ehrlich Paul Ehrlich (; 14 March 1854 – 20 August 1915) was a Nobel Prize-winning German physician and scientist who worked in the fields of hematology, immunology, and antimicrobial chemotherapy. Among his foremost achievements were finding a cure ...
proposed the so-called "side chain theory" of antibody production. According to it, certain cells exhibit on their surface different "
side chain In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called the "main chain" or backbone. The side chain is a hydrocarbon branching element of a molecule that is attached to a ...
s" (i.e. membrane-bound antibodies) able to react with different antigens. When an antigen is present, it binds to a matching side chain. Then the cell stops producing all other side chains and starts intensive synthesis and secretion of the antigen-binding side chain as a soluble antibody. Though distinct from clonal selection, Ehrlich's idea was a selection theory far more accurate than the instructive theories that dominated immunology in the next decades. In 1955, Danish immunologist Niels Jerne put forward a hypothesis that there is already a vast array of soluble antibodies in the
serum Serum may refer to: * Serum (blood), plasma from which the clotting proteins have been removed **Antiserum, blood serum with specific antibodies for passive immunity * Serous fluid, any clear bodily fluid *Truth serum, a drug that is likely to mak ...
prior to any infection. The entrance of an antigen into the body results in the selection of only one type of antibody to match it. This supposedly occurred by certain cells phagocytosing the immune complexes and somehow replicating the antibody structure to produce more of it. In 1957, David W. Talmage hypothesized that antigens bind to antibodies on the surface of antibody-producing cells and "only those cells are selected for multiplication whose synthesized product has affinity for the antigen". The key difference from Ehrlich's theory was that every cell was presumed to synthesize only one sort of antibody. After antigen binding the cell proliferates, forming clones with identical antibodies.


Burnet's clonal selection theory

Later in 1957, Australian immunologist Frank Macfarlane Burnet published a paper titled "A modification of Jerne's theory of antibody production using the concept of clonal selection" in the rather obscure ''Australian Journal of Science''. In it Burnet expanded the ideas of Talmage and named the resulting theory the "clonal selection theory". He further formalised the theory in his 1959 book ''The Clonal Selection Theory of Acquired Immunity''. He explained immunological memory as the cloning of two types of lymphocyte. One clone acts immediately to combat infection whilst the other is longer lasting, remaining in the immune system for a long time and causing immunity to that antigen. According to Burnet's hypothesis, among antibodies are molecules that can probably correspond with varying degrees of precision to all, or virtually all, the
antigenic determinant An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The epitope is the specific piece of the antigen to which an antibody binds. The ...
s that occur in biological material other than those characteristic of the body itself. Each type of pattern is a specific product of a clone of lymphocytes and it is the essence of the hypothesis that each cell automatically has available on its surface representative reactive sites equivalent to those of the
globulin The globulins are a family of globular proteins that have higher molecular weights than albumins and are insoluble in pure water but dissolve in dilute salt solutions. Some globulins are produced in the liver, while others are made by the immune ...
they produce. When an antigen enters the blood or tissue fluids it is assumed that it will attach to the surface of any lymphocyte carrying reactive sites that correspond to one of its antigenic determinants. Then the cell is activated and undergoes proliferation to produce a variety of descendants. In this way, preferential proliferation is initiated of all those clones whose reactive sites correspond to the antigenic determinants on the antigens present in the body. The descendants are capable of active liberation of soluble antibody and lymphocytes, the same functions as the parental forms. In 1958, Gustav Nossal and Joshua Lederberg showed that one B cell always produces only one antibody, which was the first direct evidence supporting the clonal selection theory.


Theories supported by clonal selection

Burnet and Peter Medawar worked together on understanding
immunological tolerance Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that would otherwise have the capacity to elicit an immune response in a given organism. It is induced by ...
, a phenomenon also explained by clonal selection. This is the organism’s ability to tolerate the introduction of cells prior to the development of an immune response as long as it occurs early in the organism’s development. There are a vast number of lymphocytes occurring in the immune system, ranging from cells that tolerate self tissue to cells that do not. However, only cells tolerant of self tissue survive the embryonic stage. If non-self tissue is introduced, lymphocytes that develop are the ones that include the non-self tissues as self tissue. In 1959, Burnet proposed that under certain circumstances, tissues could be successfully transplanted into foreign recipients. This work has led to a much greater understanding of the immune system and also great advances in tissue transplantation. Burnet and Medawar shared the
Nobel Prize in Physiology or Medicine The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accordi ...
in 1960. In 1974, Niels Kaj Jerne proposed that the immune system functions as a network that is regulated via interactions between the variable parts of lymphocytes and their secreted molecules.
Immune network theory The immune network theory is a theory of how the adaptive immune system works, that has been developed since 1974 mainly by Niels Jerne and Geoffrey W. Hoffmann. The theory states that the immune system is an interacting network of lymphocytes and m ...
is firmly based on the concept of clonal selection. Jerne won the Nobel Prize in Physiology or Medicine in 1984, largely for his contributions to immune network theory.


See also

*
Adaptive immune system The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...
*
Clonal selection algorithm In artificial immune systems, clonal selection algorithms are a class of algorithms inspired by the clonal selection theory of acquired immunity that explains how B and T lymphocytes improve their response to antigens over time called affinity mat ...
*
Universal Darwinism Universal Darwinism, also known as generalized Darwinism, universal selection theory, or Darwinian metaphysics, is a variety of approaches that extend the theory of Darwinism beyond its original domain of biological evolution on Earth. Universal ...


References


Further reading

* *"Biology in Context - The Spectrum of Life" Authors, Peter Aubusson, Eileen Kennedy. *


External links


Animation of clonal selection
from the Walter & Elisa Hall institute. {{DEFAULTSORT:Clonal Selection Immunology Immune system