Clonal selection

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Clonal selection theory of lymphocytes: 1) A hematopoietic stem cell undergoes differentiation and genetic rearrangement to produce 2) immature lymphocytes with many different antigen receptors. Those that bind to 3) antigens from the body's own tissues are destroyed, while the rest mature into 4) inactive lymphocytes. Most of these never encounter a matching 5) foreign antigen, but those that do are activated and produce 6) many clones of themselves. Clonal selection.svg
Clonal selection theory of lymphocytes:
1) A hematopoietic stem cell undergoes differentiation and genetic rearrangement to produce
2) immature lymphocytes with many different antigen receptors. Those that bind to
3) antigens from the body's own tissues are destroyed, while the rest mature into
4) inactive lymphocytes. Most of these never encounter a matching
5) foreign antigen, but those that do are activated and produce
6) many clones of themselves.

In immunology, clonal selection theory explains the functions of cells of the immune system (lymphocytes) in response to specific antigens 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 formed during initiation of the immune response. [1] [2] The theory has become the widely accepted model for how the human immune system responds to infection and how certain types of B and T lymphocytes are selected for destruction of specific antigens. [3]

Contents

The theory states that in a pre-existing group of lymphocytes (both B and T 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 and the lymph nodes. [4] In short, the theory is an explanation of the mechanism for the generation of diversity of antibody specificity. [5] The first experimental evidence came in 1958, when Gustav Nossal and Joshua Lederberg showed that one B cell always produces only one antibody. [6] The idea turned out to be the foundation of molecular immunology, especially in adaptive immunity. [7]

Postulates

The clonal selection theory can be summarised with the following four tenets:

Early work

In 1900, Paul Ehrlich proposed the so-called "side chain theory" of antibody production. According to it, certain cells exhibit on their surface different "side chains" (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 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. [8]

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 determinants 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 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. [5] [9]

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. [6]

Theories supported by clonal selection

Burnet and Peter Medawar worked together on understanding immunological tolerance, 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.[ dubious – discuss ]

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 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 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

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.

<span class="mw-page-title-main">Antibody</span> Protein(s) forming a major part of an organisms immune system

An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that cause disease. Antibodies can recognize virtually any size antigen, able to perceive diverse chemical compositions. Each antibody recognizes one or more specific antigens. Antigen literally means "antibody generator", as it is the presence of an antigen that drives the formation of an antigen-specific antibody. Each tip of the "Y" of an antibody contains a paratope that specifically binds to one particular epitope on an antigen, allowing the two molecules to bind together with precision. Using this mechanism, antibodies can effectively "tag" a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

<span class="mw-page-title-main">Immune system</span> Biological system protecting an organism against disease

The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as cancer cells, parasitic worms, and also objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.

<span class="mw-page-title-main">Immunology</span> Branch of medicine studying the immune system

Immunology is a branch of biology and medicine that covers the study of immune systems in all organisms.

<span class="mw-page-title-main">Autoimmunity</span> Immune response against an organisms own healthy cells

In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, Henoch–Schönlein purpura, systemic lupus erythematosus, Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, and multiple sclerosis. Autoimmune diseases are very often treated with steroids.

<span class="mw-page-title-main">B cell</span> Type of white blood cell

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasma membrane where they serve as a part of B-cell receptors. When a naïve or memory B cell is activated by an antigen, it proliferates and differentiates into an antibody-secreting effector cell, known as a plasmablast or plasma cell. In addition, B cells present antigens and secrete cytokines. In mammals B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, which is why the B stands for bursa and not bone marrow, as commonly believed.

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens such as viruses or bacteria, or cells that are damaged in other ways.

<span class="mw-page-title-main">Macfarlane Burnet</span> Australian virologist (1899–1985)

Sir Frank Macfarlane Burnet, usually known as Macfarlane or Mac Burnet, was an Australian virologist known for his contributions to immunology. He won a Nobel Prize in 1960 for predicting acquired immune tolerance. He also developed the theory of clonal selection.

<span class="mw-page-title-main">Niels Kaj Jerne</span> Danish immunologist (1911–1994)

Niels Kaj Jerne, FRS was a Danish immunologist. He shared the Nobel Prize in Physiology or Medicine in 1984 with Georges J. F. Köhler and César Milstein "for theories concerning the specificity in development and control of the immune system and the discovery of the principle for production of monoclonal antibodies".

<span class="mw-page-title-main">Adaptive immune system</span> Subsystem of the immune system

The adaptive immune system, AIS, also known as the acquired immune system, or specific immune system is a subsystem of the immune system that is composed of specialized cells, organs, and processes that eliminate pathogens specifically. The acquired immune system is one of the two main immunity strategies found in vertebrates.

<span class="mw-page-title-main">T-cell receptor</span> Protein complex on the surface of T cells that recognizes antigens

The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.

In immunology, central tolerance is the process of eliminating any developing T or B lymphocytes that are autoreactive, i.e. reactive to the body itself. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation occurs in primary lymphoid organs such as the bone marrow and the thymus. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.

Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear.

Immune tolerance, also known as immunological tolerance or immunotolerance, refers to the immune system's state of unresponsiveness to substances or tissues that would otherwise trigger an immune response. It arises from prior exposure to a specific antigen and contrasts the immune system's conventional role in eliminating foreign antigens. Depending on the site of induction, tolerance is categorized as either central tolerance, occurring in the thymus and bone marrow, or peripheral tolerance, taking place in other tissues and lymph nodes. Although the mechanisms establishing central and peripheral tolerance differ, their outcomes are analogous, ensuring immune system modulation.

The following are notable events in the Timeline of immunology:

<span class="mw-page-title-main">Polyclonal B cell response</span> Immune response by adaptive immune system

Polyclonal B cell response is a natural mode of immune response exhibited by the adaptive immune system of mammals. It ensures that a single antigen is recognized and attacked through its overlapping parts, called epitopes, by multiple clones of B cell.

<span class="mw-page-title-main">Cancer immunology</span> Study of the role of the immune system in cancer

Cancer immunology (immuno-oncology) is an interdisciplinary branch of biology and a sub-discipline of immunology that is concerned with understanding the role of the immune system in the progression and development of cancer; the most well known application is cancer immunotherapy, which utilises the immune system as a treatment for cancer. Cancer immunosurveillance and immunoediting are based on protection against development of tumors in animal systems and (ii) identification of targets for immune recognition of human cancer.

In immunology, clonal deletion is the process of removing T and B lymphocytes from the immune system repertoire. The process of clonal deletion helps prevent recognition and destruction of the self host cells, making it a type of negative selection. Ultimately, clonal deletion plays a role in central tolerance. Clonal deletion can help protect individuals against autoimmunity, which is when an organism produces and immune response on its own cells. It is one of many methods used by the body in immune tolerance.

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 molecules that have variable (V) regions. These V regions bind not only to things that are foreign to the vertebrate, but also to other V regions within the system. The immune system is therefore seen as a network, with the components connected to each other by V-V interactions.

<span class="mw-page-title-main">Danger model</span>

The danger model of the immune system proposes that it differentiates between components that are capable of causing damage, rather than distinguishing between self and non-self.

References

  1. ↑ Burnet, FM (1976). "A modification of Jerne's theory of antibody production using the concept of clonal selection". CA: A Cancer Journal for Clinicians. 26 (2): 119–21. doi: 10.3322/canjclin.26.2.119 . PMID   816431. S2CID   40609269.
  2. ↑ Cohn, Melvin; Av Mitchison, N.; Paul, William E.; Silverstein, Arthur M.; Talmage, David W.; Weigert, Martin (2007). "Reflections on the clonal-selection theory". Nature Reviews Immunology. 7 (10): 823–830. doi:10.1038/nri2177. PMID   17893695. S2CID   24741671.
  3. ↑ Rajewsky, Klaus (1996). "Clonal selection and learning in the antibody system". Nature. 381 (6585): 751–758. Bibcode:1996Natur.381..751R. doi:10.1038/381751a0. ISSN   0028-0836. PMID   8657279. S2CID   4279640.
  4. ↑ Murphy, Kenneth (2012). Janeway's Immunobiology 8th Edition. New York, NY: Garland Science. ISBN   9780815342434.
  5. 1 2 Jordan, Margaret A; Baxter, Alan G (2007). "Quantitative and qualitative approaches to GOD: the first 10 years of the clonal selection theory". Immunology and Cell Biology. 86 (1): 72–79. doi:10.1038/sj.icb.7100140. PMID   18040281. S2CID   19122290.
  6. 1 2 Nossal, G. J. V.; Lederberg, Joshua (1958). "Antibody Production by Single Cells". Nature. 181 (4620): 1419–1420. Bibcode:1958Natur.181.1419N. doi:10.1038/1811419a0. PMC   2082245 . PMID   13552693.
  7. ↑ Medzhitov, R. (2013). "Pattern Recognition Theory and the Launch of Modern Innate Immunity". The Journal of Immunology. 191 (9): 4473–4474. doi: 10.4049/jimmunol.1302427 . PMID   24141853.
  8. ↑ Burnet, F. M. (1976). "A Modification of Jerne's Theory of Antibody Production using the Concept of Clonal Selection". CA: A Cancer Journal for Clinicians. 26 (2): 119–121. doi: 10.3322/canjclin.26.2.119 . ISSN   0007-9235. PMID   816431. S2CID   40609269.
  9. ↑ Hodgkin, Philip D; Heath, William R; Baxter, Alan G (2007). "The clonal selection theory: 50 years since the revolution". Nature Immunology. 8 (10): 1019–1026. doi:10.1038/ni1007-1019. PMID   17878907. S2CID   29935594.

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