The clonal selection hypothesis has become a widely accepted model for how the immune system responds to infection and how certain types of B and T lymphocytes are selected for destruction of specific antigens invading the body.
Four predictions of the clonal selection hypothesis
- Each lymphocyte bears a single type of receptor with a unique specificity (by V(D)J recombination).
- Receptor occupation is required for cell activation.
- The differentiated effector cells derived from an activated lymphocyte will bear receptors of identical specificity as the parental cell.
- Those lymphocytes bearing receptors for self molecules will be deleted at an early stage.
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 comes, 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. This was a selection (though not clonal 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 may happen 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 a clone producing the same antibody.
Later in the same year, Australian immunologist Frank Macfarlane Burnet worked on this model, and was the first to name it "clonal selection theory." Burnet 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, which results in immunity to that antigen. In 1958, Sir Gustav Nossal and Joshua Lederberg showed that one B cell always produces only one antibody, which was the first evidence for clonal selection theory.
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 without an immune response as long as this occurs early in the organism’s development. There are a vast number of lymphocytes occurring in the immune system ranging from cells which are tolerant of self tissue to cells which are not tolerant of self tissue. However, only cells that are tolerant to self tissue will survive the embryonic stage. If non-self tissue is introduced, the lymphocytes which develop will be the ones which included 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 tissues transplantation. Burnet and Medawar shared the Nobel Prize for physiology and 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 for medicine or physiology in 1984, largely for his contributions to immune network theory.
- Rajewsky, Klaus (1996). "Clonal selection and learning in the antibody system". Nature 381 (6585): 751–758. doi:10.1038/381751a0. ISSN 0028-0836.
- 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.
- Nossal, G. J. V. & Lederberg, J. 1958. Antibody production by single cells. Nature 181:1419-1420
- "Biology in Context - The Spectrum of Life" Authors, Peter Aubusson, Eileen Kennedy.
- Forsdyke, D.R. 1995. The Origins of the Clonal Selection Theory of Immunity FASEB. Journal 9:164-66
- Animation of clonal selection from the Walter & Elisa Hall institute.