Clonal Selection

Norman R Klinman, The Scripps Research Institute, California, USA

By the mid-1950s numerous theories had been proposed to account for the remarkable capacity of the immune system to respond specifically to the myriad of foreign antigenic determinants. One group of theories, championed by Alexander, Mudd, Hau-rowitz, Pauling and Karush, relied on the entry of antigen into antibody-forming cells to serve as a template for the synthesis of complementary antibodies, and, as such, were considered 'instructional'. A novel 'natural selection theory', put forward by Jerne in 1955, suggested that all potential antibodies pre-existed as 'natural antibodies' and appropriate cells, internalizing antigen complexed to a given antibody, would duplicate the internalized antibody. In 1957, Talmage suggested that cells might express their potential antibody as a cell surface receptor, and in 1958 Macfarlane Burnet fully elaborated the 'clonal selection theory'. This theory, like Jerne's theory, proposed that appropriate antibodies pre-existed in the absence of antigen 'instruction' but that the diverse array of antibodies was the product of multiple cell clones, each capable of expressing a single antibody product. The major tenets of the hypothesis were as follows (all quotations excerpted from Burnet (1959), see Further reading):

1. 'in the animal there exist clones of mesenchymal cells each carrying immunologically reactive sites corresponding in appropriate complementary fashion to one (or possibly a small number of) potential antigenic determinants'.

2. These clones provide 'a population of cells which, when an appropriate stage of development has been reached, are capable of producing the population of globulin molecules which collectively provide the normal antibodies'.

3. In order that antigen-antibody complexes localize to 'cells, which are genetically determined to produce the corresponding type of antibody molecule - it would simplify matters a great deal if the antigen were in a position to react with natural antibody or a pattern equivalent thereto on the surface of the cell which produced it'.

4. 'When an antigen is introduced it will make contact with a cell of the corresponding clone, presumably a lymphocyte, and by so doing stimulate it to produce in one way or another more globulin molecules of the cell's characteristic type.'

5. That this 'stimulation initiates proliferation'.

6. 'that active sites on cell surface or globulin molecule can be modified to a wider reactivity by somatic mutation, provides the chief agent to allow change in antibody character as immunization proceeds.'

7. 'Self-not-self recognition means simply that all those clones which would recognize (that is, produce antibody against) a self-component have been eliminated in embryonic life. All the rest are retained.'

8. The secondary response is accounted for thus: 'on the simplest form of the hypothesis - the primary stimulus finds only a few examples of the appropriate clones; by the time of the secondary stimulus, many more individuals of the selected clones are accessible'.

Over the past 30 years each of these postulates has to a considerable extent been validated by experimental observation. Although other elements of Burnet's thesis are not as prescient as the above, it should be noted that prior to 1960 neither the molecular basis for antibody formation nor the T cell-B cell dichotomy and cell-cell collaboration were understood.

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