Clonal selection

Abstract: There are three current theoretical inter pretations of antibody production which, following Talmage (1957), may be referredto as the directtemplate theoryinwhich theantigenservesasa template against which the specific pat tern of the antibody is synthesized, the indirect template theory which postu lates a secondary template incorporated intothegenetic-synthetic processesof the antibody producing cells (Burnet, 1956), and the natural selection theory in which the antigen acts essentially by selection for excess production of natu ral antibody molecules of corresponding type (Jerne, 1955). The two latter theories were devised primarily to account for two sets of phe nomena for which the direct template theory seems quite irrelevant. The first is the absence of immunological re sponse to “¿ self― constituents and the related phenomena of immunological tolerance; thesecondistheevidencethat antibody production can continue in the absence of antigen. Some means for the recognition anddifferentiation ofpoten tially antigenic components of the body from foreign organic material must be provided in any acceptable formulation. In Burnet and Fenner's (1949) account, a positive recognition of “¿ self― material was ascribed to the presence of “¿ self markers― in all potentially antigenic macromolecules, and corresponding recognition units in the scavenger cells of the body. At the time it was regarded as inconceivable that a mechanism could exist which would recognise in positive fashion all foreign material and no at tempt was made to devise one, despite the fact that we have always recognised the clumsy character of the self-marker, self-recognition scheme. It is the great virtue of Jerne's hypoth esis that it provides an approach to this alternative method of recognising self from not self. There is no doubt about the presence in all mammalian or avian sera of a wide range of reactive globulins whichcan legitimately be called“¿ natu ral antibodies.― Jerne assumed that amongst these globulin molecules were all the possible patterns needed for spe cific immunological type reaction with any antigen, except for those patterns corresponding to body antigens which would be eliminated by in vivo absorp tion. When a foreign antigen enters the blood it unites, according to Jerne's scheme, with one of the corresponding natural antibody molecules. The com plex is taken up by a phagocytic cell in which the antigen plays no further part, but the antibody globulin provokes the Reprinted from The Australian Journal of Science 20 (3): 67-69, 1957.

Abstract: Antibody specificity is determined by structural v-genes that code for the amino acid sequences of the variable regions of antibody polypeptide chains. The present hypothesis proposes that the germ-cells of an animal carry a set of v-genes determining the combining sites of antibodies directed against a complete set of a certain class of histocompatibility antigens of the species to which this animal belongs. The evolutionary development of this set of v-genes in phylogeny is traced back to the requirements for cell to cell recognition in all metazoa. The hypothesis leads to a distinction between two populations of antigen-sensitive cells. One population consists of cells forming antibodies against foreign antigens; these lymphocytes have arisen as mutants in clones descending from lymphocytic stem cells which expressed v-genes belonging to the subset (subset S) coding for antibody against histocompatibility antigens that the individual happens to possess. The other population consists of allograft rejecting lymphocytes that express v-genes of the remaining subset (subset A) coding for antibody against histocompatibility antigens of the species that the individual does not possess. The primary lymphoid organs are viewed as mutant-breeding organs. In these organs (e. g. in the thymus), the proliferation of lymphocytes expressing the v-genes of subset S and the subsequent suppression of the cells of these “forbidden” clones, leads to the selection of mutant cells expressing v-genes that have been modified by spontaneous random somatic mutation. This process generates self-tolerance as well as a diverse population of antigen-sensitive cells that reflects antibody diversity. The proliferation in the primary lymphoid organs of lymphocytes expressing v-genes of subset A generates the antigen-sensitive cell population that is responsible for allo-aggression. The theory explains how a functional immune system can develop through a selection pressure exerted by self-antigens, starting during a period in early ontogeny that precedes clonal selection by foreign antigens. The hypothesis provides explanations for the variability of the N-terminal regions of antibody polypeptide chains, for the dominant genetic control of specific immune responsiveness by histocompatibility alleles, for the relative preponderance of antigen-sensitive cells directed against allogeneic histocompatibility antigens, for antibody-idiotypes, for allelic exclusion, for the precommitment of any given antigen-sensitive lymphocyte to form antibodies of only one molecular species and for the cellular dynamics in the primary lymphoid tissues.