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.