A theoretical analysis of the phenotypic expression of immune response genes

This study presents a theoretical analysis of the phenotypic expression of the products of immune response (Ir) genes linked to the major histocompatibility complex. Recent evidence indicates that animals with “low”‐responder Ir genotypes can be induced to express adequate immune responses by minor variations in the manner or site of immunization. Hence, it is unlikely that Ir genes code for defective structural products in low‐responder animals. A quantitative model is presented of the behavior of Ir genes based on two principal elements: (a) clones of lymphocytes compete for prominence through processes of growth, differentiation and feedback suppression, and (b) Ir gene products influence the affinities of lymphocyte clones for antigenic determinants, without coding for the lymphocyte receptors for antigen. The theoretical analysis of this model leads to the conclusion that small differences in affinity on the level of single cells can be amplified through differential population growth and competition between clones of cells to produce a final response that appears “all‐or‐none” on a population level. Therefore, high or low responsiveness based on Ir genes can be explained by small shifts in the strength of interaction parameters. These small shifts can result from variation in H‐2 alleles, the mode of immunization, or the array of determinants on the immunogen; factors that were observed experimentally. These shifts in interaction parameters account for the observed flexibility of phenotypic expression of Ir genes. The model explains a number of immunological observations by a few basic facts or assumptions, and avoids the problem of postulating the existence of defects to account for low responsiveness. It aims at clarifying the relationship between systemic, macroscopic observations and the underlying cellular parameters. The translation of cellular characteristics into patterns of behavior manifested by populations of cells may not necessarily result in an averaging out of the characteristics, but could also accentuate them.