Genetic control of immune response: New concepts and old misconceptions

Abstract

A common misconception about the genetic control of the immune response is that it concerns a few selected antigens. In fact, the immune response to any antigen recognized by T-lymphocytes is genetically controlled. To be able to demonstrate this control is another matter: needed are nonresponders to a particular antigen that can pass nonresponsiveness to their progeny. Only then, by mating responders with nonresponders and following the segregation of responsiveness among the progeny, can it be shown that a gene or genes are responsible for the difference in the phenotype. Another misconception is that the genetic control of immune response is exerted primarily or exclusively by the genes belonging to the major histocompatibility complex of a species (Fig. 1). Probably a large number of immune response genes map outside the Mhc. Only a few of these genes have been identified, possibly because immunologists are too preoccupied with the Mhc-associated Ir genes. Some non-Mhc genes function at the B-lymphocyte level, 1 others at the T cell receptor level, 2 and still others at the level of the macrophage? The Mhc-associated Ir genes are, however, the only Ir genes for which the mechanism of action is known. The third misconception is that the Mhc-associated Ir genes all map in the class II region, therefore sometimes referred to as the Ir or I region. This misconception has historical roots in that the class II-associated Ir genes were the first Ir genes discovered. 4,5 The discovery of class I-associated Ir genes was made more than 10 years later 6 in a form that some immunologists still do not take for what it is. I shall return to this point later. What are the Mhc-associated Ir genes? And what is the mechanism of their action? The answer to these two