THE QUANTAL THEORY OF IMMUNITY

The immune system is remarkable because it has the power to discriminate between everything in the environment, to which it reacts, vs. all molecules and structures of the body, to which it does not react. This is termed appropriately “self-nonself discrimination”, and is one of the fundamental characteristics of all higher organisms that allows them to maintain their integrity and to ward off all unwanted and potentially toxic materials in the environment. Exactly how this discrimination occurs has puzzled immunologists for at least a century, and it has only been now that enough knowledge about the immune system has accumulated that it is feasible to begin to try to unravel this mystery.

The Nobel Prize was awarded to MacFarlane Burnet and Peter Medawar in 1960 for the Theory of Clonal Selection (Burnet) and the demonstration that self-tolerance was acquired during fetal life (Medawar). As a result of experiments by many investigators performed since then, it is now realized that a process termed central tolerance occurs, whereby most lymphocytes arising in the bone marrow and thymus that are capable of reacting with self are removed through a process termed programmed cell death or apoptosis. However, it has remained unknown as to how the lymphocytes recognize self, and therefore how they know that they should die vs. survive to leave their sites of origin to populate the lymph nodes spleen and blood, so as to make up the immune system.

In addition, it is also now realized that this is not the whole story, and that some cells capable of reacting with self are not destroyed, but actually leave the central areas and circulate throughout the body. However, these “self-reactive” lymphocytes are held in check, so that they do not react with self, which has been termed the “horror autochthonous”. The process whereby these potential self-reactive cells are held in check is termed “peripheral tolerance”. However, giving the process a name does not mean that the process is understood mechanistically, i.e. how it happens.

As a result of the advances in many areas of science, we now know much more about how the immune system recognizes antigens, and consequently how it is able to discriminate between self vs. nonself. In order to understand and integrate all of the information, it is necessary to account for the behavior of the entire immune system, as well as each individual cell within the whole system, and finally at the level of the molecules expressed by each cell that are critical for triggering the cell.

The Quantal Theory of Immunity is based upon the Clonal Selection Theory, originally proposed by Burnet in 1957, which posited that cells that recognize a foreign molecule or microbe do so at the clonal level, and thereby are “selected”. Once this recognition occurs, each selected cell proliferates giving rise to a clone of cells that are identical to the original cell. Once the frequency of the antigen-reactive cells has increased, the population of clonally derived cells then acquires the capacity of responding to the invading foreign particles, thus facilitating their removal.

Accordingly, the problem confronting us is simple. How can one explain how some cells can proliferate, whereas other cells, which do not recognize the antigen, remain quiescent? The answer, as proposed by the Quantal Theory, is that cells that have recognized the antigen, express receptors on their cell surface for interleukin-2 (IL2). As well, antigen-reactive cells also are stimulated to produce IL2. Subsequently, the IL2/IL2-receptor interaction signals the cell to proliferate. Detailed studies, which we performed more than 20 years ago, showed that cells only respond to IL2 by proliferating when a critical number of IL2-receptors have been triggered. Thus, cells expressing a large number of IL2-receptors will begin to proliferate before cells with fewer IL2-receptors. When the critical number of IL2/IL2-R interactions has been reached the cell responds in an all-or-none (quantal) fashion.

We now know that receptors for antigens behave in an identical manner. Thus antigen activation of the T cell Antigen Receptors (TCR) is also quantal, and until the cell receives a critical number of “hits” it will not be activated to produce IL2 or express IL2-receptors on the cell surface. Thus, the cells and the whole system respond in a “digital” fashion, thereby exquisitely sensing changes in the environment. If you are interested in exploring immunity further and learning more about the Quantal Theory of Immunity, please browse through this web site.