Infection, evolution and autoimmunity: a hypothesis

摘要

The study of disease resistance to intracellular parasites in mice has identified resistance genes whose action appears to be on macrophage activation. Increased macrophage activation in turn leads to the preferential induction of Th-1-type T-helper cell responses, and the down-regulation of Th-2-type responses. Autoreactive T cells of the Th-1 type, normally controlled by contra-acting Th-2 cells, can be activated in experimental systems, leading to autoreactive responses. Study of resistance to myco-bacteria and the other intracellular parasites is in its infancy in humans, although human equivalents of the bcg resistance gene have been identified and sequenced, and appear to have similar polymorphisms to those seen in the mouse. The unique phenomenon of the Western TB epidemic, with its high mortality rate for people in the reproductive age group, must have exerted selective pressure for those characteristics, such as the ability to mount Th-1-type responses, which aid mycobacterial elimination. We suggest that the shift towards Th-1 -type responses, selected by disease exposure and mediated by the human bcg gene, has, as in the mouse, created an immune environment in which autoreactive Th-1 cells (demonstrated to be present in the normal immune repertoire) are incompletely controlled, giving rise to the potential to develop auto-immunity. Hence the immune background of an antigen-presenting system which inherently favours the development of Th-1-type responses rather than Th-2, represents the autoimmune phenotype. This rather suggests that the autoimmune phenotype, rather than being abnormal, represents one end of the spectrum of normality.