The hardscrabble hypothesis: a reduction in chronic tissue damage has increased the incidence of autoimmune disease

The adaptive immune system, fine tuned through millions of years of vertebrate evolution, discriminates self from foreign antigens through the deletion of auto-reactive clones and/or tolerization to self antigens. In this system, commonly encountered antigens should be recognized as self while rarely encountered antigens such as microbial or cancer derived molecules should be recognized as foreign. Throughout evolutionary history, the availability of cryptic self-antigens for presentation was enhanced though immune processing of damaged tissues due to infections, parasites and trauma - in other words, the hardscrabble conditions that prevailed throughout the vast majority of our evolutionary past. In situations where chronic tissue injury is reduced there is an increase in the incidence of autoimmune disease. A unifying hypothesis is thereby provided to explain the major epidemiological trends in autoimmune diseases, namely, (1) an historic increase in incidence, (2) increase in the incidence with increasing latitude, (3) increase in the incidence with higher socioeconomic status.