Cumulative environmental changes, skewed antigen exposure, and the increase of allergy.

The human immune system evolved over many hundreds of million of years in the ancestors of vertebrates and mammals to defend them against infectious and parasitic organisms in their natural habitats. By the time the Primates and Rodentia orders diverged about 88 million years ago, the human immune system was largely configured. From about 125,000 years ago, marked by the use of fire, Homo sapiens began to make substantial changes in their living environment and lifestyle. Here, we examine those changes in two phases, before and after the Industrial Revolution, and analyze their impact on the exposure of our immune system to infectious organisms and to harmless environmental antigens. Our analyses show that the cumulative changes in environment and lifestyle in many regions of the world have drastically altered the pattern by which humans are exposed to infectious organisms and harmless environmental antigens and that these changes have profoundly impacted the function of the immune system and enhanced the development of allergy. Our analyses expand the hygiene hypothesis by taking into consideration the immunological impact of a broader range of antigen exposure changes than simply decreased microbial infection during childhood. We subsequently examine the proposed mechanisms of TH1 to TH2 shift and Treg downregulation with regard to the hygiene hypothesis and present an immunological basis for the increased activity of the IgE-mediated pathway in allergic patients. In our "skewed antigen exposure" theory, we propose that, for many individuals living in modern societies: (i) reduced exposure to a large variety of infectious organisms and environmental antigens and (ii) increased exposure to a small variety of environmental antigens, resulting from the cumulative changes in individuals' living environment and lifestyle, together alter the balance of the immune system, and increase production of IgE and the sensitization of mast cells toward a limited variety environmental antigens unique to affected individuals, resulting in an overall increase in allergy.