Environment, Lifestyles, and Climate Change: The Many Nongenetic Contributors to The Long and Winding Road to Autoimmune Diseases

Abstract

A critical unanswered question is what is causing the increase in the prevalence of autoimmunity and autoimmune diseases around the world. Given the rapidity of change, this is likely the result of major recent alterations in our exposures to environmental risk factors for these diseases. More evidence is becoming available that the evolution of autoimmune disease, years or even decades in the making, results from multiple exposures that alter susceptible genomes and immune systems over time. Exposures during sensitive phases in key developmental or hormonal periods may set the stage for the effects of later exposures. It is likely that synergistic and additive impacts of exposure mixtures result in chronic low-level inflammation. This inflammation may eventually pass thresholds that lead to immune system activation and autoimmunity, and with further molecular and pathologic changes, the complete clinical syndrome emerges. Much work remains to be done to define the mechanisms and risk and protective factors for autoimmune conditions. However, evidence points to a variety of pollutants, xenobiotics, infections, occupational exposures, medications, smoking, psychosocial stressors, changes in diet, obesity, exercise, and sleep patterns, as well as climate change impacts of increased heat, storms, floods, wildfires, droughts, UV radiation, malnutrition, and changing infections, as possible contributors. Substantial investments in defining the role of causal factors, in whom and when their effects are most important, the necessary and sufficient gene-environment interactions, improved diagnostics and therapies, and preventive strategies are needed now to limit the many negative personal, societal, and financial impacts that will otherwise occur.

Figure 1

The multiple contributors to the long and winding road to autoimmune diseases. Numerous interacting environmental and lifestyle risk factors, as well as the impacts of climate change, in the relative absence of protective factors may work together over years or even decades to result in autoimmune diseases. Many more insults or activations of the immune system are likely needed for disease development during this process than we currently appreciate. The continuous impacts of exposures on our genes, hormones, immune systems, and metabolism—perhaps in a particular sequence of synergistic events and at particularly vulnerable periods during life as indicated in the yellow boxes—may result in chronic inflammation, autoimmunity, early signs and symptoms, and eventually fully developed clinical syndromes in a process that may be called “disease by a thousand cuts.”