Abstract
Over the past few decades, autoimmune diseases have seen a steady upsurge in global prevalence and associated costs. While the exact reasons for these increases are unknown, this trend has been attributed to increased exposure to environmental agents that are also risk factors for autoimmune disease, including xenobiotic chemicals, infections, lifestyle changes, stressful life events, and altered microbiomes, with subsequent biochemical modifications that influence immune tolerance. This review explores current understanding of mechanisms relating to environmental agents contributing to autoimmune diseases. Here we focus on the key initial mechanistic pathways that include environmentally-induced DNA damage, epigenetic alterations, protein post-translational modifications - such as hapten formation, altered autoantigen structure and cellular locations - tissue barrier disruptions, molecular mimicry, and neuroendocrine dysregulation. The processes by which these initial effects result in secondary changes to influence immunological mechanisms, which can then contribute to the development of autoimmunity and autoimmune disorders, are also discussed. While understanding of the mechanisms of environmental triggers in autoimmune diseases has expanded in recent years, and they are considered fundamental architects of autoimmune phenotypes that imprint specific molecular signatures with prognostic and therapeutic value, many important issues remain unaddressed. These include conducting longitudinal exposome studies, defining the necessary and sufficient gene-environment interactions, understanding the synergistic effects of exposure mixtures, of exposure timing and susceptibility, and impacts of chronic psychosocial stress on immune function. Addressing these knowledge gaps and advancing our understanding of the underlying causal pathways are vital for developing preventive strategies and creating safer and more effective therapies for autoimmune conditions.