Do Xenobiotics Exacerbate Idiopathic Autoimmunity?

Scripps Research Institute, The, La Jolla CA

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Abstract

7. Project Summary/Abstract Autoimmunity is thought to result from a combination of genetics, environmental triggers, and stochastic events. Although the role of environmental/xenobiotic agents in triggering autoimmunity is well established, it is unclear if idiopathic and induced disease arise by common mechanisms. Classification criteria have been developed to aid in the diagnosis of idiopathic autoimmune diseases however there is a lack of laboratory tools for identifying environmentally induced autoimmunity. This is due to the paucity of studies identifying biomarkers specific for a particular environmental exposure that leads to autoimmunity. This is a significant barrier to our understanding, diagnosis and treatment of xenobiotic-induced autoimmunity. Recent studies show that xenobiotic exposure results in a localized inflammatory response that can include ectopic lymphoid structure (ELS)-like cellular accumulations. ELS arise at sites of non-resolving, chronic inflammation and have been found in target organs of idiopathic autoimmune diseases where they may support the development of fully differentiated autoreactive B cells. In idiopathic autoimmunity innate and adaptive inflammatory mediators occur prior to or concurrent with autoantibodies and these immunological profiles are predictive of development of clinical autoimmune disease. These studies reveal that investigation of the temporal relationships between inflammatory mediators and autoantibodies can distinguish not only between autoantibody positive healthy individuals and patients with disease but also stages in the progression to clinically relevant disease. Such information does not exist in relation to exposure to a specific xenobiotic and the development of xenobiotic-induced autoimmunity. We hypothesize that xenobiotic-induced inflammatory mediators contribute to ectopic lymphoid structure formation and the development of fully differentiated autoreactive B cells producing autoantibody profiles in a xenobiotic and exposure site specific response. To test this we will undertake two distinct, yet overlapping, aims. In Aim 1 we will test the hypothesis that profiles of inflammatory mediators and autoantibodies can discriminate between xenobiotic-induced, xenobiotic-exacerbated, and idiopathic systemic autoimmunity by determining, over time, the serological profiles of autoantibodies and immune mediators relevant to both idiopathic and induced autoimmunity and correlate them with the development of features of disease including innate and adaptive immune cell activation, tissue pathology and immune deposits. In Aim 2 we will test the hypothesis that xenobiotic-induced ELS are sites of autoantibody producing B cell development by identifying conditions necessary for ELS formation and the autoantibody profiles of resident B cells. The data generated from this proposal will help determine whether specific xenobiotic exposures lead to inflammatory mediators, ELS, and autoantibody profiles that can serve as diagnostic criteria for environmental-induced autoimmunity. This will increase our knowledge of the underlying mechanisms of chronic inflammation that can progress to autoimmunity.