Objective
The objective of this pilot study is to investigate the relationship between exposure to environmental contaminants, such as per- and polyfluoroalkyl substance (PFAS), phenols and phthalates and future development of type 1 diabetes (T1D), multiple sclerosis (MS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) in individuals at-risk for these diseases. The overall goal is to identify a common mechanism behind the effect of environmental contaminants on these autoimmune diseases, in order to develop potential environmental interventions that can reduce the risk of autoimmune disease development.
Background Rationale
The burden of autoimmune diseases is growing worldwide. Type 1 diabetes (T1D), multiple sclerosis (MS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) are autoimmune diseases thought to develop via a complex interplay between inherent genetic risk and environmental exposures that can trigger autoimmunity initially and then lead to clinical disease. Individuals who ultimately develop an autoimmune disease exhibit a period of disease evolution termed ‘preclinical disease’ prior to the onset of clinically apparent disease. These diseases develop on the foundation of genetic risk, which predisposes individuals to developing future disease given certain exposures (both internal and external). Genetic risk can be defined as presence of genetic risk markers and/or family history of disease. The next period is characterized by asymptomatic autoimmunity manifest as the appearance of autoantibodies (in T1D, RA and SLE), which can precede the development of clinical disease by months or years, suggesting that the search for a potential causal exposure should start prior to the appearance of autoantibodies. However, not everyone with autoantibodies progresses to clinical disease, so another time to search for an exposure that may be impacting progression is during the transition from the autoantibody-positive stage to the development of clinical disease. Although there are no known autoantibody biomarkers for the pre-clinical state of MS, increasing evidence suggests there is a prodrome that lasts years prior to the onset of first symptoms and diagnosis of clinical disease. The complete etiologies of these four autoimmune diseases remain largely unknown. Genetic factors are thought to account for about half of the disease risk, suggesting that environmental factors explain the remaining half of the risk. The prevalence of autoimmunity and autoimmune diseases is increasing, which suggests an environmental influence and makes finding the cause of this increase an urgent public health problem. Increasing exposure to a wide range of environmental contaminants and additives may be an explanation for this increase in disease. We are interested in investigating the relationship between exposure to environmental contaminants, such as PFAS, phenols and phthalates and future development of T1D, MS, SLE, and RA in individuals at-risk for these diseases. We will accomplish this by using prospective cohorts of at-risk individuals that are followed for the development of clinical disease. At-risk is defined as having a family history of disease, possessing a genetic risk marker or being autoantibody positive. While many exposures have been implicated in the development of autoimmune diseases, a comprehensive, prospective and systematic assessment of environmental contaminants in these diseases has yet to be conducted.
Description of Project
The burden of autoimmune diseases is growing worldwide. Type 1 diabetes (T1D), multiple sclerosis (MS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) are autoimmune diseases thought to develop via a complex interplay between inherent genetic risk and environmental exposures that can trigger autoimmunity initially and then lead to clinical disease. Individuals who ultimately develop an autoimmune disease exhibit a period of disease evolution termed ‘preclinical disease’ prior to the onset of clinically apparent disease. These diseases develop on the foundation of genetic risk, which predisposes individuals to developing future disease given certain exposures (both internal and external). The next period is characterized by asymptomatic autoimmunity manifest as the appearance of autoantibodies (in T1D, RA and SLE), which can precede the development of clinical disease by months or years, suggesting that the search for a potential causal exposure should start prior to the appearance of autoantibodies. However, not everyone with autoantibodies progresses to clinical disease, so another time to search for an exposure that may be impacting progression is during the transition from the autoantibody-positive stage to the development of clinical disease. Although there are no known autoantibody biomarkers for the pre-clinical state of MS, increasing evidence suggests there is a prodrome that lasts years prior to the onset of first symptoms and diagnosis of clinical disease. The complete etiologies of these four autoimmune diseases remain largely unknown. Genetic factors are thought to account for about half of the disease risk, suggesting that environmental factors explain the remaining half of the risk. The prevalence of autoimmunity and autoimmune diseases is increasing, which suggests an environmental influence and makes finding the cause of this increase an urgent public health problem. Increasing exposure to a wide range of environmental contaminants and additives may be an explanation for this increase in disease. We are interested in investigating the relationship between exposure to environmental contaminants, such as per- and polyfluoroalkyl substance (PFAS), phenols and phthalates and future development of T1D, MS, SLE, and RA in individuals at-risk for these diseases. We will accomplish this by using prospective cohorts of at-risk individuals that are followed for the development of clinical disease. At-risk is defined as having a family history of disease, possessing a genetic risk marker or being autoantibody positive. The overall goal is to identify if environmental contaminants are associated with these autoimmune diseases, and whether there may be a common mechanism behind the effect of environmental contaminants, in order to develop potential environmental interventions that can reduce the risk of autoimmune disease development.
Anticipated Outcome
We anticipate that higher levels (and mixtures) of environmental contaminants are associated with an increased risk of progression to T1D, MS, RA, and SLE.
Relevance to T1D
This pilot study will evaluate whether exposure to environmental contaminants increases the risk of progressing to autoimmune disease in individuals at-risk for T1D, MS, RA and SLE. This will provide essential data to allow us to build a more extensive investigation of the role of environmental exposures in multiple autoimmune diseases and to determine common mechanisms of the exposure in autoimmune disease. This work is relevant to those that are at-risk for T1D, MS, RA and SLE because it will yield preliminary data to drive future research towards potential intervention options to prevent these diseases. Identifying these environmental risk factors is critical for identifying potential causes of autoimmunity, supporting public health interventions, and developing or testing effective treatments to reduce the risk of disease progression. For example, if this work reveals positive associations between PFAS exposure and autoimmune disease progression, then there is stronger evidence to support research into nascent methods to remove serum PFAS, or develop targeted treatments. However, clinical trials are needed to test the efficacy and effectiveness of PFAS-reducing treatments. Additionally, results may help support the implementation of population-level interventions and policies that reduce PFAS exposure.