Assessment of Autoimmune Responses Associated with Asbestos Exposure in Libby, Montana, USA

Systemic autoimmune responses are associated with certain environmental exposures, including crystalline particles such as silica. Positive antinuclear antibody (ANA) tests have been reported in small cohorts exposed to asbestos, but many questions remain regarding the prevalence, pattern, and significance of autoantibodies associated with asbestos exposures. The population in Libby, Montana, provides a unique opportunity for such a study because of both occupational and environmental exposures that have occurred as a result of the mining of asbestos-contaminated vermiculite near the community. As part of a multifaceted assessment of the impact of asbestos exposures on this population, this study explored the possibility of exacerbated autoimmune responses. Age- and sex-matched sets of 50 serum samples from Libby and Missoula, Montana (unexposed), were tested for ANA on HEp-2 cells using indirect immune, fluorescence. Data included frequency of positive tests, ANA titers, staining patterns, and scored fluorescence intensity, all against known controls. Serum immunoglobulin A (IgA), rheumatoid factor, and antibodies to extractable nuclear antigen (ENA) were also tested. The Libby samples showed significantly higher frequency of positive ANA and ENA tests, increased mean fluorescence intensity and titers of the ANAs, and higher serum IgA, compared with Missoula samples. In the Libby samples, positive correlations were found between ANA titers and both lung disease severity and extent of exposure. The results support the hypothesis that asbestos exposure is associated with autoimmune responses and suggests that a relationship exists between those responses and asbestos-related disease processes

Separation and Characterization of Respirable Amphibole Fibers from Libby, Montana

The vermiculite mine in Libby, Montana, was in operation for over 70 yr and was contaminated with asbestos-like amphibole fibers. The mining, processing, and shipping of this vermiculite led to significant fiber inhalation exposure throughout the community, and residents of Libby have developed numerous pulmonary diseases such as lung cancer and mesothelioma. The present study describes the separation of Libby 6-mix into respirable and nonrespirable size fractions by means of aqueous elutriation. The elutriator, designed to separate fibers with aerodynamic diameters smaller than 2.5 μm (respirable) from larger fibers, used an upward flow rate of 3.4 × 10−4 cm s−1. The resultant respirable fraction constituted only 13% of the raw Libby 6-mix mass, and less than 2% of the fibers in the elutriated fraction had aerodynamic diameters exceeding 2.5 μm. Surface area of the elutriated fibers was 5.3 m−2 g−1, compared to 0.53 m−2 g−1 for the raw fibers. There were no detectable differences in chemical composition between the larger and smaller fibers. Such harvesting of respirable fractions will allow toxicological studies to be conducted within a controlled laboratory setting, utilizing fiber sizes that may more accurately simulate historical exposure of Libby residents’ lungs. Importantly, this work describes a method that allows the use of material enriched in more uniform respirable material than raw Libby 6-mix, making comparisons with other known fiber preparations more valid on a mass basis

Nested Case–Control Study of Autoimmune Disease in an Asbestos-Exposed Population

OBJECTIVE: To explore the potential association between asbestos exposure and risk of autoimmune disease, we conducted a case–control study among a cohort of 7,307 current and former residents of Libby, Montana, a community with historical occupational and environmental exposure to asbestos-contaminated vermiculite. METHODS: Cases were defined as those who reported having one of three systemic autoimmune diseases (SAIDs): systemic lupus erythematosus, scleroderma, or rheumatoid arthritis (RA). Controls were randomly selected at a 3:1 ratio from among the remaining 6,813 screening participants using frequency-matched age and sex groupings. RESULTS: The odds ratios (ORs) and 95% confidence intervals (CIs) for SAIDs among those ≥ 65 years of age who had worked for the vermiculite mining company were 2.14 (95% CI, 0.90–5.10) for all SAIDs and 3.23 (95% CI, 1.31–7.96) for RA. In this age group, exposure to asbestos while in the military was also an independent risk factor, resulting in a tripling in risk. Other measures of occupational exposure to vermiculite indicated 54% and 65% increased risk for SAIDs and RA, respectively. Those who had reported frequent contact with vermiculite through various exposure pathways also demonstrated elevated risk for SAIDs and RA. We found increasing risk estimates for SAIDs with increasing numbers of reported vermiculite exposure pathways (p < 0.001). CONCLUSION: These preliminary findings support the hypothesis that asbestos exposure is associated with autoimmune disease. Refined measurements of asbestos exposure and SAID status among this cohort will help to further clarify the relationship between these variables

Asbestos-induced autoimmunity in C57Bl/6 mice

Environmental impacts on autoimmunity have significant public health implications. Epidemiological studies have shown associations between exposure to airborne silicates, such as crystalline silica or asbestos, and autoimmunity, but the etiology remains unclear. The purpose of this study was to test the hypothesis that asbestos could lead to a specific pattern of autoantibodies and pathology indicative of systemic autoimmune disease (SAID). Female C57Bl/6 mice were instilled intratracheally with 2 doses × 60 µg/mouse of amphibole asbestos (tremolite), wollastonite (a nonfibrogenic control fiber), or saline alone. Serum samples were collected and urine was checked for protein bi-weekly for 7 months. By 26 weeks, the asbestos-instilled animals had a significantly higher frequency of positive anti-nuclear antibody (ANA) tests compared to wollastonite and saline groups. The majority of positive ANAs showed homogeneous or combined homogeneous/speckled patterns, and tested positive for antibodies to dsDNA and SSA/Ro 52. Serum isotyping showed no significant changes in IgM, IgA, or IgG subclasses. However, there was an overall decrease in the mean IgG serum concentration in asbestos-instilled mice. IgG immune complex deposition was demonstrated in the kidneys of asbestos-instilled mice, with evidence of glomerular and tubule abnormalities suggestive of glomerulonephritis. Flow cytometry demonstrated moderate changes in the percentages of CD25 + Tsuppressor cells and B1a B-cells in the superficial cervical lymph nodes of the asbestos-instilled mice. These data demonstrate that asbestos leads to immunologic changes consistent with the development of autoimmunity. This study provides a non-autoimmune prone murine model for use in future elucidation of mechanisms involved in asbestos-induced autoimmune disease

Nonpulmonary Outcomes of Asbestos Exposure

The adverse pulmonary effects of asbestos are well accepted in scientific circles. However, the extrapulmonary consequences of asbestos exposure are not as clearly defined. In this review the potential for asbestos to produce diseases of the peritoneum, immune, gastrointestinal (GIT), and reproductive systems are explored as evidenced in published, peer-reviewed literature. Several hundred epidemiological, in vivo, and in vitro publications analyzing the extrapulmonary effects of asbestos were used as sources to arrive at the conclusions and to establish areas needing further study. In order to be considered, each study had to monitor extrapulmonary outcomes following exposure to asbestos. The literature supports a strong association between asbestos exposure and peritoneal neoplasms. Correlations between asbestos exposure and immune-related disease are less conclusive; nevertheless, it was concluded from the combined autoimmune studies that there is a possibility for a higher-than-expected risk of systemic autoimmune disease among asbestos-exposed populations. In general, the GIT effects of asbestos exposure appear to be minimal, with the most likely outcome being development of stomach cancer. However, IARC recently concluded the evidence to support asbestos-induced stomach cancer to be “limited.” The strongest evidence for reproductive disease due to asbestos is in regard to ovarian cancer. Unfortunately, effects on fertility and the developing fetus are under-studied. The possibility of other asbestos-induced health effects does exist. These include brain-related tumors, blood disorders due to the mutagenic and hemolytic properties of asbestos, and peritoneal fibrosis. It is clear from the literature that the adverse properties of asbestos are not confined to the pulmonary system

SBML Level 3: an extensible format for the exchange and reuse of biological models

Systems biology has experienced dramatic growth in the number, size, and complexity of computational models. To reproduce simulation results and reuse models, researchers must exchange unambiguous model descriptions. We review the latest edition of the Systems Biology Markup Language (SBML), a format designed for this purpose. A community of modelers and software authors developed SBML Level 3 over the past decade. Its modular form consists of a core suited to representing reaction-based models and packages that extend the core with features suited to other model types including constraint-based models, reaction-diffusion models, logical network models, and rule-based models. The format leverages two decades of SBML and a rich software ecosystem that transformed how systems biologists build and interact with models. More recently, the rise of multiscale models of whole cells and organs, and new data sources such as single-cell measurements and live imaging, has precipitated new ways of integrating data with models. We provide our perspectives on the challenges presented by these developments and how SBML Level 3 provides the foundation needed to support this evolution

Autoimmunity and Asbestos Exposure

Despite a body of evidence supporting an association between asbestos exposure and autoantibodies indicative of systemic autoimmunity, such as antinuclear antibodies (ANA), a strong epidemiological link has never been made to specific autoimmune diseases. This is in contrast with another silicate dust, crystalline silica, for which there is considerable evidence linking exposure to diseases such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Instead, the asbestos literature is heavily focused on cancer, including mesothelioma and pulmonary carcinoma. Possible contributing factors to the absence of a stronger epidemiological association between asbestos and autoimmune disease include (a) a lack of statistical power due to relatively small or diffuse exposure cohorts, (b) exposure misclassification, (c) latency of clinical disease, (d) mild or subclinical entities that remain undetected or masked by other pathologies, or (e) effects that are specific to certain fiber types, so that analyses on mixed exposures do not reach statistical significance. This review summarizes epidemiological, animal model, and in vitro data related to asbestos exposures and autoimmunity. These combined data help build toward a better understanding of the fiber-associated factors contributing to immune dysfunction that may raise the risk of autoimmunity and the possible contribution to asbestos-related pulmonary disease