SUMMARYThe genetic backgrounds of lupus-prone murine models are a valuable resource for studying the influence of environmental exposure on autoimmune diseases in sensitive populations. Epidemiological studies have shown associations between silica exposure and several autoimmune diseases, including scleroderma and systemic lupus erythematosus. To determine whether silica exposure can exacerbate systemic autoimmunity in genetically predisposed animals, New Zealand mixed mice were intranasally instilled twice with saline or saline suspensions of 1 mg silica or 500 m g TiO 2 , a dose equivalent in surface area, and were evaluated with respect to health and immune status. Survival in silica exposed NZM mice was decreased compared to saline and TiO 2 exposed mice. Proteinuria levels were elevated in silica exposed mice. Levels of circulating immune complexes, autoantibodies to nuclear antigen (ANA), histone, and double stranded DNA were measured every two weeks by ELISA. Circulating immune complexes showed a trend towards an increased acceleration in levels in the silica exposed mice compared to saline and TiO 2 exposed mice. ANA levels were significantly higher in silica exposed animals compared to saline and TiO 2 exposed animals (0·237 ± 0·03 versus 0·140 ± 0·029 and 0·125 ± 0·03, P < 0·05) 16 weeks postexposure. Autoantibodies to histone were also significantly elevated after 16 weeks in silica exposed animals compared to saline and TiO 2 exposed animals (0·227 ± 0·03 versus 0·073 ± 0·015 and 0·05 ± 0·03, P < 0·05). In contrast, serum IgG levels were decreased in silica exposed NZM mice compared to the saline controls, however, IgM levels were unaffected. Lungs of the silica-exposed mice had increased inflammatory infiltrates as well as fibrotic lesions characterized by excess collagen deposition. Therefore, although NZM mice are susceptible to SLE, silica exposure significantly exacerbated the course of disease.

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 immunofluorescence. 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.

ObjectiveTo 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.MethodsCases 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.ResultsThe 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).ConclusionThese 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.

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.

ObjectivesIn this review we summarize research on mechanisms through which environmental agents may affect the pathogenesis of lupus, discuss three exposures that have been the focus of research in this area, and propose recommendations for new research initiatives.Data sources and synthesisWe examined studies pertaining to key mechanistic events and specific exposures. Apoptosis leading to increased production or decreased clearance of immunogenic intracellular self-antigens and defective apoptosis of autoreactive immune cells both have been implicated in the loss of self-tolerance. The adjuvant or bystander effect is also needed to produce a sustained autoimmune response. Activation of toll-like receptors is one mechanism through which these effects may occur. Abnormal DNA methylation may also contribute to the pathogenesis of lupus. Each of the specific exposures we examined—Epstein-Barr virus, silica, and trichloroethylene—has been shown, in humans or in mice, to act upon one or more of these pathogenic steps. Specific recommendations for the continued advancement of our understanding of environmental influences on lupus and other autoimmune diseases include the development and use of mouse models with varying degrees of penetrance and manifestations of disease, identification of molecular or physiologic targets of specific exposures, development and use of improved exposure assessment methodologies, and multisite collaborations designed to examine understudied environmental exposures in humans.ConclusionsThe advances made in the past decade concerning our understanding of mechanisms involved in the development of lupus and the influence of environmental agents on this process provide a strong foundation for further developments in this field.

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Epidemiological studies have shown strong associations between silica exposure and several autoimmune diseases, including scleroderma and systemic lupus erythematosus. We previously reported that the New Zealand mixed (NZM) mouse develops silicosis and exacerbated autoimmunity following crystalline silica exposure, including increased levels of autoantibodies, proteinuria, circulating immune complexes, pulmonary fibrosis, and glomerulonephritis. In this study, the NZM mouse was used to examine changes in immune activation following silica exposure by measuring levels of immunoglobulin, cytokines and lymphocyte populations. Levels of immunoglobulin (Ig) G1 were significantly decreased from 1124 +/- 244 microg/ml in saline exposed mice to 614 +/- 204 microg/ml in silica-exposed mice, suggesting a decrease in the Th2 response. The levels of tumor necrosis factor (TNF)-alpha were significantly increased (1.5-fold) in the bronchoalveolar lavage fluid of the silica-exposed mice as compared to the saline-exposed mice. The number of B1a B cells were significantly increased sixfold within the superficial cervical lymph nodes of silica-exposed mice as compared with saline-exposed mice. Following silica exposure, CD4+ T cells significantly increased threefold within the superficial cervical lymph nodes. During this increase in the number of CD4+ T cells, the number of CD4+CD25+ regulatory T cells was not significantly changed, altering the ratio of regulatory T cells to T helper cells from 1:5 to 1:8 following silica exposure. Therefore, the silica-induced alterations in immunoglobulin levels, increased TNF-alpha, increased B1a B cells and CD4+ T cells, with decreased regulatory T cells, may provide an environment that allows for increased autoreactivity. These studies begin to provide possible mechanisms for environmentally induced autoimmune diseases that have been reported in many epidemiological studies.

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.