Asbestos-Induced Autoimmunity in C57Bl/6 Mice

Abstract

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.

Evaluation of anti-nuclear antibodies and kidney pathology in Lewis rats following exposure to Libby amphibole asbestos

“…High titers of ANA are common in SLE, particularly anti-dsDNA (Fenton et al, 2009), yet a causal link has not been established between asbestos exposure and lupus. Pfau et al (2008) did report elevated ANA in C57BL/6 mice 26 weeks following exposure to a single dose of tremolite, including anti-dsDNA and anti-SS-A (also identified in the Libby population [Pfau et al, 2005]), as well as renal pathology similar to that observed in SLE, and concluded that tremolite exposure led to systemic autoimmune disease in this model. Furthermore, this group reported that C57Bl/6 mice exposed to tremolite developed antibodies to the ENA SSA/Ro52, an autoantibody routinely found in serum from individuals with SLE (Hassan et al, 2002).…”

“…The link between elevated ANA in the serum and asbestos exposure is well established (Turner-Warwick & Parkes, 1970;Pfau et al, 2005Pfau et al, , 2008, although ANA are common in healthy individuals and high titer ANA are sometimes observed in healthy individuals (Li et al, 2011). High titers of ANA are common in SLE, particularly anti-dsDNA (Fenton et al, 2009), yet a causal link has not been established between asbestos exposure and lupus.…”

“…Histopathology preparation and staining were performed as described by Pfau et al (2008). Left and right kidneys were removed and fixed overnight in Histochoice Tissue Fixative (Sigma, St. Louis, MO).…”

“…However, those studies did not attempt to correlate increased ANA with other forms of SAID because it was assumed that the immunological changes associated with RA were likely to overwhelm serum markers for other types of SAID in these RA models. Pfau et al (2008) reported that exposure to tremolite, one of the amphibole fiber types found in LA, gradually increased ANA and other indicators of SLE (deposition of complement and IgG in the kidneys) in mice over 28 weeks.…”

A historical perspective of immunotoxicology

“…Correlations between asbestos exposure and autoimmune disease also suggest a higher-than-expected risk of systemic autoimmune disease among asbestos-exposed populations (Bunderson-Schelvan et al, 2011), although in general this association is less compelling than that found with silica. An animal model has been developed for asbestos-induced autoimmune disease, which is significant since the method employs normal rather than genetically prone mice (Pfau et al, 2008).…”