Silica accelerated systemic autoimmune disease in lupus-prone New Zealand mixed mice

Abstract

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.

Cell markers, cytokines, and immune parameters in cement mason apprentices

“…Regarding premorbid exposure to silica, only in mice (11,25) has there been a close examination of the relevant changes in systemic cytokine and lymphocyte marker profiles in this context. Recognizing that both immune activation and loss of peripheral tolerance to self are necessary for autoimmune phenomena, Pfau et al (25) have hypothesized that apoptosis exposes antigenic epitopes, otherwise nonexposed, that lead to reaction by the innate immune system.…”

“…Patients with silicosis and other individuals highly exposed to silica have been shown to have increased autoantibodies (8,9), immunoglobulins, and immune complexes (10). However, a recent study of lupusprone mice demonstrated a decrease in serum immunoglobulin levels associated with the development of autoimmunity (11), and decreased levels of immunoglobulins were observed in foundry and pottery workers working in their jobs for an average of ϳ15 years (12).…”

Particulate Matter Immunomodulatory Effects on Autoantibody Development in New Zealand Mixed Mice

“…These mice spontaneously develop pathologic hallmarks of SLE between 6 months and 1 year of age (Rudofsky and Lawrence, 1999;Brown et al, 2003). The most characteristic of these traits are the development of anti-ssDNA, anti-dsDNA, anti-histone, anti-nuclear antigen (ANA), and anti-IgG autoantibodies as well as increased levels of circulating immune complexes (Rudofsky and Lawrence, 1999;Brown et al, 2003).…”

“…Lupus-prone New Zealand mixed mice provide an appropriate model to assess the effects of environmental agents on the progression of autoimmune diseases such as systemic lupus erythematosus (SLE) in a sensitive population (Rudofsky and Lawrence, 1999;Brown et al, 2003). NZM mice are a moderately lupus-prone strain with reduced disease penetrance, therefore an environmental influence on SLE in these mice would be more readily observed (Rudofsky and Lawrence, 1999;Brown et al, 2003).…”

“…NZM mice are a moderately lupus-prone strain with reduced disease penetrance, therefore an environmental influence on SLE in these mice would be more readily observed (Rudofsky and Lawrence, 1999;Brown et al, 2003). These mice spontaneously develop pathologic hallmarks of SLE between 6 months and 1 year of age (Rudofsky and Lawrence, 1999;Brown et al, 2003). The most characteristic of these traits are the development of anti-ssDNA, anti-dsDNA, anti-histone, anti-nuclear antigen (ANA), and anti-IgG autoantibodies as well as increased levels of circulating immune complexes (Rudofsky and Lawrence, 1999;Brown et al, 2003).…”