Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004364 (autoimmune disease)
 24,845 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Silica exposure has been associated with development of autoantibodies and systemic autoimmune disease, but mechanisms leading to these events are unknown. This study tested the hypothesis that autoantibodies associated with silica exposure may recognize epitopes on apoptotic macrophages. Serum was obtained from New Zealand mixed (NZM) mice, in which instillation of silica significantly increased production of autoantibodies. Sera were selected that were shown, by indirect immunofluorescence (IIF), to be positive or negative for antinuclear antibodies (ANA) following silica or saline exposure, respectively. Apoptosis was induced in MH-S murine macrophages using silica or cycloheximide. The ability of the autoantibodies to preferentially recognize apoptotic cells was tested using IIF and ELISA. Apoptotic cells, but not live cells, were shown to stain with serum from ANA-positive mice, but not from ANA-negative serum. In addition, binding of antibodies from ANA-positive mice was shown to be significantly greater on cellular lysates from apoptotic cells, but not necrotic or live cell lysates using an ELISA based assay. Finally, inhibition of apoptosis with a broad spectrum caspase inhibitor, Boc-D-FMK, blocked the increased binding by the autoantibodies. These results suggest that autoantibodies from mice with silica-exacerbated autoimmune responses recognize specific epitopes on apoptotic macrophages. It is therefore possible that silica-induced apoptosis may exacerbate autoimmune responses by exposing antigenic epitopes to the immune system.
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PMID:Silica-exposed mice generate autoantibodies to apoptotic cells. 1475 72

Environmental crystalline silica exposure has been associated with formation of autoantibodies and development of systemic autoimmune disease, but the mechanisms leading to these events are unknown. Silica exposure in autoimmune-prone New Zealand mixed (NZM) mice results in a significant exacerbation of systemic autoimmunity as measured by increases in autoantibodies and glomerulonephritis. Previous studies have suggested that silica-induced apoptosis of alveolar macrophages (AM) contributes to the generation of the autoantibodies and disease. Rottlerin has been reported to inhibit apoptosis in many cell types, possibly through direct or indirect effects on PKCdelta. In this study, rottlerin reduced silica-induced apoptosis in bone marrow-derived macrophages as measured by DNA fragmentation. In NZM mice, RNA and protein levels of PKCdelta were significantly elevated in AM 14 wk after silica exposure. Therefore, rottlerin was used to reduce apoptosis of AM and evaluate the progress of silica-exacerbated systemic autoimmune disease. Fourteen weeks after silica exposure, NZM mice had increased levels of anti-histone autoantibodies, high proteinuria, and glomerulonephritis. However, silica-instilled mice that also received weekly instillations of rottlerin had significantly lower levels of proteinuria, anti-histone autoantibodies, complement C3, and IgG deposition within the kidney. Weekly instillations of rottlerin in silica-instilled NZM mice also inhibited the upregulation of PKCdelta in AM. Together, these data demonstrate that in vivo treatment with rottlerin significantly decreased the exacerbation of autoimmunity by silica exposure.
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PMID:Effects of rottlerin on silica-exacerbated systemic autoimmune disease in New Zealand mixed mice. 1604 Jun 31

Inhalation of dust containing crystalline silica is associated with a number of acute and chronic diseases including systemic autoimmune diseases. Evidence for the link with autoimmune disease comes from epidemiological studies linking occupational exposure to crystalline silica dust with the systemic autoimmune diseases systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Although little is known regarding the mechanism by which silica exposure leads to systemic autoimmune disease, there is a voluminous literature on silica exposure and silicosis that may help identify immune processes that precede development of autoimmunity. The pathophysiology of silicosis consists of deposition of silica particles in the alveoli of the lung. Ingestion of these particles by macrophages initiates an inflammatory response, which stimulates fibroblasts to proliferate and produce collagen. Silica particles are encased by collagen leading to fibrosis and the nodular lesions characteristic of the disease. The steps in the development of silicosis, including acute and chronic inflammation and fibrosis, have different molecular and cellular requirements, suggesting that silica-induced inflammation and fibrosis may be mechanistically separate. Significantly, it is unclear whether silica-induced inflammation and fibrosis contribute similarly to the development of autoimmunity. Nonetheless, the findings from human and animal model studies are consistent with an autoimmune pathogenesis that begins with activation of the innate immune system leading to proinflammatory cytokine production, pulmonary inflammation leading to activation of adaptive immunity, breaking of tolerance, and autoantibodies and tissue damage. The variable frequency of these immunological features following silica exposure suggests substantial genetic involvement and gene/environment interaction in silica-induced autoimmunity. However, numerous questions remain unanswered.
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PMID:Silica, Silicosis, and Autoimmunity. 2701 76