Immunotoxicological changes and antioxidant system in erytrocytes and neutrophils in silica-exposed workers

Abstract

The rapid growth in our understanding of the biology and genetics of the human immune system, along with new mechanistic insights into the nature of autoimmune disorders, now creates the possibility for better formulated studies of the causation of these disorders. Meanwhile, animal experimental studies of autoimmune phenomena have enhanced our insight into the underlying biology and the plausibility of various environmental factors as causes of autoimmune diseases in humans. Crystalline silica, or quartz, is an abundant mineral found in sand, rock, and soil. High level exposure to respirable silica dust can cause chronic inflammation and fibrosis in the lung and other organs. Studies of occupational groups with high-level silica exposures (e.g. miners) have shown increased rates of autoimmune diseases compared to the expected rates in the general population. Pulmonary deposition of crystaline silica can result in a cycle of lung damage, fibroblast proliferation, and excess collagen production in the lung causing lung fibrosis or silicosis. Upon contact with silica, alveolar macrophages produce a variety of inflammatory and fibrogenic factors such as reactive oxygen species (ROS), lipid mediators, cytokines (IL-I, IL-6, TNF-a), and macrophage-derived growth factors, which are critical to silica-induced pathogenesis. Experimental studies show that silica can act as an adjuvant to non-specifically enhance the immune response. This is one mechanism by which silica mar be involved in the development of autoimmune disease. There have been a number of epidemiological studies examining the relationship between exposure to silica and autoimmune disease and strong associations have been made between systemic lupus erytematosus, rheumatoid arthritis, ANCA associated vasculitis and glomerulonephritis, and scleroderma. However, a significant number of questions remain with regard to the pathophysiology, etiology, mechanisms and multiplicity of effects following silica exposure. For example, silicosis and mineral dust pneumoconiosis have been linked to increased levels of auto-antibodies, immune complexes, and excess production of immunoglobulins, even in the absence of clinical features of specific autoimmune diseases. Many cases of autoimmune disease in silica-exposed individuals have been identified during screening or treatment for silicosis. In addition, in a number of silica exposed individuals, autoimmune disease develops prior to or without overt manifestations of silicosis. It is therefore unclear whether silicosis is simply a marker for high-level silica dust exposure or whether it represents a pathologic process that may predispose some individuals to the development of autoimmune disease. To date, a majority of studies have used disease as an endpoint, and systemic examination of changes in autoimmune parameters in silica exposed individuals are lacking. Thus we have little information on what types of immunologic changes occur, what is the persistence of these changes, how these changes relate to the progression and development of autoimmune disease, and whether these changes relate to the dose of silica received. In order to further advance the field of autoimmunity associated with exposure to environmental factors, an "Exploratory Meeting Epidemiology on Occupational and Environmental Factors Associated with Autoimmunity" was organized in Bilthoven, the Netherlands, in May 2000, which was sponsored by the National Institute of Public Health and the Environment, Bilthoven, The Netherlands; the International Programme on Chemical Safety, Geneva, Switzerland, and the National lnstitute of Environmental Health Sciences, Research Triangle Park, NC, USA. The Rim of meeting in Bilthoven was to decide on the optimal methodologies to assess autoimmunity and autoimmune diseases associated with chemical or environmental exposures in the human population, and to set up collaborative studies of this association in the human population. In this meeting about 30 epidemilogists, clinical immunologists, and immunotoxicologists were present. Among the positive consequences of my participation in this meeting was the set up of the present study in association with Prof Cohen-Tervaert, who is a prominent leading researcher in the area of clinical immunotoxicology. During the last ten years, we have been studying in our laboratory the general effects of lead, pesticides, hexachlorobenzene and mercury on the immune response. Particularly, our studies on the association of occupational exposure to mercury and autoimmunity suggested that the autoregulation leading to autoimmunity described in animals exposed to mercury mar also occur in man. In the present study we intend to advance the understanding of autoimmunity associated with occupational exposure to environmental factors by evaluating immunotoxicological changes and the antioxidant system in erytrocytes and neutrophils in silica-exposed workers. (AU)