The Environment and Autoimmune Disease

1. The Environment and Autoimmune Disease Glinda S. Cooper, Ph.D. US Environmental Protection Agency National Center for Environmental Assessment Washington, DC cooper.glinda@epa.gov The views expressed are those of the author and do not necessarily reflect the views or policies of the U.S.EPA.

2. Environment and Autoimmune Disease • Background – autoimmune diseases • Two examples of environmental exposures – what do we know, what do we need to learn Solvents Silica dust

3. Burden of Autoimmune Diseases incidence prevalence percent median per 100,000 PY per 100,000 female age rheumatoid arthritis 23.7 860 75% 58 thyroiditis 21.8 792 95% 59 type 1 diabetes12.2 192 48% 10 multiple sclerosis3.2 58 64% 37 lupus (SLE) 7.3 24* 88% 40 Sjögren 3.9 14 94% 59 systemic vasculitis 1.5 15 43% 63 systemic sclerosis 0.8 4 92% 50 (scleroderma) * Most recent studies report prevalence rates of 80 – 120 per 100,000 adapted from DL Jacobson et al, Clin Immunol Immunopath 1997;84:223-43

4. Genes and Autoimmune Disease • For some autoimmune diseases, disease concordance in identical twins is higher than in most other diseases studied. For other autoimmune diseases, the genetic component is relatively small. Identical Twin Concordance systemic sclerosis 5% rheumatoid arthritis 0 - 15% multiple sclerosis 10 - 25% hyperthyroidism 15 - 20% type 1 diabetes 15 - 40% lupus (SLE) 25 - 35% • Genetic susceptibility is an important determinant of autoimmune disease - but it’s not the only determinant.

5. Solvents • More than 10 epidemiologic studies reporting 2-3 fold increased risk of scleroderma with history of occupational exposure to “solvents.” • Numerous experimental studies of trichloroethylene in lupus-prone MRL +/+ mouse. This strain typically develops a lupus condition, with a low level of renal involvement after age 12 months.Two groups: Kathleen Gilbert, University of Arkansas Ansari and Kahn, University of Texas Medical Branch

6. Experimental Studies: Trichloroethylene in MRL +/+ Mouse • With exposure (primarily via drinking water), doses 21-400 mg/kg-day: • At 4 weeks: increased autoantibody production, activation of CD4+ T cells, and interferon-γ • At 32 weeks: autoimmune hepatitis, diffuse alopecia seen; metabolite produced skin ulcerations • Effects mediated through inhibition of anti-CD3 -mediated apoptosis of CD4+ T cells; influence of specific metabolites (CYP2E1 pathway) demonstrated • A recent series of studies focus on oxidative stress, and specifically lipid-peroxidation-derived aldehydes in TCE-induced autoimmune disease .

7. Solvents and Autoimmune Disease: Questions • Which solvents? • Which diseases? (scleroderma and what else?) • What is the trichloroethylene - MRL +/+ mouse model telling us? • Does the variability in environmental exposures result in a variability in disease risk in humans?

8. Crystalline Silica (Silicon Dioxide) • Crystalline silica (quartz) - abundant mineral in sand, rock, clay • Respirable silica can result in chronic, progressive lung disease (silicosis) • Traditional “dusty trades” include mining, construction, ceramic manufacturing, pottery; grinding • “Adjuvant” - generalized stimulation of immune response • Silica is different from silicone

9. Occupational Exposure to Silica Dust

10. In highly exposed occupations (men), increased risk • (RR > 10) seen in several systemic diseases • Case-series • 1914 UK stone masons (scleroderma) • 1950’s South Africa gold miners (scleroderma) • UK coal miners (rheumatoid arthritis) • Cohort studies • 1980’s South Africa miners (rheumatoid arthritis, scleroderma) • Finland granite workers (rheumatoid arthritis) • 1990’s Silicosis patients (RA, scleroderma, SLE) • 1993 Spain scouring powder plant (SLE and scleroderma) • 1995 Germany uranium miners (SLE, scleroderma) • Case-Control studies • 1990’s UK, US, Australia (scleroderma) • 1990’s+ Italy, Belgium, US (systemic vasculitis) • 2000’s US (SLE) – men and women, population-based studies Silica Dust and Autoimmune Disease

11. Series of studies from Pfau and Holian, University of Montana • NZM lupus-prone mouse • increased autoantibody production, inflammatory cytokines, lung fibrosis, increased CD4+ T cells • silica-induced cell death (apoptosis) of macrophages results in impaired ability to clear damaged cells; cellular debris becomes targets for autoantibody formation Experimental Studies: Silica Dust

12. Silica Dust and Autoimmune Disease: Questions • Similar effects with other inhaled particles (or other adjuvants)? If so, which ones? • Intensity, duration, or cumulative exposure? (Developing the optimal approach to prevention depends on knowing what types of exposure you need to eliminate) • Are people with systemic inflammatory autoimmune diseases particularly vulnerable to an adverse effect of particulate matter (air pollution) – increased cardiovascular risk ?

13. Environment and Autoimmune Disease: Summary • A key question for many different exposures is the effect at (relatively) low levels of exposure (lower than seen in occupational settings; lower than used in some experimental studies) • Significant advances in past 10 years has been seen in the trichloroethylene and in research – examples of bridging and cross-fertilization of epidemiology, immunology, and toxicology • In addition to thinking about disease etiology, we need to think about effect of various exposures on disease progression and complications (particularly within the context of inflammatory response and cardiovascular disease)

14. References Autoimmune Disease Background and Epidemiology • Walsh SJ, Rau LM. Autoimmune diseases: a leading cause of death among young and middle-aged women in the United States. Am J Public Health 2000;90:1463-1466. • Jacobson DL, Gange SJ, Rose NR, Graham NMH. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997;84:223-243. • Cooper GS, Stroehla BC. The epidemiology of autoimmune diseases. Autoimmun Rev 2003:119-125. Genetic Susceptibility • Cooper GS, Miller FW, Pandey JP. The role of genetic factors in autoimmune disease: implications for environmental research. Environ Health Perspect 1999;107 Suppl 5:693-700. • Deapen D, Escalante A, Weinrib L, et al.: A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum 1992;35:311‑318. • Feghali-Bostwick C, Medsger TA Jr., Wright TM. Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum 2003;48:1956-1963. Environmental Exposures and Autoimmune Disease - General • Cooper GS, Gilbert KM, Greidinger EL, James JA, Pfau JC, Reinlib L, Richardson B, Rose NR. Recent Advances and Opportunities in Research on Lupus: Environmental Influences and Mechanisms of Disease. Environ Health Perspect 2008;116:695-702. • Cooper GS. Occupational Exposures and Risk of Rheumatoid Arthritis: Continued Advances and Opportunities for Research. J Rheum 2008; 35:950-2.

15. References Solvents (epidemiologic studies) • Aryal BK, Khuder SA, Schaub EA. Meta-analysis of systemic sclerosis and exposure to solvents. Am J Ind Med 2001;40:271-74. • Garabrant DH, Lacey JV, Jr., Laing TJ, Gillespie BW, Mayes MD, Cooper BC, et al. Scleroderma and solvent exposure among women. Am J Epidemiol 2003;157:493-500. Solvents (animal studies) • Blossom SJ, Pumford NR, Gilbert KM. Activation and attenuation of apoptosis of CD4+ T cells following in vivo exposure to two common environmental toxicants, trichloroacetaldehyde hydrate and trichloroacetic acid. J Autoimmun 2004;23:211-20. • Blossom SJ, Doss JC, Gilbert KM. Chronic exposure to a trichloroethylene metabolite in autoimmune-prone MRL +/+ mice promotes immune modulation and alopecia. Toxicol Sci 2007;95:401-11. • Cai P, Konig R, Khan MP, Qiu S, Kaphalia BS, Ansari GA. Autoimmune response in MRL +/+ mice following treatment with dichloroacetyl chloride or dichloroacetic anhydride. Toxicol Appl Pharmacol 2006;216:248-255. • Griffin JM, Gilbert KM, Pumford NR. Inhibition of CYP2E1 reverses CD4+ T-cell alterations in trichloroethylene-treated MRL+/+ mice. Toxicol Sci 2000;54:384-389. • Griffin JM, Blossom SJ, Jackson SK, Gilbert KM, Pumford NR. Trichloroethylene accelerates an autoimmune response by Th1 T cell activation in MRL +/+ mice. Immunopharmacology 2000;46:123-37. • Gilbert KM, Whitlow AB, Pumford NR. Environmental contaminant and disinfection by-product trichloroacetaldehyde stimulates T cells in vitro. Int Immunopharmacol 2004 4:25-36. • Wang G, Cai P, Ansari GA, Khan MF. Oxidative and nitrosative stress in trichloroethene-mediated autoimmune response. Toxicology 2007;229:186-93. • Wang G, Konig R, ANsari GA, Khan MR. Lipid peroxidation-derived aldehyde-protein adducts contribute to trichloroethene-mediated autoimmunity via activation of CD4(+) T cells. Free Radic Biol Med 2008;44:1475-82.

16. References References Silica (epidemiological studies) • Parks CG, Conrad K, Cooper GS: Occupational exposure to crystalline silica and autoimmune disease. Environ Health Perspect 1999;107 Suppl 5:793-802. • Parks CG, Cooper GS, Nylander-French L, Sanderson WR, Dement JM, Cohen PL, Dooley MA, Treadwell EL, St. Clair EW, Gilkeson GS, Hoppin JA, Savitz DA. Occupation exposure to crystalline silica and risk of systemic lupus erythematosus: a population-based, case-control study in the southeastern United States. Arthritis Rheum 2002; 46:1840-1850. (Erratum in: Arthritis Rheum. 2004;50:1694). Silica (animal studies) • Brown JM, Schwanke CM, Pershouse MA, Pfau JC, Holian A. Effects of rottlerin on silica-exacerbated systemic autoimmune disease in New Zealand mixed mice. Am J Physiol Lung Cell Mol Physiol 2005;289:L990-L998. • Brown JM, Archer AJ, Pfau JC, Holian A. 2003. Silica accelerated systemic autoimmune disease in lupus-prone New Zealand mixed mice. Clin Exp Immunol 131:415-421. • Brown JM, Pfau JC, Holian A. 2004a. Immunoglobulin and lymphocyte responses following silica exposure in New Zealand mixed mice. Inhal Toxicol 16:133-139. • Brown JM, Pfau JC, Pershouse MA, Holian A. 2004b. Silica, apoptosis, and autoimmunity. J Immunotoxicol 1:177-187. • Brown JM, Swindle EJ, Kushnir-Sukhov NM, Holian A, Metcalfe DD. 2007. Silica-directed mast cell activation is enhanced by scavenger receptors. Am J Respir Cell Mol Biol 2007 36:43-52. • Pfau JC, Brown JM, Holian A. Silica-exposed mice generate autoantibodies to apoptotic cells. Toxicology 2004;195:167-176.