in the name of god · • respirable silica can result in chronic, progressive lung disease...

In the name of God

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Environmental factors, Immune system and related

disease

Nafiseh EsmaeilPhD of Immunology

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Overview

•Brief overview of immune system

•Pulmonary Diseases

•Autoimmune Diseases

•Cancer

C •Conclusion

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Overview

•Brief overview of immune system

•Pulmonary Diseases

•Autoimmune Diseases

•Cancer

•Conclusion

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The Immune System

• A complex system that is responsible for distinguishing us from everything foreign to us, and for protecting us against infections and foreign substances. The immune system works to seek and kill invaders.

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Immune cells and other blood cells made in bone marrow -- all are descendents of self-renewing stem cells

Note these are adultstem cells, NOT

embryonic stem cells.

Make variable antibodies

Membrane-bound variable T cell receptors

Kill cells that are missing self proteins

Phagocyte

Phagocyte

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The Lines of Defense System

• First line of defense: Physical barriers that viruses, bacteria must cross– skin covers ~2 m2

– Mucous membranes that line digestive, respiratory, reproductive tracts cover ~400 m2

• Second line of defense: Innate immune system (germline-encoded receptors -- no adaptation to specific pathogens)– Macrophages (Greek for “big eater”), neutrophils, natural killer (NK)

cells– Cytokines -- hormone-like proteins that mediate inflammation,

Complement proteins

• Third line of defense (vertebrates only): Adaptive immune system (adapts to defend against specific pathogens using variable receptors)– B cells make antibodies that vary -- can make an antibody specific for

any new antigen– T cells mediate cellular responses using variable receptors (T cell

receptors; TCRs)1/6/2015 7

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Overview

•Brief overview of immune system

•Pulmonary Diseases

•Autoimmune Diseases

•Cancer

•Conclusion

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Air Pollution and Immune System

In exposure to particulate matters in air pollution(PM10,PM2.5), different aspects of immune system causes to different 

pulmonary diseases. 

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AJCEI 20131/6/2015 13

Allergic Asthma

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Chronic Obstructive Pulmonary Disease(COPD)

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Pulmonary Arterial Hypertension(PAH)

• PAH is characterized by increased pulmonary vascular resistance due to remodeling and occlusion of the pulmonary arterioles.

• Left untreated, PAH leads irremediably to right ventricular (RV) hypertrophy and eventually failure from pressure and volume overload resulting in death within 2– 3 years.

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Pulmonary Arterial Hypertension(PAH) and Immune System

Figure.2. Inflammation‐mediated vascular remodeling in PAH. Nature Reviews | Cardiology  Volume 8 | August 20111/6/2015 17

Overview

•Brief overview of immune system

•Pulmonary Diseases

•Autoimmune Diseases

•Cancer

•Conclusion

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Environment and Autoimmune Diseases

•Background – autoimmune diseases

•Two examples of environmental exposures – what do we know, what do we need to learn

Solvents Silica dust

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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 ArkansasAnsari and Kahn, University of Texas Medical Branch

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Solvents and Autoimmune Disease: Questions????

•Which solvents or pollutants?

•Which diseases? 

• Does the variability in environmental exposures result in a variability in disease risk in humans?

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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

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Occupational Exposure to Silica Dust

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Silica Dust and Autoimmune Disease

• In highly exposed occupations (men), increased risk (RR > 10) seen in several systemic diseasesCase‐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

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Environmental considerations and Multiple Sclerosis

• The identification of environmental risk factors is difficult because no single factor in isolation appears to be responsible for the development of the disease.

• The most involved environmental factors in the development of MS are vitamin D deficiency and low exposure to sunlight, cigarette smoking .

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Environmental considerations and Multiple Sclerosis

• Microbil infection:• Antigen mimicry • Bystander effects• The environmental sources include slime mold

(Dictyostelium fasciculatum), bacteria that can be found in stratified freshwater lakes (Chlorobiumchlorochromatii), and bacteria that can be present in some processed foods such as gelatin and milk (Anoxybacillus flavithermus).

• Commensal bacteria: Antibiotic,Nutrition,Cesarian1/6/2015 29

Environmental considerations and RomatoidArteritis

Studies carried out looking for environmental factors important in RA have identified numerous candidates. These include smoking and a number of infectious diseases.

Potential candidates implicated in an infectious aetiologyhave included Epstein-Barr virus (EBV), Mycobacterium tuberculosis, Escherichia coli, Proteus mirabilis, retroviruses and parvovirus B19.

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Environmental considerations and Lupus Erythmatosis

The environmental contributors are difficult to isolate, but researchers have established links between lupus and a variety of toxins, such as cigarette smoke, silica, and mercury.

Infectious disease agents such as the Epstein-Barr Virus (EBV, which causes mononucleosis or “mono”), herpes zoster virus (the virus that causes shingles), and cytomegalovirus have also been implicated.

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Overview

•Brief overview of immune system

•Pulmonary Diseases

•Autoimmune Diseases

•Cancer

•Conclusion

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THE NATURE OF CANCER 

• Cells continue to divide when new cells are not needed, and a growth or extra mass of cells called a tumor is formed. Over time, changes may take place in tumor cells that cause them to invade and interfere with the function of normal tissues. 

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THE NATURE OF CANCER 

• An alteration in growth‐promoting genes, known as oncogenes, for example, can signal the cell to divide out of control, similar to having a gas pedal stuck to the floorboard. On the other hand, an alteration in tumor suppressor genes, which normally serve as brakes for dividing cells, will allow cells with damaged DNA to continue dividing, rather than repairing the DNA or eliminating the injured cells. 

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Alteration in oncogenes and tumor suppressor genes

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Immune response to Tumor Antigens

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WHAT SUBSTANCES IN THE ENVIRONMENT ARE KNOWN TO CAUSE OR ARE LIKELY TO CAUSE CANCER IN HUMANS? WHERE ARE THEY FOUND? 

• More than 200 agents listed in the Report on Carcinogens. 

• Tobacco • Exposure to the carcinogens in tobacco products accounts for about one‐third of all cancer deaths in the United States each year. 

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Diet/Weight/Physical Inactivity 

Several studies show that heavy consumption of red and preserved meats, salt‐preserved foods, and salt probably increase the risk of colorectal and stomach cancers. There is also evidence that a diet rich in fruits and vegetables may decrease the risks of esophageal, stomach, and colorectal cancers. Alcoholic drinks 

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• Ultraviolet radiation • Viruses and bacteria 

Cancer and Environmental Factors

HPV,HCV,HBV,EBV, Helicobacter pylori 

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• Pesticides : ethylene oxide, amitrole, some chlorophenoxy herbicides, DDT, dimethylhydrazine, hexachlorobenzene, hexamethylphosphoramide, chlordecone, lead acetate, lindane, mirex, nitrofen, and toxaphene. 

Cancer and Environmental Factors

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• Ionizing radiation Everyone is exposed to very small doses of ionizing radiation from cosmic rays (rays that enter the earth’s atmosphere from outer space). Radiation from this source may account for a very small percentage (about 1 percent) of our total cancer risk. 

Cancer and Environmental Factors

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• Solvents :  benzene, carbon tetrachloride, chloroform, dichloromethane (methylene chloride), tetrachloroethylene, and trichloroethylene.

• Human studies are suggestive, but not conclusive, except for benzene. Therefore, with the exception of benzene, these substances are listed as likely to be cancer‐causing in humans. 

Cancer and Environmental Factors

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• Fibers, fine particles, and dust : Exposures to various fibers, fine particles, and dust occur in several industrial settings and are associated with increased cancer risks. Exposure can also occur in nonindustrial settings. 

• Asbestos fibers• Ceramic fibers • Silica dusts• Wood dust  

Cancer and Environmental Factors

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• Polycyclic aromatic hydrocarbons (PAHs):PAHs in air are produced by burning wood and fuel for homes. They are also contained in gasoline and diesel exhaust, soot, coke, cigar and cigarette smoke, and charcoal‐broiled foods • Metals: • Arsenic compounds , Beryllium compounds , cadmium 

compounds 

Cancer and Environmental Factors

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Overview

•Brief overview of immune system

•Pulmonary Diseases

•Autoimmune Diseases

•Cancer

•Conclusion

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• 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 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)

Diseases and Environmental Factors

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Thanks For Your Attention

ReferencesAutoimmune 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.

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ReferencesSolvents (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.

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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.

References

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