TITLE -- COPYRIGHT -- CONTENTS -- NOTE TO READERS OF THE CRITERIA MONOGRAPHS -- PREAMBLE -- WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA ON PRINCIPLES AND METHODS FOR ASSESSING AUTOIMMUNITY ASSOCIATED WITH EXPOSURE TO CHEMICALS -- ACRONYMS AND ABBREVIATIONS -- 1. SUMMARY -- 2. INTRODUCTION AND DEFINITIONS OF AUTOIMMUNITY AND AUTOIMMUNE DISEASE -- 3. INTRODUCTION TO THE IMMUNE SYSTEM: FOCUS ON AUTOIMMUNE MECHANISMS -- 3.1 Introduction -- 3.2 The innate immune response -- 3.3 The adaptive immune response -- 3.3.1 Function -- 3.3.2 Aberrant function -- 3.3.3 Ageing -- 3.4 Mechanisms of self-tolerance -- 3.5 Immunopathogenesis of autoimmune disease -- 3.5.1 Mechanisms of induction -- 3.5.2 Effector mechanisms -- 3.6 Summary -- 4. INTRINSIC FACTORS IN AUTOIMMUNITY -- 4.1 Genetic factors involved in the induction of or susceptibility for autoimmune diseases -- 4.1.1 Probable monogenic autoimmune syndromes -- 4.1.2 Multigenic autoimmune diseases -- 4.1.2.1 Immune deficiencies -- 4.1.2.2 Defects and dysregulation in apoptosis pathways and cell cycle regulation -- 4.1.2.3 Associations with MHC alleles or haplotypes -- 4.1.2.4 Polymorphisms in genes coding for regulatory and effector molecules of the immune system -- 4.1.2.5 Hormones and genes -- 4.1.2.6 Genetic polymorphisms of xenobiotic-metabolizing enzymes -- 4.1.2.7 Genes coding for autoantigens -- 4.1.2.8 Genes coding for enzymes involved in post-translational modification of autoantigens -- 4.1.2.9 DNA methylation -- 4.1.3 Problems and perspectives -- 4.2 Hormonal influence on autoimmunity -- 4.2.1 Pregnancy -- 4.2.1.1 Suppression of autoimmunity -- 4.2.1.2 Stimulation of autoimmunity -- 4.2.2 Psychological stress -- 5. CLINICAL EXPRESSION OF HUMAN AUTOIMMUNE DISEASES -- 5.1 Introduction -- 5.2 Addison disease -- 5.3 ANCA-associated vasculitis -- 5.4 Antiphospholipid syndrome.

5.5 Coeliac disease -- 5.6 Diabetes mellitus -- 5.7 Goodpasture disease -- 5.8 Guillain-Barré syndrome -- 5.9 Autoimmune haemolytic anaemia -- 5.9.1 Warm autoimmune haemolytic anaemia -- 5.9.2 Cold autoimmune haemolytic anaemia -- 5.9.3 Drug-induced autoimmune haemolytic anaemia -- 5.10 Autoimmune hepatitis -- 5.11 Inflammatory bowel disease -- 5.11.1 Crohn disease -- 5.11.2 Ulcerative colitis -- 5.12 Multiple sclerosis -- 5.13 Myasthenia gravis -- 5.14 Myocarditis -- 5.15 Autoimmune myositis -- 5.16 Paraneoplastic neurological syndromes -- 5.17 Pemphigus/pemphigoid -- 5.17.1 Pemphigus -- 5.17.2 Pemphigoid -- 5.18 Pernicious anaemia -- 5.19 Autoimmune polyglandular syndromes -- 5.19.1 APGS type 1 -- 5.19.2 APGS type 2 -- 5.19.3 APGS type 3 -- 5.20 Primary biliary cirrhosis -- 5.21 Psoriasis -- 5.22 Rheumatoid arthritis -- 5.23 Scleroderma (systemic sclerosis) -- 5.24 Sjögren syndrome -- 5.25 Systemic lupus erythematosus and lupus syndrome -- 5.25.1 Systemic lupus erythematosus -- 5.25.2 Lupus syndrome -- 5.26 Autoimmune thrombocytopenia -- 5.26.1 Immune thrombocytopenic purpura -- 5.26.2 Thrombotic thrombocytopenic purpura -- 5.26.3 Drug-induced thrombocytopenia -- 5.27 Autoimmune thyroid diseases -- 5.27.1 Graves disease -- 5.27.2 Hashimoto thyroiditis -- 5.27.3 Iodine and thyroid disease -- 5.28 Diseases with autoimmune components -- 6. EPIDEMIOLOGY -- 6.1 Descriptive epidemiology -- 6.1.1 Demographic patterns -- 6.1.2 Co-morbidity of autoimmune diseases -- 6.2 Epidemiology of autoantibodies -- 6.2.1 Prevalence of autoantibodies in the general population -- 6.2.2 Associations between autoantibodies and environmental exposures -- 7. MECHANISMS OF CHEMICAL-ASSOCIATED AUTOIMMUNE RESPONSES -- 7.1 General -- 7.2 Induction of antigen-specific responses -- 7.2.1 Formation of neoantigens -- 7.2.2 Cross-reactivity -- 7.2.3 Release of non-tolerant epitopes.

7.2.4 Interference with central tolerance -- 7.2.5 Signal 2 increasing mechanisms -- 7.2.5.1 Importance of signal 2 -- 7.2.5.2 Induction of signal 2 -- 7.2.6 Immunoregulation -- 7.3 Other mechanisms -- 8. CHEMICAL/PHYSICAL AGENTS AND AUTOIMMUNITY -- 8.1 Toxic oil syndrome -- 8.1.1 Clinical features of toxic oil syndrome -- 8.1.2 Immune markers in toxic oil syndrome -- 8.1.3 Experimental studies of toxic oil syndrome -- 8.2 TCDD (dioxins) -- 8.3 Pesticides -- 8.3.1 General -- 8.3.2 Hexachlorobenzene -- 8.3.2.1 Accidental poisoning in Turkey -- 8.3.2.2 Adverse immune effects of hexachlorobenzene -- 8.4 Ultraviolet radiation -- 8.5 Silica -- 8.5.1 Introduction to epidemiological studies of silica exposure -- 8.5.2 Occupational silica exposure and systemic autoimmune diseases -- 8.5.3 Experimental studies of immune- and autoimmune-related effects of silica -- 8.5.4 Summary -- 8.6 Heavy metals -- 8.6.1 Mercury -- 8.6.2 Gold -- 8.6.3 Cadmium -- 8.6.4 Other heavy metals -- 8.7 Solvents -- 8.8 Tobacco smoke -- 8.9 Ethanol -- 8.10 Iodine -- 8.11 Therapeutic agents -- 8.11.1 General -- 8.11.2 Hydralazine -- 8.11.3 Procainamide -- 8.11.4 D-Penicillamine -- 8.11.5 Zimeldine -- 8.11.6 Gold drugs -- 8.11.7 Biopharmaceuticals -- 8.11.8 Diethylstilbestrol -- 8.11.8.1 Diethylstilbestrol-induced immune alterations -- 8.11.8.2 Immune effects of diethylstilbestrol in humans -- 8.11.8.3 Conclusion -- 8.12 Silicones -- 8.12.1 Introduction -- 8.12.2 Silicone breast implants and systemic disease -- 8.12.3 Conclusion -- 9. NON-CHEMICAL FACTORS IN AUTOIMMUNITY -- 9.1 Infections: cause of autoimmunity, and immune programming -- 9.1.1 Streptococcus and rheumatic fever -- 9.1.2 Hepatitis C virus -- 9.1.3 Epstein-Barr virus -- 9.1.4 Other infections -- 9.1.5 Absence of infections: the hygiene hypothesis -- 9.2 Vaccine-related factors -- 9.2.1 Vaccines themselves.

9.2.2 Vaccine additives -- 9.3 Dietary factors -- 9.3.1 Caloric restriction and leptin -- 9.3.2 Dietary fat and fatty acid content -- 9.3.3 Antioxidants -- 9.3.4 Vitamin D -- 9.3.5 L-Tryptophan and eosinophilia myalgia syndrome -- 10. ANIMAL MODELS TO ASSESS CHEMICAL-INDUCED AUTOIMMUNITY -- 10.1 Introduction -- 10.2 Rat models -- 10.2.1 The Brown Norway rat model -- 10.2.1.1 Metals -- 10.2.1.2 D-Penicillamine -- 10.2.1.3 Hexachlorobenzene -- 10.2.2 Other rat models -- 10.3 Mouse models -- 10.3.1 Metals -- 10.3.2 Drugs -- 10.3.3 Pristane -- 10.4 Genetically predisposed animal models -- 10.4.1 Systemic lupus erythematosus-prone strains of mice -- 10.5 Other species -- 10.6 Local and popliteal lymph node assays -- 10.6.1 Introduction -- 10.6.2 Primary, secondary, and adoptive popliteal lymph node assays and the lymph node proliferation assay -- 10.6.3 Reporter antigen popliteal lymph node assay -- 10.6.4 Popliteal lymph node assay as predictive assay -- 10.7 Testing strategy -- 11. HUMAN TESTING FOR AUTOIMMUNE DISEASE -- 11.1 Introduction -- 11.2 Methods of human autoantibody detection -- 11.2.1 Indirect immunofluorescence technique -- 11.2.2 Counter-immunoelectrophoresis -- 11.2.3 Haemagglutination -- 11.2.4 Enzyme-linked immunosorbent assay/fluorescent enzyme immunoassay -- 11.2.5 Radioimmunoassay -- 11.2.6 Immunoblotting -- 11.2.7 Multiplex analysis -- 11.3 Selection of detection method -- 11.3.1 Autoantigens -- 11.3.2 Anti-immunoglobulin reagents -- 11.4 Clinical interpretation -- 11.5 Human immunoglobulins -- 11.5.1 Autoimmune disease and human immunoglobulin levels -- 11.5.2 Quantification of human immunoglobulins -- 11.6 Testing in the diagnosis of delayed-type chemical hypersensitivity -- 11.7 Conclusions -- 12. RISK ASSESSMENT -- 12.1 Introduction -- 12.2 Hazard identification of chemical-induced autoimmune disease (animal models).

12.3 Exposure assessment (animal models) -- 12.4 Mode of action -- 12.5 Epidemiological issues -- 12.6 Susceptibility factors -- 12.7 Burden of autoimmune disease -- 13. CONCLUSIONS AND RECOMMENDATIONS -- 13.1 Conclusions -- 13.2 Recommendations -- TERMINOLOGY -- REFERENCES -- RESUME -- RESUMEN.