Risk of Autoimmune Disease: Challenges for Immunotoxicity Testing

  • Rodney R. Dietert
  • Janice M. Dietert
  • Jerrie Gavalchin
Part of the Methods in Molecular Biology™ book series (MIMB, volume 598)


Autoimmunity represents a potentially diverse and complex category among the range of adverse outcomes for detection with immunotoxicity testing. For this reason, the risk of autoimmune disease is discussed in this overview chapter with additional mention among the later specific protocol chapters. Improvements in clinical diagnostic capabilities and disease recognition have led to a more accurate picture of the extent of autoimmune diseases across different human populations. While the risk of any single autoimmune disease remains modest when compared with that of lung or heart disease, the cumulative prevalence of autoimmune diseases is both significant and increasing. Autoimmune diseases are usually viewed in the context of the damaged tissue or organ (e.g., as a thyroid, gastrointestinal, cardiovascular or neurological disease). But improved recognition that underlying immune dysfunction can connect the risks for these as well as other diseases is critical for optimizing risk assessment. Since autoimmune diseases are chronic in nature with many first appearing in children or in young adults, these diseases exert a serious impact on both health care costs and quality of life. This chapter provides a discussion of the issues that should be considered with immunotoxicity testing for risk of autoimmunity.

Key words

Autoimmunity Autoimmune disease Target organ Systemic T cell populations Immune dysregulation Chronic inflammation Microbial triggers 


  1. 1.
    Fairweather D, Frisancho-Kiss S, Rose NR (2008) Sex differences in autoimmune disease from a pathological perspective. Am J Pathol 173:600–609CrossRefPubMedGoogle Scholar
  2. 2.
    The Autoimmune Disease Coordinating Committee of the National Institutes of Health (2005) Report to Congress, March. NIH Publication No. 05–5140 Google Scholar
  3. 3.
    Shoenfeld Y, Selmi C, Zimlichman E, Gershwin ME (2008) The autoimmunologist: geoepidemiology, a new center of gravity, and prime time for autoimmunity. J Autoimmun 31:325–330CrossRefPubMedGoogle Scholar
  4. 4.
    Dietert RD, Piepenbrink MS (2008) The managed immune system: protecting the womb to delay the tomb. Hum Exp Toxicol 27:129–134CrossRefPubMedGoogle Scholar
  5. 5.
    Dietert RR, Zelikoff JT (2009) Pediatric immune dysfunction and health risks following early-life immune insult. Curr Pediatr Rev 5(1):36–51CrossRefGoogle Scholar
  6. 6.
    Abedi-Valugerdi M (2009) Mercury and silver induce B cell activation and anti-nucleolar autoantibody production in outbred mouse stocks: are environmental factors more important than the susceptibility genes in connection with autoimmunity? Clin Exp Immunol 155:117–124CrossRefPubMedGoogle Scholar
  7. 7.
    Cooper GS, Miller FW (2008) Environmental influences on autoimmunity and autoimmune disease. In: Luebke R, House R, Kimber I (eds) Immunotoxicology and immunopharmacology, 3rd edn. CRC Press, Boca Raton, FL, pp 437–453Google Scholar
  8. 8.
    Silbergeld EK, Silva IA, Nyland JF (2005) Mercury and autoimmunity: implications for occupational and environmental health. Toxicol Appl Pharmacol 207:282–292CrossRefPubMedGoogle Scholar
  9. 9.
    Havarinasab S, Bjorn E, Ekstrand J, Hultman P (2007) Dose and Hg species determine the T-helper cell activation in murine autoimmunity. Toxicology 229:23–32CrossRefPubMedGoogle Scholar
  10. 10.
    Pilones K, Lai ZW, Gavalchan J (2007) Prenatal HgCl(2) exposure alters fetal cell phenotypes. J Immunotoxicol 4:295–301CrossRefPubMedGoogle Scholar
  11. 11.
    Bunn TL, Marsh JA, Dietert RR (2000) Gender differences in developmental immunotoxicity to lead in the chicken: analysis following a single early low-level exposure in ovo. J Toxicol Environ Health A 61:677–693CrossRefPubMedGoogle Scholar
  12. 12.
    Hudson CA, Cao L, Kasten-Jolly J, Kirkwood JN, Lawrence DA (2003) Susceptibility of lupus-prone NZM mouse strains to lead exacerbation of systemic lupus erythematosus symptoms. J Toxicol Environ Health A 66:895–918CrossRefPubMedGoogle Scholar
  13. 13.
    Havarinasab S, Johansson U, Pollard KM, Hultman P (2007) Gold causes genetically determined autoimmune and immunostimulatory responses in mice. Clin Exp Immunol 150:179–188CrossRefPubMedGoogle Scholar
  14. 14.
    Blossom SJ, Doss JC (2007) Trichloroethylene alters central and peripheral immune function in autoimmune-prone MRL(+/+) mice following continuous developmental and early life exposure. J Immunotoxicol 4:129–141CrossRefPubMedGoogle Scholar
  15. 15.
    Cripps DH, Peters HA, Gocman A, Dogramici I (1984) Porphyria turcica due to hexachlorobenzene: a 20 to 30 year follow-up study on 204 patients. Br J Dermatol 111:412–422CrossRefGoogle Scholar
  16. 16.
    Michielsen CC, van Loveren H, Vos JG (1999) The role of the immune system in hexachlorobenzene-induced toxicity. Environ Health Perspect 107:783–792CrossRefPubMedGoogle Scholar
  17. 17.
    Vidali M, Stewart SF, Rolla R, Daly AK, Chen Y, Mottaran E, Jones DE, Leathart JB, Day CP, Albano E (2003) Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease. Hepatology 37:410–419CrossRefPubMedGoogle Scholar
  18. 18.
    Brown JM, Pfau JC, Pershouse MA, Holian A (2005) Silica, apoptosis, and autoimmunity. J Immunotoxicol 1:177–187CrossRefPubMedGoogle Scholar
  19. 19.
    Otsuki T, Maeda M, Murakami S, Hayashi H, Miura Y, Kusaka M, Nakano T, Fukuoka K, Kishimoto T, Hyodoh F, Ueki A, Nishimura Y (2007) Immunological effects of silica and asbestos. Cell Mol Immunol 4:261–268PubMedGoogle Scholar
  20. 20.
    Mustafa A, Holladay SD, Goff M, Witonsky SG, Kerr R, Reilly CM, Sponenberg DP, Roddick GT, Jr M (2008) An enhanced postnatal autoimmune profile in 24 week-old C57BL/6 mice developmentally exposed to TCDD. Toxicol Appl Pharmacol 232:51–59CrossRefPubMedGoogle Scholar
  21. 21.
    Zhou Y, Lu Q (2008) DNA methylation in T cells from idiopathic lupus and drug-induced lupus patients. Autoimmun Rev 7:376–383CrossRefPubMedGoogle Scholar
  22. 22.
    Barendrecht MM, Tervaert JW, van Breda Vriesman PJ, Damoiseaux JG (2002) Susceptibility to cyclosporin A-induced autoimmunity: strain differences in relation to autoregulatory T cells. J Autoimmun 18:39–48CrossRefPubMedGoogle Scholar
  23. 23.
    Brix TH, Hansen PS, Kyvik KO, Hegedus L (2000) Cigarette smoking and risk of clinically overt thyroid disease: a population-based twin case-control study. Arch Intern Med 160:661–666CrossRefPubMedGoogle Scholar
  24. 24.
    Guilherme L, Fae KC, Oshiro SE, Tanaka AC, Pomerantzeff PM, Kalil J (2007) T cell response in rheumatic fever: crossreactivity between streptococcal M protein peptides and heart tissue proteins. Curr Protein Pept Sci 8:39–44CrossRefPubMedGoogle Scholar
  25. 25.
    Cunha-Neto E, Bilate AM, Hyland KV, Fonseen SG, Kalil J, Museum ED, Galleries A (2006) Induction of cardiac autoimmunity in Chagas heart disease: a case for molecular mimicry. Autoimmunity 39:41–54CrossRefPubMedGoogle Scholar
  26. 26.
    Rose NR (2008) The adjuvant effect in infection and autoimmunity. Clin Rev Allergy Immunol 34:279–282CrossRefPubMedGoogle Scholar
  27. 27.
    Croker BA, Lawson BR, Berger M, Rutschmann S, Berger M, Eidenschenk C, Blasius AL, Moresco EM, Sovath S, Cengia L, Shultz LD, Theofilopoulos AN, Pettersson S, Beutler BA (2008) Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger. Proc Natl Acad Sci USA 105:15028–15033CrossRefPubMedGoogle Scholar
  28. 28.
    Rose NR (2008) Autoimmunity in coxsackievirus infection. Curr Top Microbiol Immunol 323:293–314CrossRefPubMedGoogle Scholar
  29. 29.
    Larizza D, Calcaterra V, Martinetti M, Negini R, De Silvestri A, Cisternino M, Iannone AM, Solcia E (2006) Helicobacter pylori infection and autoimmune thyroid disease in young patients: the disadvantage of carrying the human leukocyte antigen-DRB1*0301 allele. Clin J Endocrinol Metab 91:176–179CrossRefGoogle Scholar
  30. 30.
    Vas J, Mattner J, Richardson S, Ndonye R, Gaughan JP, Howell A, Monestier M (2008) Regulatory roles for NKT cell ligands in environmentally induced autoimmunity. J Immunol 181:6779–6788PubMedGoogle Scholar
  31. 31.
    Cooke A (2009) Infection and autoimmunity. Blood Cells Mol Dis 42:105–107CrossRefPubMedGoogle Scholar
  32. 32.
    Mattner J, Savage PB, Peung P, Oertelt SS, Wang V, Trivedi O, Scanlon ST, Pendem K, Teyton L, Hart J, Ridgway WM, Wicker LS, Gershwin ME, Bendelac A (2008) Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell Host Microbe 3:304–315CrossRefPubMedGoogle Scholar
  33. 33.
    Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, Stockinger B (2008) The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453:106–109CrossRefPubMedGoogle Scholar
  34. 34.
    Ober C, Loisel DA, Gilad Y (2008) Sex-specific genetic architecture of human disease. Nat Rev Genet 9:911–922CrossRefPubMedGoogle Scholar
  35. 35.
    Fairweather D, Rose NR (2004) Women and autoimmune diseases. Emerg Infect Dis 10:2005–2011PubMedGoogle Scholar
  36. 36.
    Calin A, Brophy S, Blake D (1999) Impact of sex on inheritance of ankylosing spondylitis: a cohort study. Lancet 354:1687–1690CrossRefPubMedGoogle Scholar
  37. 37.
    World Health Organization. Environmental Health Criteria 236 (2006) Principles and methods for assessing autoimmunity associated with exposure to chemicals. WHO Publications, Geneva, SwitzerlandGoogle Scholar
  38. 38.
    Gleicher N, Barad DH (2007) Gender as risk factor for autoimmune diseases. J Autoimmun 28:1–6CrossRefPubMedGoogle Scholar
  39. 39.
    Zandman-Goddard G, Peeva E, Shoenfeld Y (2007) Gender and autoimmunity. Autoimmun Rev 6:366–372CrossRefPubMedGoogle Scholar
  40. 40.
    Gause WC, Jackson JV, Dietert RR, Marsh JA (1985) Autoanti-thyroglobulin production in obese chickens: influence of age and sex as measured by ELISA. Dev Comp Immunol 9:107–118CrossRefPubMedGoogle Scholar
  41. 41.
    Sorg H, Lorch B, Jaster R, Fitzner B, Ibrahim S, Holzhueter SA, Nizze H, Vollmar B (2009) Early rise in inflammation and microcirculatory disorder determine the development of autoimmune pancreatitis in the MRL/Mp-mouse. Am J Physiol Gastrointest Liver Physiol 295:G1274–G1280CrossRefGoogle Scholar
  42. 42.
    Gubbels Bupp MR, Jorgensen TN, Kotzin B (2008) Identification of candidate genes that influence sex hormone-dependent disease phenotypes in mouse lupus. Genes Immun 9:47–56CrossRefPubMedGoogle Scholar
  43. 43.
    Hughes GC, Clark EA (2007) Regulation of dendritic cells by female sex steroids: relevance to immunity and autoimmunity. Autoimmunity 40:470–481CrossRefPubMedGoogle Scholar
  44. 44.
    Stevens AM (2006) Microchimeric cells in systemic lupus erythematosus: targets or innocent bystanders? Lupus 15:820–826CrossRefPubMedGoogle Scholar
  45. 45.
    Rak JM, Maestroni L, Balandraud N, Guis S, Boudinet H, Guzian MC, Yan Z, Azzouz D, Auger I, Roudier C, Martin M, Didelot R, Roudier J, Lamber NC (2008) Transfer of the shared epitope through microchimerism in women with rheumatoid arthritis. Arthritis Rheum 60:73–80CrossRefGoogle Scholar
  46. 46.
    Selmi C, Invernizzi P, Gershwin ME (2006) The X chromosome and systemic sclerosis. Curr Opin Rheumatol 18:601–605CrossRefPubMedGoogle Scholar
  47. 47.
    Smith-Bouvier DL, Divekar AA, Sasidhar M, Du S, Tiwari-Woodruff SK, King JK, Arnold AP, Singh RR, Voskuhl RR (2008) A role for sex chromosome complement in the female bias in autoimmune disease. J Exp Med 205:1099–1108CrossRefPubMedGoogle Scholar
  48. 48.
    Invernuizzi P, Miozzo M, Oetelt-Prigione S, Meroni PL, Persani L, Selmi C, Battezzati PM, Zuin M, Lucchi S, Marasini B, Zeni S, Watnik M, Tabano S, Maitz S, Pasini S, Gershwin ME, Podda M (2007) X monosomy in female systemic lupus erythematosus. Ann N Y Acad Sci 1110:84–91CrossRefGoogle Scholar
  49. 49.
    Nandula SR, Armarnath S, Molinolo A, Bandyopadhyay BC, Hall B, Goldsmith CM, Zheng C, Larsson J, Sreenath T, Chen W, Ambudkar IS, Karlsson S, Baum BJ, Kulkarni AB (2007) Female mice are more susceptible to developing inflammatory disorders due to impaired transforming growth factor beta signaling in salivary glands. Arthritis Rheum 56:1798–1805CrossRefPubMedGoogle Scholar
  50. 50.
    Jane-wit D, Altuntas CZ, Monti J, Johnson JM, Forsthuber TG, Tuohy VK (2008) Sex-defined T-cell responses to cardiac self determine differential outcomes of murine dilated cardiomyopathy. Am J Pathol 172:11–21CrossRefPubMedGoogle Scholar
  51. 51.
    Sinha S, Kaler LT, Procter TM, Teuscher C, Vandenbark AA, Offner H (2008) IL-13-mediated gender difference in susceptibility to autoimmune encephalomyelitis. J Immunol 180:2679–2685PubMedGoogle Scholar
  52. 52.
    Hastings KL (2006) Risk assessment in drug development: autoimmunity. J Toxicol Environ Health A 69:893–898CrossRefGoogle Scholar
  53. 53.
    Goldstein NS, Bayati N, Silverman AL, Gordon SG (2000) Minocycline as a cause of drug-induced autoimmune hepatitis: report of four cases and comparison with autoimmune hepatitis. Am J Clin Pathol 114:591–598CrossRefPubMedGoogle Scholar
  54. 54.
    Chamberlain MC, Schwartzenberg SJ, Akin EU, Kurth MH (2006) Minocycline-induced autoimmune hepatitis with subsequent cirrhosis. J Pediatr Gastroenterol Nutr 42:232–235CrossRefPubMedGoogle Scholar
  55. 55.
    Schuurs AH, Dietrich H, Gruber J, Wick G (1992) Effects of sex steroid analogs on spontaneous autoimmune thyroiditis in obese strain chickens. Int Arch Allergy Immunol 97:337–344CrossRefPubMedGoogle Scholar
  56. 56.
    Lam-Tse WK, Lernmark A, Drexhage HA (2002) Animal models of endocrine/organ-specific autoimmune diseases: do they really help us to understand human autoimmunity? Springer Semin Immunopathol 24:297–321CrossRefPubMedGoogle Scholar
  57. 57.
    Morrel L (2004) Mouse models of human autoimmune diseases: essential tools that require the proper controls. PloS Biol 2:e241CrossRefGoogle Scholar
  58. 58.
    Cooper GS, Gilbert KM, Greidlinger EL, James JA, Pfau JC, Reinlib L, Richardson BC, Rose NR (2008) Recent advances and opportunities in research on lupus: environmental influences and mechanism of disease. Environ Health Perspect 116:695–702CrossRefPubMedGoogle Scholar
  59. 59.
    Gerosa M, De Angeslis V, Roboldi P, Meroni PL (2008) Rheumatoid arthritis: a female challenge. Womens Health (Lond) 4:195–201Google Scholar
  60. 60.
    Lleo A, Battezzati PM, Selmi C, Selmi C, Gershwin ME, Podda M (2008) Is autoimmunity a matter of sex? Autoimmun Rev 7:626–630CrossRefPubMedGoogle Scholar
  61. 61.
    Rose NR (2008) Predictors of autoimmune disease: autoantibodies and beyond. Autoimmunity 41:419–428CrossRefPubMedGoogle Scholar
  62. 62.
    Plot L, Amiltal H (2009) Infectious associations of Celiac disease. Autoimmun Rev 8(4):316–319CrossRefPubMedGoogle Scholar
  63. 63.
    Ercolini AM, Miller SD (2009) The role of infections in autoimmune disease. Clin Exp Immunol 155:1–15CrossRefPubMedGoogle Scholar
  64. 64.
    Tabuenca JM (1981) Toxic-allergic syndrome caused by ingestion of rapeseed oil denatured with aniline. Lancet 2:567–568PubMedGoogle Scholar
  65. 65.
    Noonan CW, Pfau JC, Larson TC, Spence MR (2006) Nested case-control study of autoimmune disease in an asbestos-exposed population. Environ Health Perspect 114:1243–1247CrossRefPubMedGoogle Scholar
  66. 66.
    Yurino H, Ishikawa S, Sato T, Akadegawa K, Ito T, Ueha S, Inadera H, Matsushima K (2004) Endocrine disruptors (environmental estrogens) enhance autoantibody production by B1 cells. Toxicol Sci 81:139–147CrossRefPubMedGoogle Scholar
  67. 67.
    Costenbader KH, Kim DJ, Peerzada J, Lockman S, Nobles-Knight D, Petri M, Karlson EW (2004) Cigarette smoking and the risk of systemic lupus erythematosus: a meta-analysis. Arthritis Rheum 50:849–857CrossRefPubMedGoogle Scholar
  68. 68.
    Burke L, Segall-Blank M, Lorenzo C, Dynesius-Trentham R, Trentham D, Mortola JF (2001) Altered immune response in adult women exposed to diethylstilbestrol in utero. Am J Gynecol 185:78–81CrossRefGoogle Scholar
  69. 69.
    Fenaux JB, Gogal RM Jr, Lindsay D, Hardy C, Ward DL, Saunders G, Ahmed SA (2005) Altered splenocyte function in aged C57BL/6 mice prenatally exposed to diethylstilbestrol. J Immunotoxicol 2:221–229CrossRefPubMedGoogle Scholar
  70. 70.
    Grimaldi CM (2006) Sex and systemic lupus erythematosus: the role of the sex hormones estrogen and prolactin on the regulation of autoreactive B cells. Curr Opin Rhematol 18:456–461CrossRefGoogle Scholar
  71. 71.
    Poole BD, Templeton AK, Guthridge JM, Brown EJ, Harley JB, James JA (2009) Aberrant Epstein-Barr viral infection in systemic lupus erythematosus. Autoimmun Rev 8:337–342CrossRefPubMedGoogle Scholar
  72. 72.
    Lunardi C, Tinazzi E, Bason C, Dolcino M, Corrocher R, Puccetti A (2008) Human parvovirus B19 infection and autoimmunity. Autoimmun Rev 8:116–120CrossRefPubMedGoogle Scholar
  73. 73.
    Vas J, Monestier M (2008) Immunology of mercury. Ann N Y Acad Sci 1143:240–267CrossRefPubMedGoogle Scholar
  74. 74.
    Wang F, Roberts SM, Butfiloski EJ, Morel L, Sobel ES (2007) Acceleration of autoimmunity by organochlorine pesticides: a comparison of splenic B-cell effects of chlordecone and estradiol in (NZBxNZW)F1 mice. Toxicol Sci 99:141–152CrossRefPubMedGoogle Scholar
  75. 75.
    Tsai PC, Ko YC, Huang W, Liu HS, Guo YL (2007) Increased liver and lupus mortalities in 24-year follow-up of the Taiwanese people highly exposed to polychlorinated biphenyls and dibenzofurans. Sci Total Environ 374:216–222CrossRefPubMedGoogle Scholar
  76. 76.
    Jara LJ, Benitez G, Medina G (2008) Prolactin, dendritic cells, and systemic lupus erythematosus. Autoimmun Rev 7:251–255CrossRefPubMedGoogle Scholar
  77. 77.
    Parks CG, Cooper GS, Nylander-French LA et al (2002) Occupational exposure to crystalline silica and risk of systemic lupus erythematosus: a population-based, case-control study in the southeastern United States. Arthritis Rheum 46:1840–1850CrossRefPubMedGoogle Scholar
  78. 78.
    Menke J, Hsu MY, Byrne KT, Lucas JA, Rabacal WA, Croker BP, Zong XH, Stanley ER, Kelley VR (2008) Sunlight triggers cutaneous lupus through a CSF-1-dependent mechanism in MRL-Fas(lpr) mice. J Immunol 181:7367–7379PubMedGoogle Scholar
  79. 79.
    Cai P, König R, Boor PJ, Kondraganti S, Kaphalia BS, Khan MF, Ansari GA (2008) Chronic exposure to trichloroethylene causes early onset of SLE-like disease in female MRL +/+ mice. Toxicol Appl Pharmacol 228:68–75CrossRefPubMedGoogle Scholar
  80. 80.
    Eidson M, Philen RM, Sewell CM, Voorhees R, Kilbourne EM (1990) L-Tryptophan and eosinophilia-myalgia syndrome in New Mexico. Lancet 335:645–648CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Rodney R. Dietert
    • 1
  • Janice M. Dietert
    • 2
  • Jerrie Gavalchin
  1. 1.Department of Microbiology and ImmunologyCollege of Veterinary Medicine, Cornell UniversityIthacaUSA
  2. 2.Department of Microbiology and ImmunologyPerformance Plus ConsultingLansingUSA

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