Immunologic Research

, Volume 56, Issue 2–3, pp 220–240

Tracing environmental markers of autoimmunity: introducing the infectome

  • Dimitrios P. Bogdanos
  • Daniel S. Smyk
  • Pietro Invernizzi
  • Eirini I. Rigopoulou
  • Miri Blank
  • Lazaros Sakkas
  • Shideh Pouria
  • Yehuda Shoenfeld
Etio Pathogenesis of Autoimmunity


We recently introduced the concept of the infectome as a means of studying all infectious factors which contribute to the development of autoimmune disease. It forms the infectious part of the exposome, which collates all environmental factors contributing to the development of disease and studies the sum total of burden which leads to the loss of adaptive mechanisms in the body. These studies complement genome-wide association studies, which establish the genetic predisposition to disease. The infectome is a component which spans the whole life and may begin at the earliest stages right up to the time when the first symptoms manifest, and may thus contribute to the understanding of the pathogenesis of autoimmunity at the prodromal/asymptomatic stages. We provide practical examples and research tools as to how we can investigate disease-specific infectomes, using laboratory approaches employed from projects studying the “immunome” and “microbiome”. It is envisioned that an understanding of the infectome and the environmental factors that affect it will allow for earlier patient-specific intervention by clinicians, through the possible treatment of infectious agents as well as other compounding factors, and hence slowing or preventing disease development.


Autoimmunity Autoimmune disease Environment Infection Immunity Microbiome 



Anti-mitochondrial antibody


Anti-nuclear antibody




Cerebrospinal fluid


Epstein–Barr virus


Environmental-wide association study


First-degree relatives


Genome-wide association study


Human herpesvirus 6


Liquid chromatography–tandem mass spectrometry


Multiple sclerosis


Irritable bowel syndrome


Primary biliary cirrhosis


Polymerase chain reaction


Pyruvate dehydrogenase complex


Systemic lupus erythematosus


  1. 1.
    Bogdanos DP, Smyk DS, Invernizzi P, Rigopoulou EI, Blank M, Pouria S, et al. Infectome: a platform to trace infectious triggers of autoimmunity. Autoimmun Rev. 2012;. doi:10.1016/j.autrev.2012.12.005.Google Scholar
  2. 2.
    Gourley M, Miller FW. Mechanisms of disease: environmental factors in the pathogenesis of rheumatic disease. Nat Clin Pract Rheumatol. 2007;3(3):172–80. doi:10.1038/ncprheum0435.PubMedCrossRefGoogle Scholar
  3. 3.
    Lettre G, Rioux JD. Autoimmune diseases: insights from genome-wide association studies. Hum Mol Genet. 2008;17(R2):R116–21. doi:10.1093/hmg/ddn246.PubMedCrossRefGoogle Scholar
  4. 4.
    Rappaport SM, Smith MT. Epidemiology. Environ dis risks Sci. 2010;330(6003):460–1. doi:10.1126/science.1192603.Google Scholar
  5. 5.
    Kivity S, Agmon-Levin N, Blank M, Shoenfeld Y. Infections and autoimmunity–friends or foes? Trends Immunol. 2009;30(8):409–14. doi:10.1016/ Scholar
  6. 6.
    Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol. 1997;84(3):223–43.PubMedCrossRefGoogle Scholar
  7. 7.
    Moroni L, Bianchi I, Lleo A. Geoepidemiology, gender and autoimmune disease. Autoimmun Rev. 2012;11(6–7):A386–92. doi:10.1016/j.autrev.2011.11.012.PubMedCrossRefGoogle Scholar
  8. 8.
    Blank M, Gershwin ME. Autoimmunity: from the mosaic to the kaleidoscope. J Autoimmun. 2008;30(1–2):1–4. doi:10.1016/j.jaut.2007.11.015.PubMedCrossRefGoogle Scholar
  9. 9.
    Brickman CM, Shoenfeld Y. The mosaic of autoimmunity. Scand J Clin Lab Invest Suppl. 2001;235:3–15.PubMedGoogle Scholar
  10. 10.
    Rahamim-Cohen D, Shoenfeld Y. The mosaic of autoimmunity. a classical case of inhalation of a polyclonal activating factor in a genetically and hormonally susceptible patient leading to multiple autoimmune diseases. Isr Med Assoc J. 2001;3(5):381–2.PubMedGoogle Scholar
  11. 11.
    Shepshelovich D, Shoenfeld Y. Prediction and prevention of autoimmune diseases: additional aspects of the mosaic of autoimmunity. Lupus. 2006;15(3):183–90.PubMedCrossRefGoogle Scholar
  12. 12.
    Shoenfeld Y, Blank M, Abu-Shakra M, Amital H, Barzilai O, Berkun Y, et al. The mosaic of autoimmunity: prediction, autoantibodies, and therapy in autoimmune diseases–2008. Isr Med Assoc J. 2008;10(1):13–9.PubMedGoogle Scholar
  13. 13.
    Shoenfeld Y, Gilburd B, Abu-Shakra M, Amital H, Barzilai O, Berkun Y, et al. The mosaic of autoimmunity: genetic factors involved in autoimmune diseases–2008. Isr Med Assoc J. 2008;10(1):3–7.PubMedGoogle Scholar
  14. 14.
    Asherson RA, Gunter K, Daya D, Shoenfeld Y. Multiple autoimmune diseases in a young woman: tuberculosis and splenectomy as possible triggering factors? Another example of the “mosaic” of autoimmunity. J Rheumatol. 2008;35(6):1224–6.PubMedGoogle Scholar
  15. 15.
    de Carvalho JF, Pereira RM, Shoenfeld Y. The mosaic of autoimmunity: the role of environmental factors. Front Biosci (Elite Ed). 2009;1:501–9.Google Scholar
  16. 16.
    Costenbader KH, Gay S, Alarcon-Riquelme ME, Iaccarino L, Doria A. Genes, epigenetic regulation and environmental factors: which is the most relevant in developing autoimmune diseases? Autoimmun Rev. 2012;11(8):604–9. doi:10.1016/j.autrev.2011.10.022.PubMedCrossRefGoogle Scholar
  17. 17.
    Mavropoulos A, Orfanidou T, Liaskos C, Smyk DS, Billinis C, Blank M, et al. p38 mitogen-activated protein kinase (p38 MAPK)-mediated autoimmunity: lessons to learn from ANCA vasculitis and pemphigus vulgaris. Autoimmun Rev. 2012;. doi:10.1016/j.autrev.2012.10.019.PubMedGoogle Scholar
  18. 18.
    Karlson EW, Deane K. Environmental and gene-environment interactions and risk of rheumatoid arthritis. Rheum Dis Clin North Am. 2012;38(2):405–26. doi:10.1016/j.rdc.2012.04.002.PubMedCrossRefGoogle Scholar
  19. 19.
    Villeda SA, Wyss-Coray T. The circulatory systemic environment as a modulator of neurogenesis and brain aging. Autoimmun Rev. 2012;. doi:10.1016/j.autrev.2012.10.014.PubMedGoogle Scholar
  20. 20.
    Simon KC, van der Mei IA, Munger KL, Ponsonby A, Dickinson J, Dwyer T, et al. Combined effects of smoking, anti-EBNA antibodies, and HLA-DRB1*1501 on multiple sclerosis risk. Neurology. 2010;74(17):1365–71. doi:10.1212/WNL.0b013e3181dad57e.PubMedCrossRefGoogle Scholar
  21. 21.
    Gatto M, Zen M, Ghirardello A, Bettio S, Bassi N, Iaccarino L, et al. Emerging and critical issues in the pathogenesis of lupus. Autoimmun Rev. 2012;. doi:10.1016/j.autrev.2012.09.003.Google Scholar
  22. 22.
    Selmi C, Leung PS, Sherr DH, Diaz M, Nyland JF, Monestier M, et al. Mechanisms of environmental influence on human autoimmunity: a national institute of environmental health sciences expert panel workshop. J Autoimmun. 2012;39(4):272–84. doi:10.1016/j.jaut.2012.05.PubMedCrossRefGoogle Scholar
  23. 23.
    Bogdanos DP, Smith H, Ma Y, Baum H, Mieli-Vergani G, Vergani D. A study of molecular mimicry and immunological cross-reactivity between hepatitis B surface antigen and myelin mimics. Clin Dev Immunol. 2005;12(3):217–24.PubMedCrossRefGoogle Scholar
  24. 24.
    Smyk DS, Rigopoulou EI, Muratori L, Burroughs AK, Bogdanos DP. Smoking as a risk factor for autoimmune liver disease: what we can learn from primary biliary cirrhosis. Ann Hepatol. 2012;11(1):7–14.PubMedGoogle Scholar
  25. 25.
    Miller FW, Alfredsson L, Costenbader KH, Kamen DL, Nelson LM, Norris JM, et al. Epidemiology of environmental exposures and human autoimmune diseases: findings from a national institute of environmental health sciences expert panel workshop. J Autoimmun. 2012;39(4):259–71. doi:10.1016/j.jaut.2012.05.002.PubMedCrossRefGoogle Scholar
  26. 26.
    Germolec D, Kono DH, Pfau JC, Pollard KM. Animal models used to examine the role of the environment in the development of autoimmune disease: findings from an NIEHS expert panel workshop. J Autoimmun. 2012;39(4):285–93. doi:10.1016/j.jaut.2012.05.020.PubMedCrossRefGoogle Scholar
  27. 27.
    Anaya JM. Common mechanisms of autoimmune diseases (the autoimmune tautology). Autoimmun Rev. 2012;11(11):781–4. doi:10.1016/j.autrev.2012.02.002.PubMedCrossRefGoogle Scholar
  28. 28.
    Arlt VM, Schwerdtle T. UKEMS/Dutch EMS-sponsored workshop on biomarkers of exposure and oxidative DNA damage & 7th GUM-32P-postlabelling workshop, University of Munster, Munster, Germany, 28-29 March 2011. Mutagenesis. 2011. doi: 10.1093/mutage/ger036.
  29. 29.
    Pleil JD, Stiegel MA, Sobus JR, Liu Q, Madden MC. Observing the human exposome as reflected in breath biomarkers: heat map data interpretation for environmental and intelligence research. J Breath Res. 2011;5(3):037104. doi:10.1088/1752-7155/5/3/037104.PubMedCrossRefGoogle Scholar
  30. 30.
    Rappaport SM. Implications of the exposome for exposure science. J Expo Sci Environ Epidemiol. 2011;21(1):5–9. doi:10.1038/jes.2010.50.PubMedCrossRefGoogle Scholar
  31. 31.
    Wild CP. Complementing the genome with an “exposome”: the outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol Biomarkers Prev. 2005;14(8):1847–50. doi:10.1158/1055-9965.EPI-05-0456.PubMedCrossRefGoogle Scholar
  32. 32.
    Wild CP. Environmental exposure measurement in cancer epidemiology. Mutagenesis. 2009;24(2):117–25. doi:10.1093/mutage/gen061.PubMedCrossRefGoogle Scholar
  33. 33.
    Smith MT, Zhang L, McHale CM, Skibola CF, Rappaport SM. Benzene, the exposome and future investigations of leukemia etiology. Chem Biol Inter. 2011;192(1–2):155–9. doi:10.1016/j.cbi.2011.02.010.CrossRefGoogle Scholar
  34. 34.
    Collin M, Shannon O, Bjorck L. IgG glycan hydrolysis by a bacterial enzyme as a therapy against autoimmune conditions. Proc Natl Acad Sci U S A. 2008;105(11):4265–70. doi:10.1073/pnas.0711271105.PubMedCrossRefGoogle Scholar
  35. 35.
    Allhorn M, Olin AI, Nimmerjahn F, Collin M. Human IgG/Fc gamma R interactions are modulated by streptococcal IgG glycan hydrolysis. PLoS ONE. 2008;3(1):e1413. doi:10.1371/journal.pone.0001413.PubMedCrossRefGoogle Scholar
  36. 36.
    McCulloch J, Zhang YW, Dawson M, Harkiss GD, Peterhans E, Vogt HR, et al. Glycosylation of IgG during potentially arthritogenic lentiviral infections. Rheumatol Int. 1995;14(6):243–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Polacco BJ, Purvine SO, Zink EM, Lavoie SP, Lipton MS, Summers AO, et al. Discovering mercury protein modifications in whole proteomes using natural isotope distributions observed in liquid chromatography-tandem mass spectrometry. Mol Cell Proteomics. 2011;. doi:10.1074/mcp.M110.004853.PubMedGoogle Scholar
  38. 38.
    McLaren Howard J. The detection of DNA adducts (risk factors for DNA damage). A method for genomic DNA, the results and some effects of nutritional intervention. J Nutr Environ Med. 2002;12:19–31.CrossRefGoogle Scholar
  39. 39.
    Patel CJ, Bhattacharya J, Butte AJ. An environment-wide association study (EWAS) on type 2 diabetes mellitus. PLoS ONE. 2010;5(5):e10746. doi:10.1371/journal.pone.0010746.PubMedCrossRefGoogle Scholar
  40. 40.
    Karges W, Hammond-McKibben D, Cheung RK, Visconti M, Shibuya N, Kemp D, et al. Immunological aspects of nutritional diabetes prevention in NOD mice: a pilot study for the cow’s milk-based IDDM prevention trial. Diabetes. 1997;46(4):557–64.PubMedCrossRefGoogle Scholar
  41. 41.
    Guggenmos J, Schubart AS, Ogg S, Andersson M, Olsson T, Mather IH, et al. Antibody cross-reactivity between myelin oligodendrocyte glycoprotein and the milk protein butyrophilin in multiple sclerosis. J Immunol. 2004;172(1):661–8.PubMedGoogle Scholar
  42. 42.
    Molina V, Shoenfeld Y. Infection, vaccines and other environmental triggers of autoimmunity. Autoimmunity. 2005;38(3):235–45. doi:10.1080/08916930500050277.PubMedCrossRefGoogle Scholar
  43. 43.
    Pordeus V, Szyper-Kravitz M, Levy RA, Vaz NM, Shoenfeld Y. Infections and autoimmunity: a panorama. Clin Rev Allergy Immunol. 2008;34(3):283–99. doi:10.1007/s12016-007-8048-8.PubMedCrossRefGoogle Scholar
  44. 44.
    Doria A, Sarzi-Puttini P, Shoenfeld Y. Infections, rheumatism and autoimmunity: the conflicting relationship between humans and their environment. Autoimmun Rev. 2008;8(1):1–4. doi:10.1016/j.autrev.2008.07.014.PubMedCrossRefGoogle Scholar
  45. 45.
    Tozzoli R, Barzilai O, Ram M, Villalta D, Bizzaro N, Sherer Y, et al. Infections and autoimmune thyroid diseases: parallel detection of antibodies against pathogens with proteomic technology. Autoimmun Rev. 2008;8(2):112–5. doi:10.1016/j.autrev.2008.07.013.PubMedCrossRefGoogle Scholar
  46. 46.
    Corthesy B. Role of secretory IgA in infection and maintenance of homeostasis. Autoimmun Rev. 2012;. doi:10.1016/j.autrev.2012.10.012.PubMedGoogle Scholar
  47. 47.
    Brown JM, Pfau JC, Pershouse MA, Holian A. Silica, apoptosis, and autoimmunity. J Immunotoxicol. 2005;1(3):177–87. doi:10.1080/15476910490911922.PubMedCrossRefGoogle Scholar
  48. 48.
    Otsuki T, Hayashi H, Nishimura Y, Hyodo F, Maeda M, Kumagai N, et al. Dysregulation of autoimmunity caused by silica exposure and alteration of Fas-mediated apoptosis in T lymphocytes derived from silicosis patients. Int J Immunopathol Pharmacol. 2011;24(1 Suppl):11S–6S.PubMedGoogle Scholar
  49. 49.
    Cooper GS, Wither J, Bernatsky S, Claudio JO, Clarke A, Rioux JD, et al. Occupational and environmental exposures and risk of systemic lupus erythematosus: silica, sunlight, solvents. Rheumatology. 2010;49(11):2172–80. doi:10.1093/rheumatology/keq214.PubMedCrossRefGoogle Scholar
  50. 50.
    Finckh A, Cooper GS, Chibnik LB, Costenbader KH, Watts J, Pankey H, et al. Occupational silica and solvent exposures and risk of systemic lupus erythematosus in urban women. Arthritis Rheum. 2006;54(11):3648–54. doi:10.1002/art.22210.PubMedCrossRefGoogle Scholar
  51. 51.
    Parks CG, Cooper GS. Occupational exposures and risk of systemic lupus erythematosus: a review of the evidence and exposure assessment methods in population- and clinic-based studies. Lupus. 2006;15(11):728–36.PubMedCrossRefGoogle Scholar
  52. 52.
    Griffin JM, Gilbert KM, Lamps LW, Pumford NR. CD4(+) T-cell activation and induction of autoimmune hepatitis following trichloroethylene treatment in MRL +/+ mice. Toxicol Sci. 2000;57(2):345–52.PubMedCrossRefGoogle Scholar
  53. 53.
    Khan MF, Kaphalia BS, Prabhakar BS, Kanz MF, Ansari GA. Trichloroethene-induced autoimmune response in female MRL +/+ mice. Toxicol Appl Pharmacol. 1995;134(1):155–60. doi:10.1006/taap.1995.1179.PubMedCrossRefGoogle Scholar
  54. 54.
    Duntas LH. Environmental factors and thyroid autoimmunity. Ann Endocrinol (Paris). 2011;72(2):108–13. doi:10.1016/j.ando.2011.03.019.PubMedCrossRefGoogle Scholar
  55. 55.
    Parks CG, Walitt BT, Pettinger M, Chen JC, de Roos AJ, Hunt J, et al. Insecticide use and risk of rheumatoid arthritis and systemic lupus erythematosus in the women’s health initiative observational study. Arthritis Care Res. 2011;63(2):184–94. doi:10.1002/acr.20335.CrossRefGoogle Scholar
  56. 56.
    Fortes C. Lupus erythematosus. are residential insecticides exposure the missing link? Med Hypotheses. 2010;75(6):590–3. doi:10.1016/j.mehy.2010.07.041.PubMedCrossRefGoogle Scholar
  57. 57.
    Burek CL, Talor MV. Environmental triggers of autoimmune thyroiditis. J Autoimmun. 2009;33(3–4):183–9. doi:10.1016/j.jaut.2009.09.001.PubMedCrossRefGoogle Scholar
  58. 58.
    Gold LS, Ward MH, Dosemeci M, De Roos AJ. Systemic autoimmune disease mortality and occupational exposures. Arthritis Rheum. 2007;56(10):3189–201. doi:10.1002/art.22880.PubMedCrossRefGoogle Scholar
  59. 59.
    Sobel ES, Gianini J, Butfiloski EJ, Croker BP, Schiffenbauer J, Roberts SM. Acceleration of autoimmunity by organochlorine pesticides in (NZB x NZW)F1 mice. Environ Health Perspect. 2005;113(3):323–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Mayes MD. Epidemiologic studies of environmental agents and systemic autoimmune diseases. Environ Health Perspect. 1999;107(Suppl 5):743–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Artukovic M, Ikic M, Kustelega J, Artukovic IN, Kaliterna DM. Influence of UV radiation on immunological system and occurrence of autoimmune diseases. Coll Antropol. 2010;34(Suppl 2):175–8.PubMedGoogle Scholar
  62. 62.
    Handunnetthi L, Ramagopalan SV. UV radiation, vitamin D, and multiple sclerosis. Proc Natl Acad Sci U S A. 2010;107(33):E130; author reply E1. doi: 10.1073/pnas.1004603107.
  63. 63.
    Prieto S, Grau JM. The geoepidemiology of autoimmune muscle disease. Autoimmun Rev. 2010;9(5):A330–4. doi:10.1016/j.autrev.2009.11.006.PubMedCrossRefGoogle Scholar
  64. 64.
    Kuhn A, Beissert S. Photosensitivity in lupus erythematosus. Autoimmunity. 2005;38(7):519–29. doi:10.1080/08916930500285626.PubMedCrossRefGoogle Scholar
  65. 65.
    Tumgor G, Balkan C, Arikan C, Kavakli K, Aydogdu S. Immune haemolytic anaemia induced by allopurinol after liver transplantation. Acta Paediatr. 2006;95(6):762–3. doi:10.1080/08035250500499465.PubMedCrossRefGoogle Scholar
  66. 66.
    Pujol M, Duran-Suarez JR, Martin Vega C, Sanchez C, Tovar JL, Valles M. Autoimmune thrombocytopenia in three patients treated with captopril. Vox Sang. 1989;57(3):218.PubMedCrossRefGoogle Scholar
  67. 67.
    Gharavi AE, Sammaritano LR, Wen J, Miyawaki N, Morse JH, Zarrabi MH, et al. Characteristics of human immunodeficiency virus and chlorpromazine induced antiphospholipid antibodies: effect of beta 2 glycoprotein I on binding to phospholipid. J Rheumatol. 1994;21(1):94–9.PubMedGoogle Scholar
  68. 68.
    Canoso RT, de Oliveira RM. Chlorpromazine-induced anticardiolipin antibodies and lupus anticoagulant: absence of thrombosis. Am J Hematol. 1988;27(4):272–5.PubMedCrossRefGoogle Scholar
  69. 69.
    Stein PB, Inwood MJ. Hemolytic anemia associated with chlorpromazine therapy. Can J Psychiatry. 1980;25(8):659–61.PubMedGoogle Scholar
  70. 70.
    Hadnagy C. Letter: coombs-positive haemolytic anaemia provoked by chlorpromazine. Lancet. 1976;1(7956):423.PubMedCrossRefGoogle Scholar
  71. 71.
    Berglund S, Gottfries CG, Gottfries I, Stormby K. Chlorpromazine-induced antinuclear factors. Act Med Scand. 1970;187(1–2):67–74.Google Scholar
  72. 72.
    Liu ZX, Kaplowitz N. Immune-mediated drug-induced liver disease. Clin Liver Dis. 2002;6(3):755–74.PubMedCrossRefGoogle Scholar
  73. 73.
    Yung RL, Richardson BC. Drug-induced lupus. Rheum Dis Clin North Am. 1994;20(1):61–86.PubMedGoogle Scholar
  74. 74.
    Czaja AJ. Drug-induced autoimmune-like hepatitis. Dig Dis Sci. 2011;56(4):958–76. doi:10.1007/s10620-011-1611-4.PubMedCrossRefGoogle Scholar
  75. 75.
    Chighizola C, Meroni PL. The role of environmental estrogens and autoimmunity. Autoimmun Rev. 2012;11(6–7):A493–501. doi:10.1016/j.autrev.2011.11.027.PubMedCrossRefGoogle Scholar
  76. 76.
    Shapira Y, Agmon-Levin N, Renaudineau Y, Porat-Katz BS, Barzilai O, Ram M, et al. Serum markers of infections in patients with primary biliary cirrhosis: evidence of infection burden. Exp Mol Pathol. 2012;93(3):386–90. doi:10.1016/j.yexmp.2012.09.012.PubMedCrossRefGoogle Scholar
  77. 77.
    Shapira Y, Agmon-Levin N, Shoenfeld Y. Defining and analyzing geoepidemiology and human autoimmunity. J Autoimmun. 2010;34(3):J168–77. doi:10.1016/j.jaut.2009.11.018.PubMedCrossRefGoogle Scholar
  78. 78.
    Berlin T, Zandman-Goddard G, Blank M, Matthias T, Pfeiffer S, Weis I, et al. Autoantibodies in nonautoimmune individuals during infections. Ann N Y Acad Sci. 2007;1108:584–93.PubMedCrossRefGoogle Scholar
  79. 79.
    Saad R, Rizkallah MR, Aziz RK. Gut Pharmacomicrobiomics: the tip of an iceberg of complex interactions between drugs and gut-associated microbes. Gut Pathog. 2012;4(1):16. doi:10.1186/1757-4749-4-16.PubMedGoogle Scholar
  80. 80.
    Buccigrossi V, Nicastro E, Guarino A. Functions of intestinal microflora in children. Curr Opin Gastroenterol. 2013;29(1):31–8. doi:10.1097/MOG.0b013e32835a3500.PubMedCrossRefGoogle Scholar
  81. 81.
    Gielda LM, DiRita VJ. Zinc competition among the intestinal microbiota. MBio. 2012;3(4):e00171. doi:10.1128/mBio.00171-12.PubMedCrossRefGoogle Scholar
  82. 82.
    Kivity S, Katz M, Langevitz P, Eshed I, Olchovski D, Barzilai A. Autoimmune syndrome induced by adjuvants (ASIA) in the middle east: morphea following silicone implantation. Lupus. 2012;21(2):136–9. doi:10.1177/0961203311429551.PubMedCrossRefGoogle Scholar
  83. 83.
    Lidar M, Agmon-Levin N, Langevitz P, Shoenfeld Y. Silicone and scleroderma revisited. Lupus. 2012;21(2):121–7. doi:10.1177/0961203311430703.PubMedCrossRefGoogle Scholar
  84. 84.
    Shoenfeld Y, Toubi E. Protective autoantibodies: role in homeostasis, clinical importance, and therapeutic potential. Arthritis Rheum. 2005;52(9):2599–606. doi:10.1002/art.21252.PubMedCrossRefGoogle Scholar
  85. 85.
    Toubi E, Shoenfeld Y. Predictive and protective autoimmunity in cardiovascular diseases: is vaccination therapy a reality? Lupus. 2005;14(9):665–9.PubMedCrossRefGoogle Scholar
  86. 86.
    Ram M, Anaya JM, Barzilai O, Izhaky D, Porat Katz BS, Blank M, et al. The putative protective role of hepatitis B virus (HBV) infection from autoimmune disorders. Autoimmun Rev. 2008;7(8):621–5. doi:10.1016/j.autrev.2008.06.008.PubMedCrossRefGoogle Scholar
  87. 87.
    Meroni PL, Shoenfeld Y. Predictive, protective, orphan autoantibodies: the example of anti-phospholipid antibodies. Autoimmun Rev. 2008;7(8):585–7. doi:10.1016/j.autrev.2008.08.001.PubMedCrossRefGoogle Scholar
  88. 88.
    Plot L, Amital H, Barzilai O, Ram M, Nicola B, Shoenfeld Y. Infections may have a protective role in the etiopathogenesis of celiac disease. Ann N Y Acad Sci. 2009;1173:670–4. doi:10.1111/j.1749-6632.2009.04814.x.PubMedCrossRefGoogle Scholar
  89. 89.
    Guilherme L, Oshiro SE, Fae KC, Cunha-Neto E, Renesto G, Goldberg AC, et al. T-cell reactivity against streptococcal antigens in the periphery mirrors reactivity of heart-infiltrating T lymphocytes in rheumatic heart disease patients. Infect Immun. 2001;69(9):5345–51.PubMedCrossRefGoogle Scholar
  90. 90.
    Amedei A, Bergman MP, Appelmelk BJ, Azzurri A, Benagiano M, Tamburini C, et al. Molecular mimicry between Helicobacter pylori antigens and H + , K + –adenosine triphosphatase in human gastric autoimmunity. J Exp Med. 2003;198(8):1147–56. doi:10.1084/jem.20030530.PubMedCrossRefGoogle Scholar
  91. 91.
    Cunha-Neto E, Coelho V, Guilherme L, Fiorelli A, Stolf N, Kalil J. Autoimmunity in Chagas’ disease. identification of cardiac myosin-b13 trypanosoma cruzi protein crossreactive T cell clones in heart lesions of a chronic Chagas’ cardiomyopathy patient. J Clin Invest. 1996;98(8):1709–12. doi:10.1172/JCI118969.PubMedCrossRefGoogle Scholar
  92. 92.
    da Rocha Sobrinho HM, Jarach R, da Silva NA, Shio MT, Jancar S, Timenetsky J. Mycoplasmal lipid-associated membrane proteins and Mycoplasma arthritidis mitogen recognition by serum antibodies from patients with rheumatoid arthritis. Rheumatol Int. 2011;31(7):951–7. doi:10.1007/s00296-010-1612-1.PubMedCrossRefGoogle Scholar
  93. 93.
    Tobon GJ, Pers JO, Canas CA, Rojas-Villarraga A, Youinou P, Anaya JM. Are autoimmune diseases predictable? Autoimmun Rev. 2012;11(4):259–66. doi:10.1016/j.autrev.2011.10.004.PubMedCrossRefGoogle Scholar
  94. 94.
    Jones DE. Pathogenesis of primary biliary cirrhosis. Gut. 2007;56(11):1615–24. doi:10.1136/gut.2007.122150.PubMedGoogle Scholar
  95. 95.
    Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005;353(12):1261–73. doi:10.1056/NEJMra043898.PubMedCrossRefGoogle Scholar
  96. 96.
    Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003;349(16):1526–33. doi:10.1056/NEJMoa021933.PubMedCrossRefGoogle Scholar
  97. 97.
    Harley JB, Harley IT, Guthridge JM, James JA. The curiously suspicious: a role for Epstein-Barr virus in lupus. Lupus. 2006;15(11):768–77.PubMedCrossRefGoogle Scholar
  98. 98.
    Harley JB, James JA. Epstein-barr virus infection induces lupus autoimmunity. Bull NYU Hosp Jt Dis. 2006;64(1–2):45–50.PubMedGoogle Scholar
  99. 99.
    Navarra SV, Ishimori MI, Uy EA, Hamijoyo L, Sama J, James JA, et al. Studies of Filipino patients with systemic lupus erythematosus: autoantibody profile of first-degree relatives. Lupus. 2011;20(5):537–43. doi:10.1177/0961203310385164.PubMedCrossRefGoogle Scholar
  100. 100.
    Zandman-Goddard G, Berkun Y, Barzilai O, Boaz M, Blank M, Ram M, et al. Exposure to Epstein-Barr virus infection is associated with mild systemic lupus erythematosus disease. Ann N Y Acad Sci. 2009;1173:658–63. doi:10.1111/j.1749-6632.2009.04754.x.PubMedCrossRefGoogle Scholar
  101. 101.
    Barzilai O, Sherer Y, Ram M, Izhaky D, Anaya JM, Shoenfeld Y. Epstein-Barr virus and cytomegalovirus in autoimmune diseases: are they truly notorious? a preliminary report. Ann N Y Acad Sci. 2007;1108:567–77.PubMedCrossRefGoogle Scholar
  102. 102.
    Bengtsson A, Widell A, Elmstahl S, Sturfelt G. No serological indications that systemic lupus erythematosus is linked with exposure to human parvovirus B19. Ann Rheum Dis. 2000;59(1):64–6.PubMedCrossRefGoogle Scholar
  103. 103.
    Hemauer A, Beckenlehner K, Wolf H, Lang B, Modrow S. Acute parvovirus B19 infection in connection with a flare of systemic lupus erythematodes in a female patient. J Clin Virol. 1999;14(1):73–7.PubMedCrossRefGoogle Scholar
  104. 104.
    Hrycek A, Kusmierz D, Mazurek U, Wilczok T. Human cytomegalovirus in patients with systemic lupus erythematosus. Autoimmunity. 2005;38(7):487–91. doi:10.1080/08916930500285667.PubMedCrossRefGoogle Scholar
  105. 105.
    James JA, Neas BR, Moser KL, Hall T, Bruner GR, Sestak AL, et al. Systemic lupus erythematosus in adults is associated with previous Epstein-Barr virus exposure. Arthritis Rheum. 2001;44(5):1122–6. doi:10.1002/1529-0131(200105)44:5<1122:AID-ANR193>3.0.CO;2-D.PubMedCrossRefGoogle Scholar
  106. 106.
    Seishima M, Oyama Z, Yamamura M. Two-year follow-up study after human parvovirus B19 infection. Dermatology. 2003;206(3):192–6. doi:10.1159/000068885.PubMedCrossRefGoogle Scholar
  107. 107.
    Chang M, Pan MR, Chen DY, Lan JL. Human cytomegalovirus pp 65 lower matrix protein: a humoral immunogen for systemic lupus erythematosus patients and autoantibody accelerator for NZB/W F1 mice. Clin Exp Immunol. 2006;143(1):167–79. doi:10.1111/j.1365-2249.2005.02974.x.PubMedCrossRefGoogle Scholar
  108. 108.
    Gilden DH. Infectious causes of multiple sclerosis. Lancet Neurol. 2005;4(3):195–202. doi:10.1016/S1474-4422(05)01017-3.PubMedGoogle Scholar
  109. 109.
    Kakalacheva K, Lunemann JD. Environmental triggers of multiple sclerosis. FEBS Lett. 2011;. doi:10.1016/j.febslet.2011.04.006.PubMedGoogle Scholar
  110. 110.
    Hammond SR, English DR, McLeod JG. The age-range of risk of developing multiple sclerosis: evidence from a migrant population in Australia. Brain. 2000;123(Pt 5):968–74.PubMedCrossRefGoogle Scholar
  111. 111.
    Kurtzke JF, Delasnerie-Laupretre N, Wallin MT. Multiple sclerosis in North African migrants to France. Acta Neurol Scand. 1998;98(5):302–9.PubMedCrossRefGoogle Scholar
  112. 112.
    Kurtzke JF, Hyllested K. Multiple sclerosis in the Faroe Islands: i Clinical and epidemiological features. Ann Neurol. 1979;5(1):6–21. doi:10.1002/ana.410050104.PubMedCrossRefGoogle Scholar
  113. 113.
    Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343(13):938–52. doi:10.1056/NEJM200009283431307.PubMedCrossRefGoogle Scholar
  114. 114.
    Frohman EM, Racke MK, Raine CS. Multiple sclerosis–the plaque and its pathogenesis. N Engl J Med. 2006;354(9):942–55. doi:10.1056/NEJMra052130.PubMedCrossRefGoogle Scholar
  115. 115.
    Ebers GC, Sadovnick AD, Risch NJ. A genetic basis for familial aggregation in multiple sclerosis Canadian collaborative study group. Nature. 1995;377(6545):150–1. doi:10.1038/377150a0.PubMedCrossRefGoogle Scholar
  116. 116.
    Sadovnick AD, Ebers GC, Dyment DA, Risch NJ. Evidence for genetic basis of multiple sclerosis the Canadian collaborative study group. Lancet. 1996;347(9017):1728–30.PubMedCrossRefGoogle Scholar
  117. 117.
    Barcellos LF, Sawcer S, Ramsay PP, Baranzini SE, Thomson G, Briggs F, et al. Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis. Hum Mol Genet. 2006;15(18):2813–24. doi:10.1093/hmg/ddl223.PubMedCrossRefGoogle Scholar
  118. 118.
    Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL, et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med. 2007;357(9):851–62. doi:10.1056/NEJMoa073493.PubMedCrossRefGoogle Scholar
  119. 119.
    Qu HQ, Bradfield JP, Belisle A, Grant SF, Hakonarson H, Polychronakos C. The type I diabetes association of the IL2RA locus. Genes Immun. 2009;10(Suppl 1):S42–8. doi:10.1038/gene.2009.90.PubMedCrossRefGoogle Scholar
  120. 120.
    Giovannoni G, Cutter GR, Lunemann J, Martin R, Munz C, Sriram S, et al. Infectious causes of multiple sclerosis. Lancet Neurol. 2006;5(10):887–94. doi:10.1016/S1474-4422(06)70577-4.PubMedCrossRefGoogle Scholar
  121. 121.
    Giovannoni G, Ebers G. Multiple sclerosis: the environment and causation. Curr Opin Neurol. 2007;20(3):261–8. doi:10.1097/WCO.0b013e32815610c2.PubMedCrossRefGoogle Scholar
  122. 122.
    Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis. 2007;66(9):1137–42. doi:10.1136/ard.2007.069831.PubMedCrossRefGoogle Scholar
  123. 123.
    Carvalho JF, Blank M, Kiss E, Tarr T, Amital H, Shoenfeld Y. Anti-vitamin D, vitamin D in SLE: preliminary results. Ann N Y Acad Sci. 2007;1109:550–7. doi:10.1196/annals.1398.061.PubMedCrossRefGoogle Scholar
  124. 124.
    Shoenfeld N, Amital H, Shoenfeld Y. The effect of melanism and vitamin D synthesis on the incidence of autoimmune disease. Nat Clin Pract Rheumatol. 2009;5(2):99–105. doi:10.1038/ncprheum0989.PubMedCrossRefGoogle Scholar
  125. 125.
    Shapira Y, Agmon-Levin N, Shoenfeld Y. Mycobacterium tuberculosis, autoimmunity, and vitamin D. Clin Rev Allergy Immunol. 2010;38(2–3):169–77. doi:10.1007/s12016-009-8150-1.PubMedCrossRefGoogle Scholar
  126. 126.
    Amital H, Szekanecz Z, Szucs G, Danko K, Nagy E, Csepany T, et al. Serum concentrations of 25-OH vitamin D in patients with systemic lupus erythematosus (SLE) are inversely related to disease activity: is it time to routinely supplement patients with SLE with vitamin D? Ann Rheum Dis. 2010;69(6):1155–7. doi:10.1136/ard.2009.120329.PubMedCrossRefGoogle Scholar
  127. 127.
    Toubi E, Shoenfeld Y. The role of vitamin D in regulating immune responses. Isr Med Assoc J. 2010;12(3):174–5.PubMedGoogle Scholar
  128. 128.
    Souberbielle JC, Body JJ, Lappe JM, Plebani M, Shoenfeld Y, Wang TJ, et al. Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: recommendations for clinical practice. Autoimmun Rev. 2010;9(11):709–15. doi:10.1016/j.autrev.2010.06.009.PubMedCrossRefGoogle Scholar
  129. 129.
    Agmon-Levin N, Blank M, Zandman-Goddard G, Orbach H, Meroni PL, Tincani A, et al. Vitamin D: an instrumental factor in the anti-phospholipid syndrome by inhibition of tissue factor expression. Ann Rheum Dis. 2011;70(1):145–50. doi:10.1136/ard.2010.134817.PubMedCrossRefGoogle Scholar
  130. 130.
    Oren Y, Shapira Y, Agmon-Levin N, Kivity S, Zafrir Y, Altman A, et al. Vitamin D insufficiency in a sunny environment: a demographic and seasonal analysis. Isr Med Assoc J. 2010;12(12):751–6.PubMedGoogle Scholar
  131. 131.
    Kivity S, Agmon-Levin N, Zisappl M, Shapira Y, Nagy EV, Danko K, et al. Vitamin D and autoimmune thyroid diseases. Cell Mol Immunol. 2011;8(3):243–7. doi:10.1038/cmi.2010.73.PubMedCrossRefGoogle Scholar
  132. 132.
    Lerner A, Shapira Y, Agmon-Levin N, Pacht A, Ben Ami Shor D, Lopez HM, et al. The clinical significance of 25OH-Vitamin D status in celiac disease. Clin Rev Allergy Immunol. 2012;42(3):322–30. doi:10.1007/s12016-010-8237-8.PubMedCrossRefGoogle Scholar
  133. 133.
    Hajas A, Sandor J, Csathy L, Csipo I, Barath S, Paragh G, et al. Vitamin D insufficiency in a large MCTD population. Autoimmun Rev. 2011;10(6):317–24. doi:10.1016/j.autrev.2010.11.006.PubMedCrossRefGoogle Scholar
  134. 134.
    Cutolo M, Pizzorni C, Sulli A. Vitamin D endocrine system involvement in autoimmune rheumatic diseases. Autoimmun Rev. 2011;11(2):84–7. doi:10.1016/j.autrev.2011.08.003.PubMedCrossRefGoogle Scholar
  135. 135.
    Lucas RM, Ponsonby AL, Dear K, Valery PC, Pender MP, Taylor BV, et al. Sun exposure and vitamin D are independent risk factors for CNS demyelination. Neurology. 2011;76(6):540–8. doi:10.1212/WNL.0b013e31820af93d.PubMedCrossRefGoogle Scholar
  136. 136.
    Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296(23):2832–8. doi:10.1001/jama.296.23.2832.PubMedCrossRefGoogle Scholar
  137. 137.
    Handel AE, Williamson AJ, Disanto G, Dobson R, Giovannoni G, Ramagopalan SV. Smoking and multiple sclerosis: an updated meta-analysis. PLoS ONE. 2011;6(1):e16149. doi:10.1371/journal.pone.0016149.PubMedCrossRefGoogle Scholar
  138. 138.
    Hedstrom AK, Sundqvist E, Baarnhielm M, Nordin N, Hillert J, Kockum I, et al. Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis. Brain. 2011;134(Pt 3):653–64. doi:10.1093/brain/awq371.PubMedCrossRefGoogle Scholar
  139. 139.
    Stejskal V, Hudecek R, Stejskal J, Sterzl I. Diagnosis and treatment of metal-induced side-effects. Neuro Endocrinol Lett. 2006;27(Suppl 1):7–16.PubMedGoogle Scholar
  140. 140.
    Fleming JO. Helminths and multiple sclerosis: will old friends give us new treatments for MS? J Neuroimmunol. 2011;233(1–2):3–5. doi:10.1016/j.jneuroim.2011.01.003.PubMedCrossRefGoogle Scholar
  141. 141.
    Gaisford W, Cooke A. Can infections protect against autoimmunity? Curr Opin Rheumatol. 2009;21(4):391–6. doi:10.1097/BOR.0b013e32832c2dee.PubMedCrossRefGoogle Scholar
  142. 142.
    Kim JS, Lee KS, Park JH, Kim MY, Shin WS. Detection of human herpesvirus 6 variant A in peripheral blood mononuclear cells from multiple sclerosis patients. Eur Neurol. 2000;43(3):170–3.PubMedCrossRefGoogle Scholar
  143. 143.
    Opsahl ML, Kennedy PG. Early and late HHV-6 gene transcripts in multiple sclerosis lesions and normal appearing white matter. Brain. 2005;128(Pt 3):516–27. doi:10.1093/brain/awh390.PubMedCrossRefGoogle Scholar
  144. 144.
    Albright AV, Lavi E, Black JB, Goldberg S, O’Connor MJ, Gonzalez-Scarano F. The effect of human herpesvirus-6 (HHV-6) on cultured human neural cells: oligodendrocytes and microglia. J Neurovirol. 1998;4(5):486–94.PubMedCrossRefGoogle Scholar
  145. 145.
    Chan PK, Ng HK, Cheng AF. Detection of human herpesviruses 6 and 7 genomic sequences in brain tumours. J Clin Path. 1999;52(8):620–3.PubMedCrossRefGoogle Scholar
  146. 146.
    Mirandola P, Stefan A, Brambilla E, Campadelli-Fiume G, Grimaldi LM. Absence of human herpesvirus 6 and 7 from spinal fluid and serum of multiple sclerosis patients. Neurology. 1999;53(6):1367–8.PubMedCrossRefGoogle Scholar
  147. 147.
    Sospedra M, Zhao Y, ZurHausen H, Muraro PA, Hamashin C, DeVilliers EM, et al. Recognition of conserved amino acid motifs of common viruses and its role in autoimmunity. PLoS Pathog. 2005;1(4):e41. doi:10.1371/journal.ppat.0010041.PubMedCrossRefGoogle Scholar
  148. 148.
    Bogdanos DP, Gershwin ME. What is new in primary biliary cirrhosis? Dig Dis. 2012;30(Suppl 1):20–31. doi:10.1159/000341118.PubMedCrossRefGoogle Scholar
  149. 149.
    Corpechot C, Chretien Y, Chazouilleres O, Poupon R. Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis. J Hepatol. 2010;53(1):162–9. doi:10.1016/j.jhep.2010.02.019.PubMedCrossRefGoogle Scholar
  150. 150.
    Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, et al. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology. 2005;42(5):1194–202. doi:10.1002/hep.20907.PubMedCrossRefGoogle Scholar
  151. 151.
    Parikh-Patel A, Gold EB, Worman H, Krivy KE, Gershwin ME. Risk factors for primary biliary cirrhosis in a cohort of patients from the United States. Hepatology. 2001;33(1):16–21. doi:10.1053/jhep.2001.21165.PubMedCrossRefGoogle Scholar
  152. 152.
    Prince MI, Ducker SJ, James OF. Case-control studies of risk factors for primary biliary cirrhosis in two United Kingdom populations. Gut. 2010;59(4):508–12. doi:10.1136/gut.2009.184218.PubMedCrossRefGoogle Scholar
  153. 153.
    Invernizzi P, Selmi C, Gershwin ME. Update on primary biliary cirrhosis. Dig Liver Dis. 2010;42(6):401–8. doi:10.1016/j.dld.2010.02.014.PubMedCrossRefGoogle Scholar
  154. 154.
    Selmi C, Invernizzi P, Zuin M, Podda M, Gershwin ME. Genetics and geoepidemiology of primary biliary cirrhosis: following the footprints to disease etiology. Semin Liver Dis. 2005;25(3):265–80. doi:10.1055/s-2005-916319.PubMedCrossRefGoogle Scholar
  155. 155.
    Selmi C, Invernizzi P, Zuin M, Podda M, Seldin MF, Gershwin ME. Genes and (auto)immunity in primary biliary cirrhosis. Genes Immun. 2005;6(7):543–56. doi:10.1038/sj.gene.6364248.PubMedCrossRefGoogle Scholar
  156. 156.
    Smyk D, Cholongitas E, Kriese S, Rigopoulou EI, Bogdanos DP. Primary biliary cirrhosis: family stories. Autoimmune Dis. 2011;2011:189585. doi:10.4061/2011/189585.PubMedGoogle Scholar
  157. 157.
    Bogdanos DP, Smyk DS, Rigopoulou EI, Mytilinaiou MG, Heneghan MA, Selmi C, et al. Twin studies in autoimmune disease: genetics, gender and environment. J Autoimmun. 2012;38(2–3):J156–69. doi:10.1016/j.jaut.2011.11.003.PubMedCrossRefGoogle Scholar
  158. 158.
    Gershwin ME, Mackay IR. The causes of primary biliary cirrhosis: convenient and inconvenient truths. Hepatology. 2008;47(2):737–45. doi:10.1002/hep.22042.PubMedCrossRefGoogle Scholar
  159. 159.
    Konikoff F, Pecht M, Theodor E, Shoenfeld Y. Primary biliary cirrhosis: lymphocyte subsets and function in a time frame. Hepatology. 1989;10(4):525–6.PubMedCrossRefGoogle Scholar
  160. 160.
    Schlesinger M, Benbassat C, Shoenfeld Y. Complement profile in primary biliary cirrhosis. Immunol Res. 1992;11(2):98–103.PubMedCrossRefGoogle Scholar
  161. 161.
    Shoenfeld Y. Primary biliary cirrhosis and autoimmune rheumatic diseases: prediction and prevention. Isr J Med Sci. 1992;28(2):113–6.PubMedGoogle Scholar
  162. 162.
    Weiss P, Shoenfeld Y. Primary biliary cirrhosis is a multisystem disorder. Ann Med Interne (Paris). 1991;142(4):283–7.Google Scholar
  163. 163.
    Weiss P, Shoenfeld Y. Primary biliary cirrhosis: increasing problem, approaching solution. Isr J Med Sci. 1992;28(10):726–8.PubMedGoogle Scholar
  164. 164.
    Benbassat C, Schlesinger M, Shoenfeld Y. The complement system and primary biliary cirrhosis. J Clin Lab Immunol. 1992;38(2):51–61.PubMedGoogle Scholar
  165. 165.
    Rotman P, Levy Y, Shoenfeld Y. Primary biliary cirrhosis–association or overlap with other autoimmune diseases. Isr J Med Sci. 1997;33(12):823–5.PubMedGoogle Scholar
  166. 166.
    Shapira S, Bar-Dayan Y, Gershwin ME, Shoenfeld Y. Is it possible to predict and prevent primary biliary cirrhosis? Harefuah. 1999;137(1–2):39–41.PubMedGoogle Scholar
  167. 167.
    Aoki CA, Roifman CM, Lian ZX, Bowlus CL, Norman GL, Shoenfeld Y, et al. IL-2 receptor alpha deficiency and features of primary biliary cirrhosis. J Autoimmun. 2006;27(1):50–3. doi:10.1016/j.jaut.2006.04.005.PubMedCrossRefGoogle Scholar
  168. 168.
    Barak V, Selmi C, Schlesinger M, Blank M, Agmon-Levin N, Kalickman I, et al. Serum inflammatory cytokines, complement components, and soluble interleukin 2 receptor in primary biliary cirrhosis. J Autoimmun. 2009;33(3–4):178–82. doi:10.1016/j.jaut.2009.09.010.PubMedCrossRefGoogle Scholar
  169. 169.
    Bogdanos DP, Baum H, Vergani D. Antimitochondrial and other autoantibodies. Clin Liver Dis. 2003;7(4):759–77.PubMedCrossRefGoogle Scholar
  170. 170.
    Bogdanos DP, Baum H, Vergani D, Burroughs AK. The role of E. coli infection in the pathogenesis of primary biliary cirrhosis. Dis Markers. 2010;29(6):301–11. doi:10.3233/DMA-2010-0745.PubMedCrossRefGoogle Scholar
  171. 171.
    Bogdanos DP, Vergani D. Origin of cross-reactive autoimmunity in primary biliary cirrhosis. Liver Int. 2006;26(6):633–5. doi:10.1111/j.1478-3231.2006.01291.x.PubMedCrossRefGoogle Scholar
  172. 172.
    Bogdanos DP, Vergani D. Bacteria and primary biliary cirrhosis. Clin Rev Allergy Immunol. 2009;36(1):30–9. doi:10.1007/s12016-008-8087-9.PubMedCrossRefGoogle Scholar
  173. 173.
    Gershwin ME, Mackay IR. Primary biliary cirrhosis: paradigm or paradox for autoimmunity. Gastroenterology. 1991;100(3):822–33.PubMedGoogle Scholar
  174. 174.
    Mackay IR, Whittingham S, Fida S, Myers M, Ikuno N, Gershwin ME, et al. The peculiar autoimmunity of primary biliary cirrhosis. Immunol Rev. 2000;174:226–37.PubMedCrossRefGoogle Scholar
  175. 175.
    Shimoda S, Nakamura M, Ishibashi H, Hayashida K, Niho Y. HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases. J Exp Med. 1995;181(5):1835–45.PubMedCrossRefGoogle Scholar
  176. 176.
    Shimoda S, Nakamura M, Shigematsu H, Tanimoto H, Gushima T, Gershwin ME, et al. Mimicry peptides of human PDC-E2 163–176 peptide, the immunodominant T-cell epitope of primary biliary cirrhosis. Hepatology. 2000;31(6):1212–6. doi:10.1053/jhep.2000.8090.PubMedCrossRefGoogle Scholar
  177. 177.
    Shimoda S, Van de Water J, Ansari A, Nakamura M, Ishibashi H, Coppel RL, et al. Identification and precursor frequency analysis of a common T cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis. J Clin Invest. 1998;102(10):1831–40. doi:10.1172/JCI4213.PubMedCrossRefGoogle Scholar
  178. 178.
    Vergani D, Bogdanos DP. Positive markers in AMA-negative PBC. Am J Gastroenterol. 2003;98(2):241–3. doi:10.1111/j.1572-0241.2003.07270.x.PubMedCrossRefGoogle Scholar
  179. 179.
    Hohenester S, Oude-Elferink RP, Beuers U. Primary biliary cirrhosis. Semin Immunopathol. 2009;31(3):283–307. doi:10.1007/s00281-009-0164-5.PubMedCrossRefGoogle Scholar
  180. 180.
    Neuberger J. Primary biliary cirrhosis. Lancet. 1997;350(9081):875–9. doi:10.1016/S0140-6736(97)05419-6.PubMedCrossRefGoogle Scholar
  181. 181.
    Bogdanos DP, Invernizzi P, Mackay IR, Vergani D. Autoimmune liver serology: current diagnostic and clinical challenges. World J Gastroenterol. 2008;14(21):3374–87.PubMedCrossRefGoogle Scholar
  182. 182.
    Bogdanos DP, Komorowski L. Disease-specific autoantibodies in primary biliary cirrhosis. Clin Chim Acta. 2011;412(7–8):502–12. doi:10.1016/j.cca.2010.12.019.PubMedCrossRefGoogle Scholar
  183. 183.
    Dahnrich C, Pares A, Caballeria L, Rosemann A, Schlumberger W, Probst C, et al. New ELISA for detecting primary biliary cirrhosis-specific antimitochondrial antibodies. Clin Chem. 2009;55(5):978–85. doi:10.1373/clinchem.2008.118299.PubMedCrossRefGoogle Scholar
  184. 184.
    Liu H, Norman GL, Shums Z, Worman HJ, Krawitt EL, Bizzaro N, et al. PBC screen: an IgG/IgA dual isotype ELISA detecting multiple mitochondrial and nuclear autoantibodies specific for primary biliary cirrhosis. J Autoimmun. 2010;35(4):436–42. doi:10.1016/j.jaut.2010.09.005.PubMedCrossRefGoogle Scholar
  185. 185.
    Ma Y, Thomas MG, Okamoto M, Bogdanos DP, Nagl S, Kerkar N, et al. Key residues of a major cytochrome P4502D6 epitope are located on the surface of the molecule. J Immunol. 2002;169(1):277–85.PubMedGoogle Scholar
  186. 186.
    Rigopoulou EI, Davies ET, Bogdanos DP, Liaskos C, Mytilinaiou M, Koukoulis GK, et al. Antimitochondrial antibodies of immunoglobulin G3 subclass are associated with a more severe disease course in primary biliary cirrhosis. Liver Int. 2007;27(9):1226–31. doi:10.1111/j.1478-3231.2007.01586.x.PubMedCrossRefGoogle Scholar
  187. 187.
    Wen L, Ma Y, Bogdanos DP, Wong FS, Demaine A, Mieli-Vergani G, et al. Pediatric autoimmune liver diseases: the molecular basis of humoral and cellular immunity. Curr Molec Med. 2001;1(3):379–89.CrossRefGoogle Scholar
  188. 188.
    Invernizzi P, Lleo A, Podda M. Interpreting serological tests in diagnosing autoimmune liver diseases. Semin Liver Dis. 2007;27(2):161–72. doi:10.1055/s-2007-979469.PubMedCrossRefGoogle Scholar
  189. 189.
    Rigopoulou EI, Bogdanos DP, Liaskos C, Koutsoumpas A, Baum H, Vergani D, et al. Anti-mitochondrial antibody immunofluorescent titres correlate with the number and intensity of immunoblot-detected mitochondrial bands in patients with primary biliary cirrhosis. Clin Chim Acta. 2007;380(1–2):118–21. doi:10.1016/j.cca.2007.01.023.PubMedCrossRefGoogle Scholar
  190. 190.
    Gilburd B, Ziporen L, Zharhary D, Blank M, Zurgil N, Scheinberg MA, et al. Antimitochondrial (pyruvate dehydrogenase) antibodies in leprosy. J Clin Immunol. 1994;14(1):14–9.PubMedCrossRefGoogle Scholar
  191. 191.
    Konikoff F, Isenberg DA, Barrison I, Theodor E, Shoenfeld Y. Antinuclear autoantibodies in chronic liver diseases. Hepatogastroenterology. 1989;36(5):341–5.PubMedGoogle Scholar
  192. 192.
    Konikoff F, Isenberg DA, Kooperman O, Kennedy RC, Rauch J, Theodor E, et al. Common lupus anti-DNA antibody idiotypes in chronic liver diseases. Clin Immunol Immunopathol. 1987;43(2):265–72.PubMedCrossRefGoogle Scholar
  193. 193.
    Konikoff F, Shoenfeld Y, Isenberg DA, Barrison I, Sobe T, Theodor E, et al. Anti-Rnp antibodies in chronic liver diseases. Clin Exp Rheumatol. 1987;5(4):359–61.PubMedGoogle Scholar
  194. 194.
    Krause I, Hacham S, Gilburd B, Damianovitch M, Blank M, Shoenfeld Y. Absence of anti-idiotypic antibodies in IVIG preparations to autoantibodies of rare autoimmune diseases. Clin Immunol Immunopathol. 1995;77(3):229–35.PubMedCrossRefGoogle Scholar
  195. 195.
    Lorber M, Kra-Oz Z, Guilbrud B, Shoenfeld Y. Natural (antiphospholipid-PDH,-DNA) autoantibodies and their physiologic serum inhibitors. Isr J Med Sci. 1995;31(1):31–5.PubMedGoogle Scholar
  196. 196.
    Maran R, Dueymes M, Adler Y, Shoenfeld Y, Youinou P. Isotypic distribution of anti-pyruvate dehydrogenase antibodies in patients with primary biliary cirrhosis and their family members. J Clin Immunol. 1994;14(5):323–6.PubMedCrossRefGoogle Scholar
  197. 197.
    Shoenfeld Y, Beresovski A, Zharhary D, Tomer Y, Swissa M, Sela E, et al. Natural autoantibodies in sera of patients with Gaucher’s disease. J Clin Immunol. 1995;15(6):363–72.PubMedCrossRefGoogle Scholar
  198. 198.
    Zurgil N, Bakimer R, Kaplan M, Youinou P, Shoenfeld Y. Anti-pyruvate dehydrogenase autoantibodies in primary biliary cirrhosis. J Clin Immunol. 1991;11(5):239–45.PubMedCrossRefGoogle Scholar
  199. 199.
    Zurgil N, Bakimer R, Moutsopoulos HM, Tzioufas AG, Youinou P, Isenberg DA, et al. Antimitochondrial (pyruvate dehydrogenase) autoantibodies in autoimmune rheumatic diseases. J Clin Immunol. 1992;12(3):201–9.PubMedCrossRefGoogle Scholar
  200. 200.
    Zurgil N, Bakimer R, Slor H, Kaplan M, Moutsopoulos H, Shoenfeld Y. Pyruvate dehydrogenase as an antigen to detect antimitochondrial antibodies. Isr J Med Sci. 1990;26(12):682–5.PubMedGoogle Scholar
  201. 201.
    Zurgil N, Konikoff F, Bakimer R, Slor H, Shoenfeld Y. Detection of antimitochondrial antibodies: characterization by enzyme immunoassay and immunoblotting. Autoimmunity. 1989;4(4):289–97.PubMedCrossRefGoogle Scholar
  202. 202.
    Tishler M, Alosachie I, Barka N, Lin HC, Gershwin ME, Peter JB, et al. Primary Sjogren’s syndrome and primary biliary cirrhosis: differences and similarities in the autoantibody profile. Clin Exp Rheumatol. 1995;13(4):497–500.PubMedGoogle Scholar
  203. 203.
    Bean P, Sutphin MS, Liu Y, Anton R, Reynolds TB, Shoenfeld Y, et al. Carbohydrate-deficient transferrin and false-positive results for alcohol abuse in primary biliary cirrhosis: differential diagnosis by detection of mitochondrial autoantibodies. Clin Chem. 1995;41(6 Pt 1):858–61.PubMedGoogle Scholar
  204. 204.
    Agmon-Levin N, Shapira Y, Selmi C, Barzilai O, Ram M, Szyper-Kravitz M, et al. A comprehensive evaluation of serum autoantibodies in primary biliary cirrhosis. J Autoimmun. 2010;34(1):55–8. doi:10.1016/j.jaut.2009.08.009.PubMedCrossRefGoogle Scholar
  205. 205.
    Metcalf JV, Mitchison HC, Palmer JM, Jones DE, Bassendine MF, James OF. Natural history of early primary biliary cirrhosis. Lancet. 1996;348(9039):1399–402. doi:10.1016/S0140-6736(96)04410-8.PubMedCrossRefGoogle Scholar
  206. 206.
    Dubel L, Tanaka A, Leung PS, Van de Water J, Coppel R, Roche T, et al. Autoepitope mapping and reactivity of autoantibodies to the dihydrolipoamide dehydrogenase-binding protein (E3BP) and the glycine cleavage proteins in primary biliary cirrhosis. Hepatology. 1999;29(4):1013–8. doi:10.1002/hep.510290403.PubMedCrossRefGoogle Scholar
  207. 207.
    Leung PS, Coppel RL, Ansari A, Munoz S, Gershwin ME. Antimitochondrial antibodies in primary biliary cirrhosis. Semin Liver Dis. 1997;17(1):61–9. doi:10.1055/s-2007-1007183.PubMedCrossRefGoogle Scholar
  208. 208.
    Palmer JM, Jones DE, Quinn J, McHugh A, Yeaman SJ. Characterization of the autoantibody responses to recombinant E3 binding protein (protein X) of pyruvate dehydrogenase in primary biliary cirrhosis. Hepatology. 1999;30(1):21–6. doi:10.1002/hep.510300106.PubMedCrossRefGoogle Scholar
  209. 209.
    Van de Water J, Fregeau D, Davis P, Ansari A, Danner D, Leung P, et al. Autoantibodies of primary biliary cirrhosis recognize dihydrolipoamide acetyltransferase and inhibit enzyme function. J Immunol. 1988;141(7):2321–4.PubMedGoogle Scholar
  210. 210.
    Bogdanos DP, Liaskos C, Pares A, Norman G, Rigopoulou EI, Caballeria L et al. Anti-gp210 antibody mirrors disease severity in primary biliary cirrhosis. Hepatology. 2007;45(6):1583; author reply -4. doi: 10.1002/hep.21678.Google Scholar
  211. 211.
    Invernizzi P, Podda M, Battezzati PM, Crosignani A, Zuin M, Hitchman E, et al. Autoantibodies against nuclear pore complexes are associated with more active and severe liver disease in primary biliary cirrhosis. J Hepatol. 2001;34(3):366–72.PubMedCrossRefGoogle Scholar
  212. 212.
    Miyachi K, Hankins RW, Matsushima H, Kikuchi F, Inomata T, Horigome T, et al. Profile and clinical significance of anti-nuclear envelope antibodies found in patients with primary biliary cirrhosis: a multicenter study. J Autoimmun. 2003;20(3):247–54.PubMedCrossRefGoogle Scholar
  213. 213.
    Nakamura M, Kondo H, Mori T, Komori A, Matsuyama M, Ito M, et al. Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis. Hepatology. 2007;45(1):118–27. doi:10.1002/hep.21472.PubMedCrossRefGoogle Scholar
  214. 214.
    Rigopoulou EI, Davies ET, Pares A, Zachou K, Liaskos C, Bogdanos DP, et al. Prevalence and clinical significance of isotype specific antinuclear antibodies in primary biliary cirrhosis. Gut. 2005;54(4):528–32. doi:10.1136/gut.2003.036558.PubMedCrossRefGoogle Scholar
  215. 215.
    Itoh S, Ichida T, Yoshida T, Hayakawa A, Uchida M, Tashiro-Itoh T, et al. Autoantibodies against a 210 kDa glycoprotein of the nuclear pore complex as a prognostic marker in patients with primary biliary cirrhosis. J Gastroenterol Hepatol. 1998;13(3):257–65.PubMedCrossRefGoogle Scholar
  216. 216.
    Lassoued K, Guilly MN, Andre C, Paintrand M, Dhumeaux D, Danon F, et al. Autoantibodies to 200 kD polypeptide(s) of the nuclear envelope: a new serologic marker of primary biliary cirrhosis. Clin Exp Immunol. 1988;74(2):283–8.PubMedGoogle Scholar
  217. 217.
    Muratori P, Muratori L, Ferrari R, Cassani F, Bianchi G, Lenzi M, et al. Characterization and clinical impact of antinuclear antibodies in primary biliary cirrhosis. Am J Gastroenterol. 2003;98(2):431–7. doi:10.1111/j.1572-0241.2003.07257.x.PubMedCrossRefGoogle Scholar
  218. 218.
    Wesierska-Gadek J, Penner E, Battezzati PM, Selmi C, Zuin M, Hitchman E, et al. Correlation of initial autoantibody profile and clinical outcome in primary biliary cirrhosis. Hepatology. 2006;43(5):1135–44. doi:10.1002/hep.21172.PubMedCrossRefGoogle Scholar
  219. 219.
    Yang WH, Yu JH, Nakajima A, Neuberg D, Lindor K, Bloch DB. Do antinuclear antibodies in primary biliary cirrhosis patients identify increased risk for liver failure? Clin Gastroenterol Hepatol. 2004;2(12):1116–22.PubMedCrossRefGoogle Scholar
  220. 220.
    Duarte-Rey C, Bogdanos D, Yang CY, Roberts K, Leung PS, Anaya JM, et al. Primary biliary cirrhosis and the nuclear pore complex. Autoimmun Rev. 2012;11(12):898–902. doi:10.1016/j.autrev.2012.03.005.PubMedCrossRefGoogle Scholar
  221. 221.
    Duarte-Rey C, Bogdanos DP, Leung PS, Anaya JM, Gershwin ME. IgM predominance in autoimmune disease: genetics and gender. Autoimmun Rev. 2012;11(6–7):A404–12. doi:10.1016/j.autrev.2011.12.001.PubMedCrossRefGoogle Scholar
  222. 222.
    Bach N, Schaffner F. Familial primary biliary cirrhosis. J Hepatol. 1994;20(6):698–701.PubMedCrossRefGoogle Scholar
  223. 223.
    Floreani A, Naccarato R, Chiaramonte M. Prevalence of familial disease in primary biliary cirrhosis in Italy. J Hepatol. 1997;26(3):737–8.PubMedCrossRefGoogle Scholar
  224. 224.
    Tsuji K, Watanabe Y, Van De Water J, Nakanishi T, Kajiyama G, Parikh-Patel A, et al. Familial primary biliary cirrhosis in Hiroshima. J Autoimmun. 1999;13(1):171–8. doi:10.1006/jaut.1999.0299.PubMedCrossRefGoogle Scholar
  225. 225.
    Lazaridis KN, Juran BD, Boe GM, Slusser JP, de Andrade M, Homburger HA, et al. Increased prevalence of antimitochondrial antibodies in first-degree relatives of patients with primary biliary cirrhosis. Hepatology. 2007;46(3):785–92. doi:10.1002/hep.21749.PubMedCrossRefGoogle Scholar
  226. 226.
    Douglas JG, Finlayson ND. Are increased individual susceptibility and environmental factors both necessary for the development of primary biliary cirrhosis? BMJ. 1979;2(6187):419–20.PubMedCrossRefGoogle Scholar
  227. 227.
    Fagan E, Williams R, Cox S. Primary biliary cirrhosis in mother and daughter. BMJ. 1977;2(6096):1195.PubMedCrossRefGoogle Scholar
  228. 228.
    Tong MJ, Nies KM, Reynolds TB, Quismorio FP. Immunological studies in familial primary biliary cirrhosis. Gastroenterology. 1976;71(2):305–7.PubMedGoogle Scholar
  229. 229.
    Smyk DS, Rigopoulou EI, Bogdanos DP. Potential roles for infectious agents in the pathophysiology of primary biliary cirrhosis: what’s new? Curr Infect Dis Rep. 2012;. doi:10.1007/s11908-012-0304-2.Google Scholar
  230. 230.
    Chuang YH, Ridgway WM, Ueno Y, Gershwin ME. Animal models of primary biliary cirrhosis. Clin Liver Dis. 2008;12(2):333–47. doi:10.1016/j.cld.2008.02.011.PubMedCrossRefGoogle Scholar
  231. 231.
    Hirschfield GM, Invernizzi P. Progress in the genetics of primary biliary cirrhosis. Semin Liver Dis. 2011;31(2):147–56. doi:10.1055/s-0031-1276644.PubMedCrossRefGoogle Scholar
  232. 232.
    Lleo A, Invernizzi P, Mackay IR, Prince H, Zhong RQ, Gershwin ME. Etiopathogenesis of primary biliary cirrhosis. World J Gastroenterol. 2008;14(21):3328–37.PubMedCrossRefGoogle Scholar
  233. 233.
    Selmi C, Zuin M, Gershwin ME. The unfinished business of primary biliary cirrhosis. J Hepatol. 2008;49(3):451–60. doi:10.1016/j.jhep.2008.06.006.PubMedCrossRefGoogle Scholar
  234. 234.
    Wu SJ, Yang YH, Tsuneyama K, Leung PS, Illarionov P, Gershwin ME, et al. Innate immunity and primary biliary cirrhosis: activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis. Hepatology. 2011;53(3):915–25. doi:10.1002/hep.24113.PubMedCrossRefGoogle Scholar
  235. 235.
    Hirschfield GM, Gershwin ME. Primary biliary cirrhosis: one disease with many faces. Isr Med Assoc J. 2011;13(1):55–9.PubMedGoogle Scholar
  236. 236.
    Invernizzi P. Human leukocyte antigen in primary biliary cirrhosis: an old story now reviving. Hepatology. 2011;. doi:10.1002/hep.24414.Google Scholar
  237. 237.
    Hemminki K, Li X, Sundquist K, Sundquist J. Shared familial aggregation of susceptibility to autoimmune diseases. Arthritis Rheum. 2009;60(9):2845–7. doi:10.1002/art.24749.PubMedCrossRefGoogle Scholar
  238. 238.
    Hirschfield GM, Liu X, Han Y, Gorlov IP, Lu Y, Xu C, et al. Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis. Nat Genet. 2010;42(8):655–7. doi:10.1038/ng.631.PubMedCrossRefGoogle Scholar
  239. 239.
    Hirschfield GM, Liu X, Xu C, Lu Y, Xie G, Gu X, et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med. 2009;360(24):2544–55. doi:10.1056/NEJMoa0810440.PubMedCrossRefGoogle Scholar
  240. 240.
    Liu X, Invernizzi P, Lu Y, Kosoy R, Bianchi I, Podda M, et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet. 2010;42(8):658–60. doi:10.1038/ng.627.PubMedCrossRefGoogle Scholar
  241. 241.
    Mells GF, Floyd JA, Morley KI, Cordell HJ, Franklin CS, Shin SY, et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet. 2011;43(4):329–32. doi:10.1038/ng.789.PubMedCrossRefGoogle Scholar
  242. 242.
    Tanaka A, Invernizzi P, Ohira H, Kikuchi K, Nezu S, Kosoy R, et al. Replicated association of 17q12-21 with susceptibility of primary biliary cirrhosis in a Japanese cohort. Tissue Antigens. 2011;78(1):65–8. doi:10.1111/j.1399-0039.2011.01684.x.PubMedCrossRefGoogle Scholar
  243. 243.
    Tanaka A, Ohira H, Kikuchi K, Nezu S, Shibuya A, Bianchi I, et al. Genetic association of Fc receptor-like 3 polymorphisms with susceptibility to primary biliary cirrhosis: ethnic comparative study in Japanese and Italian patients. Tissue Antigens. 2011;77(3):239–43. doi:10.1111/j.1399-0039.2010.01600.x.PubMedCrossRefGoogle Scholar
  244. 244.
    Invernizzi P, Miozzo M, Battezzati PM, Bianchi I, Grati FR, Simoni G, et al. Frequency of monosomy X in women with primary biliary cirrhosis. Lancet. 2004;363(9408):533–5. doi:10.1016/S0140-6736(04)15541-4.PubMedCrossRefGoogle Scholar
  245. 245.
    Invernizzi P, Pasini S, Selmi C, Gershwin ME, Podda M. Female predominance and X chromosome defects in autoimmune diseases. J Autoimmun. 2009;33(1):12–6. doi:10.1016/j.jaut.2009.03.005.PubMedCrossRefGoogle Scholar
  246. 246.
    Miozzo M, Selmi C, Gentilin B, Grati FR, Sirchia S, Oertelt S, et al. Preferential X chromosome loss but random inactivation characterize primary biliary cirrhosis. Hepatology. 2007;46(2):456–62. doi:10.1002/hep.21696.PubMedCrossRefGoogle Scholar
  247. 247.
    Bogdanos DP, Baum H, Butler P, Rigopoulou EI, Davies ET, Ma Y, et al. Association between the primary biliary cirrhosis specific anti-sp100 antibodies and recurrent urinary tract infection. Dig Liver Dis. 2003;35(11):801–5.PubMedCrossRefGoogle Scholar
  248. 248.
    Bogdanos DP, Baum H, Grasso A, Okamoto M, Butler P, Ma Y, et al. Microbial mimics are major targets of crossreactivity with human pyruvate dehydrogenase in primary biliary cirrhosis. J Hepatol. 2004;40(1):31–9.PubMedCrossRefGoogle Scholar
  249. 249.
    Bogdanos DP, Pares A, Rodes J, Vergani D. Primary biliary cirrhosis specific antinuclear antibodies in patients from Spain. Am J Gastroenterol. 2004;99(4):763-4; author reply 5. doi: 10.1111/j.1572-0241.2004.04119.x.Google Scholar
  250. 250.
    Bogdanos DP, Baum H, Okamoto M, Montalto P, Sharma UC, Rigopoulou EI, et al. Primary biliary cirrhosis is characterized by IgG3 antibodies cross-reactive with the major mitochondrial autoepitope and its Lactobacillus mimic. Hepatology. 2005;42(2):458–65. doi:10.1002/hep.20788.PubMedCrossRefGoogle Scholar
  251. 251.
    Bogdanos DP, Baum H, Sharma UC, Grasso A, Ma Y, Burroughs AK, et al. Antibodies against homologous microbial caseinolytic proteases P characterise primary biliary cirrhosis. J Hepatol. 2002;36(1):14–21.PubMedCrossRefGoogle Scholar
  252. 252.
    Fussey SP, Lindsay JG, Fuller C, Perham RN, Dale S, James OF, et al. Autoantibodies in primary biliary cirrhosis: analysis of reactivity against eukaryotic and prokaryotic 2-oxo acid dehydrogenase complexes. Hepatology. 1991;13(3):467–74.PubMedCrossRefGoogle Scholar
  253. 253.
    Koutsoumpas A, Mytilinaiou M, Polymeros D, Dalekos GN, Bogdanos DP. Anti-Helicobacter pylori antibody responses specific for VacA do not trigger primary biliary cirrhosis-specific antimitochondrial antibodies. Eur J Gastroenterol Hepatol. 2009;21(10):1220. doi:10.1097/MEG.0b013e32831a4807.PubMedCrossRefGoogle Scholar
  254. 254.
    Abdulkarim AS, Petrovic LM, Kim WR, Angulo P, Lloyd RV, Lindor KD. Primary biliary cirrhosis: an infectious disease caused by Chlamydia pneumoniae? J Hepatol. 2004;40(3):380–4. doi:10.1016/j.jhep.2003.11.033.PubMedCrossRefGoogle Scholar
  255. 255.
    Burroughs AK, Butler P, Sternberg MJ, Baum H. Molecular mimicry in liver disease. Nature. 1992;358(6385):377–8.PubMedCrossRefGoogle Scholar
  256. 256.
    Burroughs AK, Rosenstein IJ, Epstein O, Hamilton-Miller JM, Brumfitt W, Sherlock S. Bacteriuria and primary biliary cirrhosis. Gut. 1984;25(2):133–7.PubMedCrossRefGoogle Scholar
  257. 257.
    Butler P, Hamilton-Miller J, Baum H, Burroughs AK. Detection of M2 antibodies in patients with recurrent urinary tract infection using an ELISA and purified PBC specific antigens. Evidence for a molecular mimicry mechanism in the pathogenesis of primary biliary cirrhosis? Biochem Mol Biol Int. 1995;35(3):473–85.PubMedGoogle Scholar
  258. 258.
    Butler P, Hamilton-Miller JM, McIntyre N, Burroughs AK. Natural history of bacteriuria in women with primary biliary cirrhosis and the effect of antimicrobial therapy in symptomatic and asymptomatic groups. Gut. 1995;36(6):931–4.PubMedCrossRefGoogle Scholar
  259. 259.
    Butler P, Valle F, Hamilton-Miller JM, Brumfitt W, Baum H, Burroughs AK. M2 mitochondrial antibodies and urinary rough mutant bacteria in patients with primary biliary cirrhosis and in patients with recurrent bacteriuria. J Hepatol. 1993;17(3):408–14.PubMedCrossRefGoogle Scholar
  260. 260.
    Donaldson PT. Genetics of liver disease: immunogenetics and disease pathogenesis. Gut. 2004;53(4):599–608.PubMedCrossRefGoogle Scholar
  261. 261.
    Floreani A, Bassendine MF, Mitchison H, Freeman R, James OF. No specific association between primary biliary cirrhosis and bacteriuria? J Hepatol. 1989;8(2):201–7.PubMedCrossRefGoogle Scholar
  262. 262.
    Leung PS, Park O, Matsumura S, Ansari AA, Coppel RL, Gershwin ME. Is there a relation between Chlamydia infection and primary biliary cirrhosis? Clin Dev Immunol. 2003;10(2–4):227–33.PubMedCrossRefGoogle Scholar
  263. 263.
    Mason A, Xu L, Shen Z, Fodera B, Joplin R, Neuberger J et al. Patients with primary biliary cirrhosis make anti-viral and anti-mitochondrial antibodies to mouse mammary tumor virus. Gastroenterology. 2004;127(6):1863-4; author reply 4-5.Google Scholar
  264. 264.
    McNally RJ, Ducker S, James OF. Are transient environmental agents involved in the cause of primary biliary cirrhosis? Evidence from space-time clustering analysis. Hepatology. 2009;50(4):1169–74.PubMedCrossRefGoogle Scholar
  265. 265.
    Selmi C, Balkwill DL, Invernizzi P, Ansari AA, Coppel RL, Podda M, et al. Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium. Hepatology. 2003;38(5):1250–7.PubMedCrossRefGoogle Scholar
  266. 266.
    Smyk D, Mytilinaiou MG, Rigopoulou EI, Bogdanos DP. PBC triggers in water reservoirs, coal mining areas and waste disposal sites: from Newcastle to New York. Dis Markers. 2010;29(6):337–44. doi:10.3233/DMA-2010-0744.PubMedCrossRefGoogle Scholar
  267. 267.
    Xu L, Sakalian M, Shen Z, Loss G, Neuberger J, Mason A. Cloning the human betaretrovirus proviral genome from patients with primary biliary cirrhosis. Hepatology. 2004;39(1):151–6. doi:10.1002/hep.20024.PubMedCrossRefGoogle Scholar
  268. 268.
    Xu L, Shen Z, Guo L, Fodera B, Keogh A, Joplin R, et al. Does a betaretrovirus infection trigger primary biliary cirrhosis? Proc Natl Acad Sci U S A. 2003;100(14):8454–9.PubMedCrossRefGoogle Scholar
  269. 269.
    Selmi C, De Santis M, Cavaciocchi F, Gershwin ME. Infectious agents and xenobiotics in the etiology of primary biliary cirrhosis. Dis Markers. 2010;29(6):287–99. doi:10.3233/DMA-2010-0746.PubMedCrossRefGoogle Scholar
  270. 270.
    Bogdanos D, Pusl T, Rust C, Vergani D, Beuers U. Primary biliary cirrhosis following Lactobacillus vaccination for recurrent vaginitis. J Hepatol. 2008;49(3):466–73. doi:10.1016/j.jhep.2008.05.022.PubMedCrossRefGoogle Scholar
  271. 271.
    Oldstone MB. Molecular mimicry and autoimmune disease. Cell. 1987;50(6):819–20.PubMedCrossRefGoogle Scholar
  272. 272.
    Bogdanos DP, Choudhuri K, Vergani D. Molecular mimicry and autoimmune liver disease: virtuous intentions, malign consequences. Liver. 2001;21(4):225–32.PubMedCrossRefGoogle Scholar
  273. 273.
    Vergani D, Bogdanos DP, Baum H. Unusual suspects in primary biliary cirrhosis. Hepatology. 2004;39(1):38–41. doi:10.1002/hep.20028.PubMedCrossRefGoogle Scholar
  274. 274.
    Rigopoulou EI, Smyk DS, Matthews CE, Billinis C, Burroughs AK, Lenzi M, et al. Epstein-barr virus as a trigger of autoimmune liver diseases. Adv Virol. 2012;2012:987471. doi:10.1155/2012/987471.PubMedGoogle Scholar
  275. 275.
    Vergani D, Choudhuri K, Bogdanos DP, Mieli-Vergani G. Pathogenesis of autoimmune hepatitis. Clin Liver Dis. 2002;6(3):727–37.PubMedCrossRefGoogle Scholar
  276. 276.
    Vergani D, Longhi MS, Bogdanos DP, Ma Y, Mieli-Vergani G. Autoimmune hepatitis. Semin Immunopathol. 2009;31(3):421–35. doi:10.1007/s00281-009-0170-7.PubMedCrossRefGoogle Scholar
  277. 277.
    Ahn J, Yang L, Paster BJ, Ganly I, Morris L, Pei Z, et al. Oral microbiome profiles: 16S rRNA pyrosequencing and microarray assay comparison. PLoS ONE. 2011;6(7):e22788. doi:10.1371/journal.pone.0022788.PubMedCrossRefGoogle Scholar
  278. 278.
    Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, et al. Enterotypes of the human gut microbiome. Nature. 2011;473(7346):174–80. doi:10.1038/nature09944.PubMedCrossRefGoogle Scholar
  279. 279.
    Gill SR, Pop M, Deboy RT, Eckburg PB, Turnbaugh PJ, Samuel BS, et al. Metagenomic analysis of the human distal gut microbiome. Science. 2006;312(5778):1355–9. doi:10.1126/science.1124234.PubMedCrossRefGoogle Scholar
  280. 280.
    Kurokawa K, Itoh T, Kuwahara T, Oshima K, Toh H, Toyoda A, et al. Comparative metagenomics revealed commonly enriched gene sets in human gut microbiomes. DNA Res. 2007;14(4):169–81. doi:10.1093/dnares/dsm018.PubMedCrossRefGoogle Scholar
  281. 281.
    Marchesi JR. Human distal gut microbiome. Environ Microbiol. 2011;. doi:10.1111/j.1462-2920.2011.02574.x.PubMedGoogle Scholar
  282. 282.
    Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59–65. doi:10.1038/nature08821.PubMedCrossRefGoogle Scholar
  283. 283.
    Saulnier DM, Riehle K, Mistretta TA, Diaz MA, Mandal D, Raza S, et al. Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome. Gastroenterology. 2011;. doi:10.1053/j.gastro.2011.06.072.PubMedGoogle Scholar
  284. 284.
    Siezen RJ, Kleerebezem M. The human gut microbiome: are we our enterotypes? Microbiol Biotechnol. 2011;4(5):550–3. doi:10.1111/j.1751-7915.2011.00290.x.CrossRefGoogle Scholar
  285. 285.
    Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, et al. A core gut microbiome in obese and lean twins. Nature. 2009;457(7228):480–4. doi:10.1038/nature07540.PubMedCrossRefGoogle Scholar
  286. 286.
    Nasidze I, Li J, Schroeder R, Creasey JL, Li M, Stoneking M. High diversity of the saliva microbiome in batwa pygmies. PLoS ONE. 2011;6(8):e23352. doi:10.1371/journal.pone.0023352.PubMedCrossRefGoogle Scholar
  287. 287.
    Smyk DS, Bogdanos DP, Kriese S, Billinis C, Burroughs AK, Rigopoulou EI. Urinary tract infection as a risk factor for autoimmune liver disease: from bench to bedside. Clin Res Hepatol Gastroenterol. 2011;. doi:10.1016/j.clinre.2011.07.013.PubMedGoogle Scholar
  288. 288.
    Varyani FK, West J, Card TR. An increased risk of urinary tract infection precedes development of primary biliary cirrhosis. BMC Gastroenterol. 2011;11:95. doi:10.1186/1471-230X-11-95.PubMedCrossRefGoogle Scholar
  289. 289.
    Smyk D, Rigopoulou EI, Baum H, Burroughs AK, Vergani D, Bogdanos DP. Autoimmunity and environment: am I at risk? Clin Rev Allergy Immunol. 2011;. doi:10.1007/s12016-011-8259-x.Google Scholar
  290. 290.
    Gordon J, Michel G. Discerning trends in multiplex immunoassay technology with potential for resource-limited settings. Clin Chem. 2012;58(4):690–8. doi:10.1373/clinchem.2011.176503.PubMedCrossRefGoogle Scholar
  291. 291.
    Bissonnette L, Bergeron MG. Next revolution in the molecular theranostics of infectious diseases: microfabricated systems for personalized medicine. Expert Rev Mol Diagn. 2006;6(3):433–50. doi:10.1586/14737159.6.3.433.PubMedCrossRefGoogle Scholar
  292. 292.
    Bissonnette L, Bergeron MG. Multiparametric technologies for the diagnosis of syndromic infections. Clinical Microbiology Newsletter. 2012;34(20):159–68.CrossRefGoogle Scholar
  293. 293.
    Natesan M, Ulrich RG. Protein microarrays and biomarkers of infectious disease. Int J Mol Sci. 2010;11(12):5165–83. doi:10.3390/ijms11125165.PubMedCrossRefGoogle Scholar
  294. 294.
    Quintana FJ, Hagedorn PH, Elizur G, Merbl Y, Domany E, Cohen IR. Functional immunomics: microarray analysis of IgG autoantibody repertoires predicts the future response of mice to induced diabetes. Proc Natl Acad Sci U S A. 2004;101(Suppl 2):14615–21. doi:10.1073/pnas.0404848101.PubMedCrossRefGoogle Scholar
  295. 295.
    Larman HB, Zhao Z, Laserson U, Li MZ, Ciccia A, Gakidis MA, et al. Autoantigen discovery with a synthetic human peptidome. Nat Biotechnol. 2011;29(6):535–41. doi:10.1038/nbt.1856.PubMedCrossRefGoogle Scholar
  296. 296.
    Drebber U, Kasper HU, Ratering J, Wedemeyer I, Schirmacher P, Dienes HP, et al. Hepatic granulomas: histological and molecular pathological approach to differential diagnosis–a study of 442 cases. Liver Int. 2008;28(6):828–34. doi:10.1111/j.1478-3231.2008.01695.x.PubMedCrossRefGoogle Scholar
  297. 297.
    O’Donohue J, Fidler H, Garcia-Barcelo M, Nouri-Aria K, Williams R, McFadden J. Mycobacterial DNA not detected in liver sections from patients with primary biliary cirrhosis. J Hepatol. 1998;28(3):433–8.PubMedCrossRefGoogle Scholar
  298. 298.
    Tanaka A, Prindiville TP, Gish R, Solnick JV, Coppel RL, Keeffe EB, et al. Are infectious agents involved in primary biliary cirrhosis? A PCR approach. J Hepatol. 1999;31(4):664–71.PubMedCrossRefGoogle Scholar
  299. 299.
    Vilagut L, Pares A, Rodes J, Vila J, Vinas O, Gines A, et al. Mycobacteria–related to the aetiopathogenesis of primary biliary cirrhosis? J Hepatol. 1996;24(1):125.PubMedCrossRefGoogle Scholar
  300. 300.
    Chen EC, Miller SA, DeRisi JL, Chiu CY. Using a pan-viral microarray assay (Virochip) to screen clinical samples for viral pathogens. J Vis Exp. 2011;(50):e2536. doi:10.3791/2536.
  301. 301.
    Kistler A, Avila PC, Rouskin S, Wang D, Ward T, Yagi S, et al. Pan-viral screening of respiratory tract infections in adults with and without asthma reveals unexpected human coronavirus and human rhinovirus diversity. J Infect Dis. 2007;196(6):817–25. doi:10.1086/520816.PubMedCrossRefGoogle Scholar
  302. 302.
    Nakamura S, Nakaya T, Iida T. Metagenomic analysis of bacterial infections by means of high-throughput DNA sequencing. Exp Biol Med. 2011;236(8):968–71. doi:10.1258/ebm.2011.010378.CrossRefGoogle Scholar
  303. 303.
    Tang P, Chiu C. Metagenomics for the discovery of novel human viruses. Future Microbiol. 2010;5(2):177–89. doi:10.2217/fmb.09.120.PubMedCrossRefGoogle Scholar
  304. 304.
    Moore RA, Warren RL, Freeman JD, Gustavsen JA, Chenard C, Friedman JM, et al. The sensitivity of massively parallel sequencing for detecting candidate infectious agents associated with human tissue. PLoS ONE. 2011;6(5):e19838. doi:10.1371/journal.pone.0019838.PubMedCrossRefGoogle Scholar
  305. 305.
    Broome U, Scheynius A, Hultcrantz R. Induced expression of heat-shock protein on biliary epithelium in patients with primary sclerosing cholangitis and primary biliary cirrhosis. Hepatology. 1993;18(2):298–303.PubMedGoogle Scholar
  306. 306.
    Singhal S, Dian D, Keshavarzian A, Fogg L, Fields JZ, Farhadi A. The role of oral hygiene in inflammatory bowel disease. Dig Dis Sci. 2011;56(1):170–5. doi:10.1007/s10620-010-1263-9.PubMedCrossRefGoogle Scholar
  307. 307.
    Ochoa-Reparaz J, Mielcarz DW, Ditrio LE, Burroughs AR, Foureau DM, Haque-Begum S, et al. Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J Immunol. 2009;183(10):6041–50. doi:10.4049/jimmunol.0900747.PubMedCrossRefGoogle Scholar
  308. 308.
    Helenius LM, Meurman JH, Helenius I, Kari K, Hietanen J, Suuronen R, et al. Oral and salivary parameters in patients with rheumatic diseases. Acta Odontol Scand. 2005;63(5):284–93.PubMedCrossRefGoogle Scholar
  309. 309.
    Mason AL, Xu L, Guo L, Munoz S, Jaspan JB, Bryer-Ash M, et al. Detection of retroviral antibodies in primary biliary cirrhosis and other idiopathic biliary disorders. Lancet. 1998;351(9116):1620–4. doi:10.1016/S0140-6736(97)10290-2.PubMedCrossRefGoogle Scholar
  310. 310.
    Alvaro D, Alpini G, Onori P, Franchitto A, Glaser SS, Le Sage G, et al. Alfa and beta estrogen receptors and the biliary tree. Mol Cell Endocrinol. 2002;193(1–2):105–8.PubMedCrossRefGoogle Scholar
  311. 311.
    Cunningham M, Gilkeson G. Estrogen receptors in immunity and autoimmunity. Clin Rev Allergy Immunol. 2011;40(1):66–73. doi:10.1007/s12016-010-8203-5.PubMedCrossRefGoogle Scholar
  312. 312.
    Duvic M, Steinberg AD, Klassen LW. Effect of the anti-estrogen, Nafoxidine, on NZB/W autoimmune disease. Arthritis Rheum. 1978;21(4):414–7.PubMedCrossRefGoogle Scholar
  313. 313.
    Holmdahl R. Estrogen exaggerates lupus but suppresses T-cell-dependent autoimmune disease. J Autoimmun. 1989;2(5):651–6.PubMedCrossRefGoogle Scholar
  314. 314.
    Walker SE. Estrogen and autoimmune disease. Clin Rev Allergy Immunol. 2011;40(1):60–5. doi:10.1007/s12016-010-8199-x.PubMedCrossRefGoogle Scholar
  315. 315.
    Mizutani T, Shinoda M, Tanaka Y, Kuno T, Hattori A, Usui T, et al. Autoantibodies against CYP2D6 and other drug-metabolizing enzymes in autoimmune hepatitis type 2. Drug Metab Rev. 2005;37(1):235–52. doi:10.1081/DMR-200028798.PubMedGoogle Scholar
  316. 316.
    Obermayer-Straub P, Strassburg CP, Manns MP. Autoimmune hepatitis. J Hepatol. 2000;32(1 Suppl):181–97.PubMedCrossRefGoogle Scholar
  317. 317.
    Garratty G. Drug-induced immune hemolytic anemia. Hematology Am Soc Hematol Educ Program. 2009:73-9. doi: 10.1182/asheducation-2009.1.73.
  318. 318.
    Khokhar O, Gange C, Clement S, Lewis J. Autoimmune hepatitis and thyroiditis associated with rifampin and pyrazinamide prophylaxis: an unusual reaction. Dig Dis Sci. 2005;50(1):207–11.PubMedCrossRefGoogle Scholar
  319. 319.
    Takasu N, Takara M, Komiya I. Rifampin-induced hypothyroidism in patients with Hashimoto’s thyroiditis. N Engl J Med. 2005;352(5):518–9. doi:10.1056/NEJM200502033520524.PubMedCrossRefGoogle Scholar
  320. 320.
    Ahrens N, Genth R, Salama A. Belated diagnosis in three patients with rifampicin-induced immune haemolytic anaemia. Br J Haematol. 2002;117(2):441–3.PubMedCrossRefGoogle Scholar
  321. 321.
    Heurgue-Berlot A, Bernard-Chabert B, Diebold MD, Thiefin G. Drug-induced autoimmune-like hepatitis: a case of chronic course after drug withdrawal. Dig Dis Sci. 2011;56(8):2504-5; author reply 5. doi:10.1007/s10620-011-1786-8.
  322. 322.
    Bjornsson E, Talwalkar J, Treeprasertsuk S, Kamath PS, Takahashi N, Sanderson S, et al. Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology. 2010;51(6):2040–8. doi:10.1002/hep.23588.PubMedCrossRefGoogle Scholar
  323. 323.
    Geddes MR, Sinnreich M, Chalk C. Minocycline-induced dermatomyositis. Muscle Nerve. 2010;41(4):547–9. doi:10.1002/mus.21487.PubMedCrossRefGoogle Scholar
  324. 324.
    Angulo JM, Sigal LH, Espinoza LR. Minocycline induced lupus and autoimmune hepatitis. J Rheumatol. 1999;26(6):1420–1.PubMedGoogle Scholar
  325. 325.
    Bachmeyer C, Cadranel JF. Minocycline-induced lupus and autoimmune hepatitis: family autoimmune disorders as possible risk factors. Dermatology. 2002;205(2):185–6.PubMedCrossRefGoogle Scholar
  326. 326.
    Bhat G, Jordan J Jr, Sokalski S, Bajaj V, Marshall R, Berkelhammer C. Minocycline-induced hepatitis with autoimmune features and neutropenia. J Clin Gastroenterol. 1998;27(1):74–5.PubMedCrossRefGoogle Scholar
  327. 327.
    Chamberlain MC, Schwarzenberg SJ, Akin EU, Kurth MH. Minocycline-induced autoimmune hepatitis with subsequent cirrhosis. J Pediatr Gastroenterol Nutr. 2006;42(2):232–5. doi:10.1097/ Scholar
  328. 328.
    Colmegna I, Perandones CE, Chaves JG. Minocycline induced lupus and autoimmune hepatitis. J Rheumatol. 2000;27(6):1567–8.PubMedGoogle Scholar
  329. 329.
    Gough A, Chapman S, Wagstaff K, Emery P, Elias E. Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome. BMJ. 1996;312(7024):169–72.PubMedCrossRefGoogle Scholar
  330. 330.
    Healy J, Alexander B, Eapen C, Roberts-Thomson IC. Minocycline-induced autoimmune hepatitis. Int Med J. 2009;39(7):487–8. doi:10.1111/j.1445-5994.2009.01971.x.CrossRefGoogle Scholar
  331. 331.
    Della Corte C, Carlucci A, Francalanci P, Alisi A, Nobili V. Autoimmune hepatitis type 2 following anti-papillomavirus vaccination in a 11-year-old girl. Vaccine. 2011;29(29-30):4654–6. doi:10.1016/j.vaccine.2011.05.002.PubMedCrossRefGoogle Scholar
  332. 332.
    Karali Z, Basaranoglu ST, Karali Y, Oral B, Kilic SS. Autoimmunity and hepatitis A vaccine in children. J Investig Allergol Clin Immunol. 2011;21(5):389–93.PubMedGoogle Scholar
  333. 333.
    Stubgen JP. Neuromuscular disorders associated with Hepatitis B vaccination. J Neurol Sci. 2010;292(1–2):1–4. doi:10.1016/j.jns.2010.02.016.PubMedCrossRefGoogle Scholar
  334. 334.
    Cacoub P, Terrier B. Hepatitis B-related autoimmune manifestations. Rheum Dis Clin North Am. 2009;35(1):125–37. doi:10.1016/j.rdc.2009.03.006.PubMedCrossRefGoogle Scholar
  335. 335.
    Aron-Maor A, Shoenfeld Y. Vaccination and systemic lupus erythematosus: the bidirectional dilemmas. Lupus. 2001;10(3):237–40.PubMedCrossRefGoogle Scholar
  336. 336.
    Borchers AT, Keen CL, Shoenfeld Y, Silva J Jr, Gershwin ME. Vaccines, viruses, and voodoo. J Investig Allergol Clin Immunol. 2002;12(3):155–68.PubMedGoogle Scholar
  337. 337.
    Chen RT, Pless R, Destefano F. Epidemiology of autoimmune reactions induced by vaccination. J Autoimmun. 2001;16(3):309–18. doi:10.1006/jaut.2000.0491.PubMedCrossRefGoogle Scholar
  338. 338.
    Cohen AD, Shoenfeld Y. Vaccine-induced autoimmunity. J Autoimmun. 1996;9(6):699–703. doi:10.1006/jaut.1996.0091.PubMedCrossRefGoogle Scholar
  339. 339.
    Nadler JP. Multiple sclerosis and hepatitis B vaccination. Clin Infect Dis. 1993;17(5):928–9.PubMedCrossRefGoogle Scholar
  340. 340.
    Ravel G, Christ M, Horand F, Descotes J. Autoimmunity, environmental exposure and vaccination: is there a link? Toxicology. 2004;196(3):211–6. doi:10.1016/j.tox.2003.10.005.PubMedCrossRefGoogle Scholar
  341. 341.
    Shoenfeld Y, Aharon-Maor A, Sherer Y. Vaccination as an additional player in the mosaic of autoimmunity. Clin Exp Rheumatol. 2000;18(2):181–4.PubMedGoogle Scholar
  342. 342.
    Shoenfeld Y, Aron-Maor A. Vaccination and autoimmunity-’vaccinosis’: a dangerous liaison? J Autoimmun. 2000;14(1):1–10. doi:10.1006/jaut.1999.0346.PubMedCrossRefGoogle Scholar
  343. 343.
    Shoenfeld Y, Aron-Maor A, Tanai A, Ehrenfeld M. Bcg and autoimmunity: another two-edged sword. J Autoimmun. 2001;16(3):235–40. doi:10.1006/jaut.2000.0494.PubMedCrossRefGoogle Scholar
  344. 344.
    Costenbader KH, Gay S, Riquelme ME, Iaccarino L, Doria A. Genes, epigenetic regulation and environmental factors: which is the most relevant in developing autoimmune diseases? Autoimmun Rev. 2011;. doi:10.1016/j.autrev.2011.10.022.Google Scholar
  345. 345.
    Arnson Y, Shoenfeld Y, Amital H. Effects of tobacco smoke on immunity, inflammation and autoimmunity. J Autoimmun. 2010;34(3):J258–65. doi:10.1016/j.jaut.2009.12.003.PubMedCrossRefGoogle Scholar
  346. 346.
    Brusselle GG, Joos GF, Bracke KR. New insights into the immunology of chronic obstructive pulmonary disease. Lancet. 2011;378(9795):1015–26. doi:10.1016/S0140-6736(11)60988-4.PubMedCrossRefGoogle Scholar
  347. 347.
    Simard JF, Costenbader KH. What can epidemiology tell us about systemic lupus erythematosus? Int J Clin Pract. 2007;61(7):1170–80. doi:10.1111/j.1742-1241.2007.01434.x.PubMedCrossRefGoogle Scholar
  348. 348.
    Costenbader KH, Karlson EW. Cigarette smoking and autoimmune disease: what can we learn from epidemiology? Lupus. 2006;15(11):737–45.PubMedCrossRefGoogle Scholar
  349. 349.
    Rubin RL, Hermanson TM, Bedrick EJ, McDonald JD, Burchiel SW, Reed MD, et al. Effect of cigarette smoke on autoimmunity in murine and human systemic lupus erythematosus. Toxicol Sci. 2005;87(1):86–96. doi:10.1093/toxsci/kfi217.PubMedCrossRefGoogle Scholar
  350. 350.
    Asherson RA, Shoenfeld Y, Jacobs P, Bosman C. An unusually complicated case of primary Sjogren’s syndrome: development of transient “lupus-type” autoantibodies following silicone implant rejection. J Rheumatol. 2004;31(1):196–7.PubMedGoogle Scholar
  351. 351.
    Bar-Meir E, Eherenfeld M, Shoenfeld Y. Silicone gel breast implants and connective tissue disease–a comprehensive review. Autoimmunity. 2003;36(4):193–7.PubMedCrossRefGoogle Scholar
  352. 352.
    Bar-Meir E, Teuber SS, Lin HC, Alosacie I, Goddard G, Terybery J, et al. Multiple autoantibodies in patients with silicone breast implants. J Autoimmun. 1995;8(2):267–77.PubMedCrossRefGoogle Scholar
  353. 353.
    Vasey FB, Zarabadi SA, Seleznick M, Ricca L. Where there’s smoke there’s fire: the silicone breast implant controversy continues to flicker: a new disease that needs to be defined. J Rheumatol. 2003;30(10):2092–4.PubMedGoogle Scholar
  354. 354.
    Vermeulen RC, Scholte HR. Rupture of silicone gel breast implants and symptoms of pain and fatigue. J Rheumatol. 2003;30(10):2263–7.PubMedGoogle Scholar
  355. 355.
    Zandman-Goddard G, Blank M, Ehrenfeld M, Gilburd B, Peter J, Shoenfeld Y. A comparison of autoantibody production in asymptomatic and symptomatic women with silicone breast implants. J Rheumatol. 1999;26(1):73–7.PubMedGoogle Scholar
  356. 356.
    Hajdu SD, Agmon-Levin N, Shoenfeld Y. Silicone and autoimmunity. Eur J Clin Invest. 2011;41(2):203–11. doi:10.1111/j.1365-2362.2010.02389.x.PubMedCrossRefGoogle Scholar
  357. 357.
    Alotaibi S, Kennedy J, Tellier R, Stephens D, Banwell B. Epstein-Barr virus in pediatric multiple sclerosis. JAMA. 2004;291(15):1875–9. doi:10.1001/jama.291.15.1875.PubMedCrossRefGoogle Scholar
  358. 358.
    DeLorenze GN, Munger KL, Lennette ET, Orentreich N, Vogelman JH, Ascherio A. Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up. Arch Neurol. 2006;63(6):839–44. doi:10.1001/archneur.63.6.noc50328.PubMedCrossRefGoogle Scholar
  359. 359.
    Goodin DS. The causal cascade to multiple sclerosis: a model for MS pathogenesis. PLoS ONE. 2009;4(2):e4565. doi:10.1371/journal.pone.0004565.PubMedCrossRefGoogle Scholar
  360. 360.
    Levin LI, Munger KL, O’Reilly EJ, Falk KI, Ascherio A. Primary infection with the Epstein-Barr virus and risk of multiple sclerosis. Ann Neurol. 2010;67(6):824–30. doi:10.1002/ana.21978.PubMedGoogle Scholar
  361. 361.
    Levin LI, Munger KL, Rubertone MV, Peck CA, Lennette ET, Spiegelman D, et al. Temporal relationship between elevation of epstein-barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA. 2005;293(20):2496–500. doi:10.1001/jama.293.20.2496.PubMedCrossRefGoogle Scholar
  362. 362.
    Lindberg C, Andersen O, Vahlne A, Dalton M, Runmarker B. Epidemiological investigation of the association between infectious mononucleosis and multiple sclerosis. Neuroepidemiology. 1991;10(2):62–5.PubMedCrossRefGoogle Scholar
  363. 363.
    Lunemann JD, Edwards N, Muraro PA, Hayashi S, Cohen JI, Munz C, et al. Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis. Brain. 2006;129(Pt 6):1493–506. doi:10.1093/brain/awl067.PubMedCrossRefGoogle Scholar
  364. 364.
    Lunemann JD, Huppke P, Roberts S, Bruck W, Gartner J, Munz C. Broadened and elevated humoral immune response to EBNA1 in pediatric multiple sclerosis. Neurology. 2008;71(13):1033–5. doi:10.1212/01.wnl.0000326576.91097.87.PubMedCrossRefGoogle Scholar
  365. 365.
    Lunemann JD, Jelcic I, Roberts S, Lutterotti A, Tackenberg B, Martin R, et al. EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-gamma and IL-2. J Exp Med. 2008;205(8):1763–73. doi:10.1084/jem.20072397.PubMedCrossRefGoogle Scholar
  366. 366.
    Operskalski EA, Visscher BR, Malmgren RM, Detels R. A case-control study of multiple sclerosis. Neurology. 1989;39(6):825–9.PubMedCrossRefGoogle Scholar
  367. 367.
    Peferoen LA, Lamers F, Lodder LN, Gerritsen WH, Huitinga I, Melief J, et al. Epstein Barr virus is not a characteristic feature in the central nervous system in established multiple sclerosis. Brain. 2010;133(Pt 5):e137. doi:10.1093/brain/awp296.PubMedCrossRefGoogle Scholar
  368. 368.
    Sargsyan SA, Shearer AJ, Ritchie AM, Burgoon MP, Anderson S, Hemmer B, et al. Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis. Neurology. 2010;74(14):1127–35. doi:10.1212/WNL.0b013e3181d865a1.PubMedCrossRefGoogle Scholar
  369. 369.
    Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P, et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med. 2007;204(12):2899–912. doi:10.1084/jem.20071030.PubMedCrossRefGoogle Scholar
  370. 370.
    Thorley-Lawson DA. Epstein-Barr virus: exploiting the immune system. Nat Rev Immunol. 2001;1(1):75–82. doi:10.1038/35095584.PubMedCrossRefGoogle Scholar
  371. 371.
    Warner HB, Carp RI. Multiple sclerosis and Epstein-Barr virus. Lancet. 1981;2(8258):1290.PubMedCrossRefGoogle Scholar
  372. 372.
    Willis SN, Stadelmann C, Rodig SJ, Caron T, Gattenloehner S, Mallozzi SS, et al. Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain. 2009;132(Pt 12):3318–28. doi:10.1093/brain/awp200.PubMedCrossRefGoogle Scholar
  373. 373.
    Sriram S, Stratton CW, Yao S, Tharp A, Ding L, Bannan JD, et al. Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis. Ann Neurol. 1999;46(1):6–14.PubMedCrossRefGoogle Scholar
  374. 374.
    Challoner PB, Smith KT, Parker JD, MacLeod DL, Coulter SN, Rose TM, et al. Plaque-associated expression of human herpesvirus 6 in multiple sclerosis. Proc Natl Acad Sci U S A. 1995;92(16):7440–4.PubMedCrossRefGoogle Scholar
  375. 375.
    Dockrell DH, Smith TF, Paya CV. Human herpesvirus 6. Mayo Clin Proc. 1999;74(2):163–70.PubMedCrossRefGoogle Scholar
  376. 376.
    Chmielewska-Badora J, Cisak E, Dutkiewicz J. Lyme borreliosis and multiple sclerosis: any connection? A seroepidemic study. Ann Agric Environ Med. 2000;7(2):141–3.PubMedGoogle Scholar
  377. 377.
    Mancuso R, Delbue S, Borghi E, Pagani E, Calvo MG, Caputo D, et al. Increased prevalence of varicella zoster virus DNA in cerebrospinal fluid from patients with multiple sclerosis. J Med Virol. 2007;79(2):192–9. doi:10.1002/jmv.20777.PubMedCrossRefGoogle Scholar
  378. 378.
    Ordonez G, Pineda B, Garcia-Navarrete R, Sotelo J. Brief presence of varicella-zoster vral DNA in mononuclear cells during relapses of multiple sclerosis. Arch Neurol. 2004;61(4):529–32. doi:10.1001/archneur.61.4.529.PubMedCrossRefGoogle Scholar
  379. 379.
    Sotelo J, Martinez-Palomo A, Ordonez G, Pineda B. Varicella-zoster virus in cerebrospinal fluid at relapses of multiple sclerosis. Ann Neurol. 2008;63(3):303–11. doi:10.1002/ana.21316.PubMedCrossRefGoogle Scholar
  380. 380.
    Birnbaum G, Kotilinek L, Albrecht L. Spinal fluid lymphocytes from a subgroup of multiple sclerosis patients respond to mycobacterial antigens. Ann Neurol. 1993;34(1):18–24. doi:10.1002/ana.410340106.PubMedCrossRefGoogle Scholar
  381. 381.
    Wroblewska Z, Gilden D, Devlin M, Huang ES, Rorke LB, Hamada T, et al. Cytomegalovirus isolation from a chimpanzee with acute demyelinating disease after inoculation of multiple sclerosis brain cells. Infect Immun. 1979;25(3):1008–15.PubMedGoogle Scholar
  382. 382.
    Perron H, Garson JA, Bedin F, Beseme F, Paranhos-Baccala G, Komurian-Pradel F, et al. Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. the collaborative research group on multiple sclerosis. Proc Natl Acad Sci U S A. 1997;94(14):7583–8.PubMedCrossRefGoogle Scholar
  383. 383.
    Rasmussen HB, Geny C, Deforges L, Perron H, Tourtelotte W, Heltberg A, et al. Expression of endogenous retroviruses in blood mononuclear cells and brain tissue from multiple sclerosis patients. Acta Neurol Scand Supplementum. 1997;169:38–44.CrossRefGoogle Scholar
  384. 384.
    Murray RS, Brown B, Brian D, Cabirac GF. Detection of coronavirus RNA and antigen in multiple sclerosis brain. Ann Neurol. 1992;31(5):525–33. doi:10.1002/ana.410310511.PubMedCrossRefGoogle Scholar
  385. 385.
    Stewart JN, Mounir S, Talbot PJ. Human coronavirus gene expression in the brains of multiple sclerosis patients. Virology. 1992;191(1):502–5.PubMedCrossRefGoogle Scholar
  386. 386.
    Ferrante P, Omodeo-Zorini E, Caldarelli-Stefano R, Mediati M, Fainardi E, Granieri E, et al. Detection of JC virus DNA in cerebrospinal fluid from multiple sclerosis patients. Mult Scler. 1998;4(2):49–54.PubMedGoogle Scholar
  387. 387.
    Stoner GL, Agostini HT, Ryschkewitsch CF, Baumhefner RW, Tourtellotte WW. Characterization of JC virus DNA amplified from urine of chronic progressive multiple sclerosis patients. Mult Scler. 1996;1(4):193–9.PubMedGoogle Scholar
  388. 388.
    Forghani B, Cremer NE, Johnson KP, Ginsberg AH, Likosky WH. Viral antibodies in cerebrospinal fluid of multiple sclerosis and control patients: comparison between radioimmunoassay and conventional techniques. J Clin Microbiol. 1978;7(1):63–9.PubMedGoogle Scholar
  389. 389.
    ter Meulen V, Koprowski H, Iwasaki Y, Kackell YM, Muller D. Fusion of cultured multiple-sclerosis brain cells with indicator cells: presence of nucleocapsids and virions and isolation of parainfluenza-type virus. Lancet. 1972;2(7766):1–5.PubMedCrossRefGoogle Scholar
  390. 390.
    Haase AT, Ventura P, Gibbs CJ Jr, Tourtellotte WW. Measles virus nucleotide sequences: detection by hybridization in situ. Science. 1981;212(4495):672–5.PubMedCrossRefGoogle Scholar
  391. 391.
    Jacobson S, Flerlage ML, McFarland HF. Impaired measles virus-specific cytotoxic T cell responses in multiple sclerosis. J Exp Med. 1985;162(3):839–50.PubMedCrossRefGoogle Scholar
  392. 392.
    Alpérovitch A, Berr C, Cambon-Thomsen A, Puel J, Dugoujon JM, Ruidavets JB, et al. Viral antibody titers, immunogenetic markers, and their interrelations in multiple sclerosis patients and controls. Hum Immunol. 1991;31(2):94–9. doi:10.1016/0198-8859(91)90011-W.PubMedCrossRefGoogle Scholar
  393. 393.
    Ortega-Hernandez OD, Levin NA, Altman A, Shoenfeld Y. Infectious agents in the pathogenesis of primary biliary cirrhosis. Dis Markers. 2010;29(6):277–86. doi:10.3233/DMA-2010-0771.PubMedCrossRefGoogle Scholar
  394. 394.
    Shigematsu H, Shimoda S, Nakamura M, Matsushita S, Nishimura Y, Sakamoto N, et al. Fine specificity of T cells reactive to human PDC-E2 163–176 peptide, the immunodominant autoantigen in primary biliary cirrhosis: implications for molecular mimicry and cross-recognition among mitochondrial autoantigens. Hepatology. 2000;32(5):901–9. doi:10.1053/jhep.2000.18714.PubMedCrossRefGoogle Scholar
  395. 395.
    Bogdanos DP, Pares A, Baum H, Caballeria L, Rigopoulou EI, Ma Y, et al. Disease-specific cross-reactivity between mimicking peptides of heat shock protein of Mycobacterium gordonae and dominant epitope of E2 subunit of pyruvate dehydrogenase is common in Spanish but not British patients with primary biliary cirrhosis. J Autoimmun. 2004;22(4):353–62. doi:10.1016/j.jaut.2004.03.002.PubMedCrossRefGoogle Scholar
  396. 396.
    Vilagut L, Pares A, Vinas O, Vila J, Jimenez de Anta MT, Rodes J. Antibodies to mycobacterial 65-kD heat shock protein cross-react with the main mitochondrial antigens in patients with primary biliary cirrhosis. Eur J Clin Invest. 1997;27(8):667–72.PubMedCrossRefGoogle Scholar
  397. 397.
    Vilagut L, Vila J, Vinas O, Pares A, Gines A, Jimenez de Anta MT, et al. Cross-reactivity of anti-Mycobacterium gordonae antibodies with the major mitochondrial autoantigens in primary biliary cirrhosis. J Hepatol. 1994;21(4):673–7.PubMedCrossRefGoogle Scholar
  398. 398.
    Xu L, Shen Z, Guo L, Fodera B, Keogh A, Joplin R, et al. Does a betaretrovirus infection trigger primary biliary cirrhosis? Proc Natl Acad Sci U S A. 2003;100(14):8454–9. doi:10.1073/pnas.1433063100.PubMedCrossRefGoogle Scholar
  399. 399.
    Zhang G, Chen M, Graham D, Subsin B, McDougall C, Gilady S, et al. Mouse mammary tumor virus in anti-mitochondrial antibody producing mouse models. J Hepatol. 2011;55(4):876–84. doi:10.1016/j.jhep.2011.01.037.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Dimitrios P. Bogdanos
    • 1
    • 2
  • Daniel S. Smyk
    • 1
  • Pietro Invernizzi
    • 3
  • Eirini I. Rigopoulou
    • 2
  • Miri Blank
    • 4
  • Lazaros Sakkas
    • 2
  • Shideh Pouria
    • 5
  • Yehuda Shoenfeld
    • 4
  1. 1.Division of Transplantation Immunology and Mucosal Biology, Institute of Liver StudiesKing’s College London School of Medicine at King’s College HospitalLondonUK
  2. 2.Department of Medicine, Faculty of Medicine, School of Health SciencesUniversity of ThessalyLarissaGreece
  3. 3.Liver Unit and Center for Autoimmune Liver DiseasesHumanitas Clinical and Research CentreRozzanoItaly
  4. 4.The Zabludowicz Center for Autoimmune DiseasesSheba Medical CenterRamat GanIsrael
  5. 5.Nutritional Sciences DivisionKing’s College School of MedicineLondonUK

Personalised recommendations