Autoimmune Disease and the Human Metagenome

  • Amy D. Proal
  • Paul J. Albert
  • Trevor G. Marshall


The prevailing theory of autoimmune disease, that the body creates autoantibodies that attack “self,” was developed during an era when culture-based methods vastly underestimated the number of microbes capable of persisting in and on Homo sapiens. Thanks to the advent of culture-independent tools, the human body is now known to harbor billions of microbes whose collective genomes work in concert with the human genome. Thus, the human genome can no longer be studied in isolation. Some of these microbes persist by slowing the activity of the vitamin D receptor nuclear receptor, affecting the expression of endogenous antimicrobials and other key components of the innate immune system. It seems that bacteria that cause autoimmune disease accumulate over a lifetime, with individuals picking up pathogens with greater ease over time, as the immune response becomes increasingly compromised. Any one autoimmune disease is likely due to many different microbes within the metagenomic microbiota. This helps explain the high levels of comorbidity observed among patients with autoimmune conditions. What are commonly believed to be autoantibodies may instead be created in response to this metagenomic microbiota when the adaptive immune system is forced to deal with disintegration of infected cells. Similarly, haplotypes associated with autoimmune conditions vary widely among individuals and populations. They are more suggestive of a regional infectious model rather than a model in which an illness is caused by inherited variation of HLA haplotypes


Irritable Bowel Syndrome Horizontal Gene Transfer Chronic Fatigue Syndrome Autoimmune Condition Palliative Drug 



The authors wish to acknowledge the assistance of Dr. Elena Kashuba for sharing her data and helping us prepare Fig. 12.2.


  1. Abreu MT, Kantorovich V, Vasiliauskas EA et al (2004) Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn’s disease patients with elevated 1,25-dihydroxyvitamin D and low bone mineral density. Gut 53(8):1129–1136PubMedCentralPubMedGoogle Scholar
  2. Allie N, Alexopoulou L, Quesniaux VJF et al (2008) Protective role of membrane tumour necrosis factor in the host’s resistance to mycobacterial infection. Immunology 125(4):522–534PubMedCentralPubMedGoogle Scholar
  3. Almenoff PL, Johnson A, Lesser M et al (1996) Growth of acid fast L-forms from the blood of patients with sarcoidosis. Thorax 51(5):530–533PubMedCentralPubMedGoogle Scholar
  4. Anderson G, Horvath J (2004) The growing burden of chronic disease in America. Public Health Rep 119(3):263–270PubMedCentralPubMedGoogle Scholar
  5. Arend SM, Breedveld FC, van Dissel JT (2003) TNF-alpha blockade and tuberculosis: better look before you leap. Neth J Med 61(4):111–119PubMedGoogle Scholar
  6. Arnson Y, Amital H, Shoenfeld Y (2007) Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis 66(9):1137–1142PubMedCentralPubMedGoogle Scholar
  7. Asahi A, Kuwana M, Suzuki H et al (2006) Effects of a Helicobacter pylori eradication regimen on anti-platelet autoantibody response in infected and uninfected patients with idiopathic thrombocytopenic purpura. Haematologica 91(10):1436–1437PubMedGoogle Scholar
  8. Avila M, Said N, Ojcius DM (2008) The book reopened on infectious diseases. Microbes Infect 10(9):942–947PubMedGoogle Scholar
  9. Azer SA (1999) Arterial disease in antiquity. Med J Aust 171(5):280PubMedGoogle Scholar
  10. Bailey CJ (2009) New therapies for diabesity. Curr Diab Rep 9(5):360–367PubMedGoogle Scholar
  11. Baldwin CL, Goenka R (2006) Host immune responses to the intracellular bacteria Brucella: does the bacteria instruct the host to facilitate chronic infection? Crit Rev Immunol 26(5):407–442PubMedGoogle Scholar
  12. Barcellos LF, Kamdar BB, Ramsay PP et al (2006) Clustering of autoimmune diseases in families with a high-risk for multiple sclerosis: a descriptive study. Lancet Neurol 5(11):924–931PubMedGoogle Scholar
  13. Barzilai O, Ram M, Shoenfeld Y (2007) Viral infection can induce the production of autoantibodies. Curr Opin Rheumatol 19(6):636–643PubMedGoogle Scholar
  14. Begovich AB, Chang M, Schrodi SJ (2007) Meta-analysis evidence of a differential risk of the FCRL3 -169T–>C polymorphism in white and East Asian rheumatoid arthritis patients. Arthritis Rheum 56(9):3168–3171PubMedGoogle Scholar
  15. Bell NH (1998) Renal and nonrenal 25-hydroxyvitamin D-1alpha-hydroxylases and their clinical significance. J Bone Miner Res 13(3):350–353PubMedGoogle Scholar
  16. Bentley RW, Keenan JI, Gearry RB et al (2008) Incidence of Mycobacterium avium subspecies paratuberculosis in a population-based cohort of patients with Crohn’s disease and control subjects. Am J Gastroenterol 103(5):1168–1172PubMedGoogle Scholar
  17. Berlin T, Zandman-Goddard G, Blank M et al (2007) Autoantibodies in nonautoimmune individuals during infections. Ann N Y Acad Sci 1108:584–593PubMedGoogle Scholar
  18. Birmingham CL, Canadien V, Gouin E et al (2007) Listeria monocytogenes evades killing by autophagy during colonization of host cells. Autophagy 3(5):442–451PubMedGoogle Scholar
  19. Bisgaard H, Hermansen MN, Buchvald F et al (2007) Childhood asthma after bacterial colonization of the airway in neonates. N Engl J Med 357(15):1487–1495PubMedGoogle Scholar
  20. Blaney GP, Albert PJ, Proal AD (2009) Vitamin D metabolites as clinical markers in autoimmune and chronic disease. Ann N Y Acad Sci 1173:384–390PubMedGoogle Scholar
  21. Bogdan C (2001) Nitric oxide and the immune response. Nat Immunol 2(10):907–916PubMedGoogle Scholar
  22. Bogdanos DP, Baum H, Grasso A et al (2004) Microbial mimics are major targets of crossreactivity with human pyruvate dehydrogenase in primary biliary cirrhosis. J Hepatol 40(1):31–39PubMedGoogle Scholar
  23. Bolzan AD, Bianchi MS (2002) Genotoxicity of streptozotocin. Mutat Res 512(2–3):121–134PubMedGoogle Scholar
  24. Boscarino JA (2004) Posttraumatic stress disorder and physical illness: results from clinical and epidemiologic studies. Ann N Y Acad Sci 1032:141–153PubMedGoogle Scholar
  25. Bozic B, Cucnik S, Kveder T et al (2007) Autoimmune reactions after electro-oxidation of IgG from healthy persons: relevance of electric current and antioxidants. Ann N Y Acad Sci 1109:158–166PubMedGoogle Scholar
  26. Brahmachary M, Schonbach C, Yang L et al (2006) Computational promoter analysis of mouse, rat and human antimicrobial peptide-coding genes. BMC Bioinformatics 7(Suppl 5):S8PubMedCentralPubMedGoogle Scholar
  27. Brock TD (1988) Robert Koch, a life in medicine and bacteriology. Science Tech Publishers, Springer, New York, NYGoogle Scholar
  28. Brown AS (2006) Prenatal infection as a risk factor for schizophrenia. Schizophr Bull 32(2):200–202PubMedCentralPubMedGoogle Scholar
  29. Buchanan AV, Weiss KM, Fullerton SM (2006) Dissecting complex disease: the quest for the Philosopher’s Stone? Int J Epidemiol 35(3):562–571PubMedGoogle Scholar
  30. Bukholm G, Modalsli K, Degre M (1986) Effect of measles-virus infection and interferon treatment on invasiveness of Shigella flexneri in HEp2-cell cultures. J Med Microbiol 22(4):335–341PubMedGoogle Scholar
  31. Bull TJ, McMinn EJ, Sidi-Boumedine K et al (2003) Detection and verification of Mycobacterium avium subsp. paratuberculosis in fresh ileocolonic mucosal biopsy specimens from individuals with and without Crohn’s disease. J Clin Microbiol 41(7):2915–2923PubMedCentralPubMedGoogle Scholar
  32. Bunge J (2009) Statistical estimation of uncultivated microbial diversity uncultivated microorganisms. Springer, New York, NY, pp 1–18Google Scholar
  33. Burnham WR, Lennard-Jones JE, Stanford JL et al (1978) Mycobacteria as a possible cause of inflammatory bowel disease. Lancet 2(8092 Pt 1):693–696PubMedGoogle Scholar
  34. Burton PR, Hansell AL, Fortier I et al (2009) Size matters: just how big is BIG?: quantifying realistic sample size requirements for human genome epidemiology. Int J Epidemiol 38(1):263–273PubMedCentralPubMedGoogle Scholar
  35. Casadesus J (2007) Bacterial L-forms require peptidoglycan synthesis for cell division. Bioessays 29(12):1189–1191PubMedGoogle Scholar
  36. Casali P, Burastero SE, Nakamura M et al (1987) Human lymphocytes making rheumatoid factor and antibody to ssDNA belong to Leu-1+ B-cell subset. Science 236(4797):77–81PubMedGoogle Scholar
  37. Cheung CM, Chee SP (2009) Jarisch–Herxheimer reaction: paradoxical worsening of tuberculosis chorioretinitis following initiation of antituberculous therapy. Eye (Lond) 23(6):1472–1473Google Scholar
  38. Christakis NA, Fowler JH (2007) The spread of obesity in a large social network over 32 years. N Engl J Med 357(4):370–379PubMedGoogle Scholar
  39. Christen U, Hintermann E, Holdener M et al (2010) Viral triggers for autoimmunity: Is the ‘glass of molecular mimicry’ half full or half empty? J Autoimmun 34(1):38–44Google Scholar
  40. Chung CC, Magalhaes W, Gonzalez-Bosquet J et al (2010) Genome-wide association studies in cancer – current and future directions. Carcinogenesis 31(1):111–120Google Scholar
  41. Cochran GM, Ewald PW, Cochran KD (2000) Infectious causation of disease: an evolutionary perspective. Perspect Biol Med 43(3):406–448PubMedGoogle Scholar
  42. Cohen ML (2000) Changing patterns of infectious disease. Nature 406(6797):762–767PubMedGoogle Scholar
  43. Collins FS, McKusick VA (2001) Implications of the human genome project for medical science. JAMA 285(5):540–544PubMedGoogle Scholar
  44. Collins FS, Morgan M, Patrinos A (2003) The human genome project: lessons from large-scale biology. Science 300(5617):286–290PubMedGoogle Scholar
  45. Committee on Metagenomics, and National Research Council (2007) New science of metagenomics: revealing the secrets of our microbial planet. National Academies Press, Washington, DCGoogle Scholar
  46. Cunningham MW (2003) Autoimmunity and molecular mimicry in the pathogenesis of post-streptococcal heart disease. Front Biosci 8:s533–543PubMedGoogle Scholar
  47. Curran LK, Newschaffer CJ, Lee LC et al (2007) Behaviors associated with fever in children with autism spectrum disorders. Pediatrics 120(6):e1386–1392PubMedGoogle Scholar
  48. Daniels JL, Forssen U, Hultman CM et al (2008) Parental psychiatric disorders associated with autism spectrum disorders in the offspring. Pediatrics 121(5):e1357–1362PubMedGoogle Scholar
  49. Davenport MP, Belz GT, Ribeiro RM (2009) The race between infection and immunity: how do pathogens set the pace? Trends Immunol 30(2):61–66PubMedGoogle Scholar
  50. Davey Smith G, Ebrahim S, Lewis S et al (2005) Genetic epidemiology and public health: hope, hype, and future prospects. Lancet 366(9495):1484–1498PubMedGoogle Scholar
  51. Dell’Era S, Buchrieser C, Couve E et al (2009) Listeria monocytogenes L-forms respond to cell wall deficiency by modifying gene expression and the mode of division. Mol Microbiol 73(2):306–322PubMedGoogle Scholar
  52. Dempsey KE, Riggio MP, Lennon A et al (2007) Identification of bacteria on the surface of clinically infected and non-infected prosthetic hip joints removed during revision arthroplasties by 16S rRNA gene sequencing and by microbiological culture. Arthritis Res Ther 9(3):R46PubMedCentralPubMedGoogle Scholar
  53. DePaula AL, Macedo AL, Rassi N et al (2008) Laparoscopic treatment of type 2 diabetes mellitus for patients with a body mass index less than 35. Surg Endosc 22(3):706–716PubMedGoogle Scholar
  54. Dickson JH, Oeggl K, Handley LL (2003) The iceman reconsidered. Sci Am 288(5):70–79PubMedGoogle Scholar
  55. DiGiulio DB, Romero R, Amogan HP et al (2008) Microbial prevalence, diversity and abundance in amniotic fluid during preterm labor: a molecular and culture-based investigation. PLoS One 3(8):e3056PubMedCentralPubMedGoogle Scholar
  56. Dimitrov JD, Lacroix-Desmazes S, Kaveri SV et al (2008) Insight into the mechanism of the acquired antibody auto-reactivity. Autoimmun Rev 7(6):410–414PubMedGoogle Scholar
  57. Djavad N, Bas S, Shi X et al (1996) Comparison of rheumatoid factors of rheumatoid arthritis patients, of individuals with mycobacterial infections and of normal controls: evidence for maturation in the absence of an autoimmune response. Eur J Immunol 26(10):2480–2486PubMedGoogle Scholar
  58. Domingue GJ Sr, Woody HB (1997) Bacterial persistence and expression of disease. Clin Microbiol Rev 10(2):320–344PubMedCentralPubMedGoogle Scholar
  59. Doolittle WF, Papke RT (2006) Genomics and the bacterial species problem. Genome Biol 7(9):116PubMedCentralPubMedGoogle Scholar
  60. Dowd SE, Wolcott RD, Sun Y et al (2008) Polymicrobial nature of chronic diabetic foot ulcer biofilm infections determined using bacterial tag encoded FLX amplicon pyrosequencing (bTEFAP). PLoS One 3(10):e3326PubMedCentralPubMedGoogle Scholar
  61. Dumas ME, Maibaum EC, Teague C et al (2006) Assessment of analytical reproducibility of 1H NMR spectroscopy based metabonomics for large-scale epidemiological research: the INTERMAP Study. Anal Chem 78(7):2199–2208PubMedGoogle Scholar
  62. Dunny GM, Brickman TJ, Dworkin M (2008) Multicellular behavior in bacteria: communication, cooperation, competition and cheating. Bioessays 30(4):296–298PubMedGoogle Scholar
  63. Eckburg PB, Bik EM, Bernstein CN et al (2005) Diversity of the human intestinal microbial flora. Science 308(5728):1635–1638PubMedCentralPubMedGoogle Scholar
  64. el-Zaatari FA, Naser SA, Markesich DC et al (1996) Identification of Mycobacterium avium complex in sarcoidosis. J Clin Microbiol 34(9):2240–2245PubMedCentralPubMedGoogle Scholar
  65. Enck P, Zimmermann K, Rusch K et al (2009) The effects of ageing on the colonic bacterial microflora in adults. Z Gastroenterol 47(7):653–658PubMedGoogle Scholar
  66. English PJ, Ghatei MA, Malik IA et al (2002) Food fails to suppress ghrelin levels in obese humans. J Clin Endocrinol Metab 87(6):2984PubMedGoogle Scholar
  67. Fatemi SH, Reutiman TJ, Folsom TD et al (2008) The role of cerebellar genes in pathology of autism and schizophrenia. Cerebellum 7(3):279–294PubMedGoogle Scholar
  68. Fetissov SO, Hamze Sinno M, Coeffier M et al (2008) Autoantibodies against appetite-regulating peptide hormones and neuropeptides: putative modulation by gut microflora. Nutrition 24(4):348–359PubMedGoogle Scholar
  69. Fierer N, Hamady M, Lauber CL et al (2008) The influence of sex, handedness, and washing on the diversity of hand surface bacteria. Proc Natl Acad Sci USA 105(46):17994–17999PubMedCentralPubMedGoogle Scholar
  70. Fredricks DN, Relman DA (1998) Infectious agents and the etiology of chronic idiopathic diseases. Curr Clin Top Infect Dis 18:180–200PubMedGoogle Scholar
  71. Fu W, Sanders-Beer BE, Katz KS et al (2009) Human immunodeficiency virus type 1, human protein interaction database at NCBI. Nucleic Acids Res 37(Database issue):D417–422PubMedCentralPubMedGoogle Scholar
  72. Geddes R (2007) Minocycline-induced lupus in adolescents: clinical implications for physical therapists. J Orthop Sports Phys Ther 37(2):65–71PubMedGoogle Scholar
  73. Giunta S (2006) Is inflammaging an auto[innate]immunity subclinical syndrome? Immun Ageing 3:12PubMedCentralPubMedGoogle Scholar
  74. Glover WA, Yang Y, Zhang Y (2009) Insights into the molecular basis of L-form formation and survival in Escherichia coli. PLoS One 4(10):e7316PubMedCentralPubMedGoogle Scholar
  75. Goh KI, Cusick ME, Valle D et al (2007) The human disease network. Proc Natl Acad Sci USA 104(21):8685–8690PubMedCentralPubMedGoogle Scholar
  76. Gombart AF, Saito T, Koeffler HP (2009) Exaptation of an ancient Alu short interspersed element provides a highly conserved vitamin D-mediated innate immune response in humans and primates. BMC Genomics 10:321PubMedCentralPubMedGoogle Scholar
  77. Gottlieb B, Chalifour LE, Mitmaker B et al (2009) BAK1 gene variation and abdominal aortic aneurysms. Hum Mutat 30(7):1043–1047PubMedGoogle Scholar
  78. Gottlieb JE, Israel HL, Steiner RM et al (1997) Outcome in sarcoidosis. The relationship of relapse to corticosteroid therapy. Chest 111(3):623–631PubMedGoogle Scholar
  79. Gribbin J, Hubbard RB, Le Jeune I et al (2006) Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK. Thorax 61(11):980–985PubMedCentralPubMedGoogle Scholar
  80. Grice EA, Kong HH, Renaud G et al (2008) A diversity profile of the human skin microbiota. Genome Res 18(7):1043–1050PubMedCentralPubMedGoogle Scholar
  81. Grutters JC, van den Bosch JM (2006) Corticosteroid treatment in sarcoidosis. Eur Respir J 28(3):627–636PubMedGoogle Scholar
  82. Guarneri F, Guarneri C, Benvenga S (2005) Helicobacter pylori and autoimmune pancreatitis: role of carbonic anhydrase via molecular mimicry? J Cell Mol Med 9(3):741–744PubMedGoogle Scholar
  83. Gumpert J, Taubeneck U (1983) Characteristic properties and biological significance of stable protoplast type L-forms. Experientia Suppl 46:227–241PubMedGoogle Scholar
  84. Hall CB, Caserta MT, Schnabel K et al (2008) Chromosomal integration of human herpesvirus 6 is the major mode of congenital human herpesvirus 6 infection. Pediatrics 122(3):513–520PubMedGoogle Scholar
  85. Harada M, Kishimoto Y, Makino S (1990) Prevention of overt diabetes and insulitis in NOD mice by a single BCG vaccination. Diabetes Res Clin Pract 8(2):85–89PubMedGoogle Scholar
  86. Harley JB, James JA (2006) Epstein-Barr virus infection induces lupus autoimmunity. Bull NYU Hosp Jt Dis 64(1–2):45–50PubMedGoogle Scholar
  87. Hawke CG, Painter DM, Kirwan PD et al (2003) Mycobacteria, an environmental enhancer of lupus nephritis in a mouse model of systemic lupus erythematosus. Immunology 108(1):70–78PubMedCentralPubMedGoogle Scholar
  88. Hazlett KR, Caldon SD, McArthur DG et al (2008) Adaptation of Francisella tularensis to the mammalian environment is governed by cues which can be mimicked in vitro. Infect Immun 76(10):4479–4488PubMedCentralPubMedGoogle Scholar
  89. Hibbert-Jones E, Regan G, Bramwell J (2004) What do we know about diabetes and obesity in adults and children? J Fam Health Care 14(4):95–98PubMedGoogle Scholar
  90. Hill Gaston JS, Lillicrap MS (2003) Arthritis associated with enteric infection. Best Pract Res Clin Rheumatol 17(2):219–239PubMedGoogle Scholar
  91. Hoffman LR, Deziel E, D’Argenio DA et al (2006) Selection for Staphylococcus aureus small-colony variants due to growth in the presence of Pseudomonas aeruginosa. Proc Natl Acad Sci USA 103(52):19890–19895PubMedCentralPubMedGoogle Scholar
  92. Holick MF (2008) Vitamin D: a D-Lightful health perspective. Nutr Rev 66(10 Suppl 2):S182–194PubMedGoogle Scholar
  93. Holmes E, Loo RL, Stamler J et al (2008) Human metabolic phenotype diversity and its association with diet and blood pressure. Nature 453(7193):396–400PubMedGoogle Scholar
  94. Joseleau-Petit D, Liebart JC, Ayala JA et al (2007) Unstable Escherichia coli L forms revisited: growth requires peptidoglycan synthesis. J Bacteriol 189(18):6512–6520PubMedCentralPubMedGoogle Scholar
  95. Kern DG, Neill MA, Wrenn DS et al (1993) Investigation of a unique time-space cluster of sarcoidosis in firefighters. Am Rev Respir Dis 148(4 Pt 1):974–980PubMedGoogle Scholar
  96. Kinross JM, von Roon AC, Holmes E et al (2008) The human gut microbiome: implications for future health care. Curr Gastroenterol Rep 10(4):396–403PubMedGoogle Scholar
  97. Kissler H (2001) Is multiple sclerosis caused by a silent infection with malarial parasites? A historico-epidemiological approach: part II. Med Hypotheses 57(3):292–301PubMedGoogle Scholar
  98. Kleineberger-Nobel E (1951) Filterable forms of bacteria. Bacteriol Rev 15(2):77–103Google Scholar
  99. Knodler LA, Finlay BB (2001) Salmonella and apoptosis: to live or let die? Microbes Infect/Inst Pasteur 3(14–15):1321–1326Google Scholar
  100. Kodati VL, Govindan S, Movva S et al (2008) Role of Shigella infection in endometriosis: a novel hypothesis. Med Hypotheses 70(2):239–243PubMedGoogle Scholar
  101. Kozarov EV, Dorn BR, Shelburne CE et al (2005) Human atherosclerotic plaque contains viable invasive Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis. Arterioscler Thromb Vasc Biol 25(3):e17–18PubMedGoogle Scholar
  102. Kuijl C, Savage ND, Marsman M et al (2007) Intracellular bacterial growth is controlled by a kinase network around PKB/AKT1. Nature 450(7170):725–730PubMedGoogle Scholar
  103. Kuroki S, Saida T, Nukina M et al (1993) Campylobacter jejuni strains from patients with Guillain–Barre syndrome belong mostly to Penner serogroup 19 and contain beta-N-acetylglucosamine residues. Ann Neurol 33(3):243–247PubMedGoogle Scholar
  104. Lamell CW, Griffen AL, McClellan DL et al (2000) Acquisition and colonization stability of Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis in children. J Clin Microbiol 38(3):1196–1199PubMedCentralPubMedGoogle Scholar
  105. Lekakh IV, Rott GM, Poverennyi AM (1991) “Masked” autoantibodies from the serum of healthy blood donors cross-reacting with DNA and bacterial lipopolysaccharides. Biull Eksp Biol Med 111(5):516–518PubMedGoogle Scholar
  106. Lie JA, Andersen A, Kjaerheim K (2007) Cancer risk among 43000 Norwegian nurses. Scand J Work Environ Health 33(1):66–73PubMedGoogle Scholar
  107. Liolios K, Mavromatis K, Tavernarakis N et al (2008) The Genomes On Line Database (GOLD) in 2007: status of genomic and metagenomic projects and their associated metadata. Nucleic Acids Res 36(Database issue):D475–479PubMedCentralPubMedGoogle Scholar
  108. Liu PT, Stenger S, Tang DH et al (2007) Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J Immunol 179(4):2060–2063PubMedGoogle Scholar
  109. Liu Y, Penttinen MA, Granfors K (2001) Insights into the role of infection in the spondyloarthropathies. Curr Rheumatol Rep 3(5):428–434PubMedGoogle Scholar
  110. Lombardi VC, Ruscetti FW, Das Gupta J et al (2009) Detection of an infectious retrovirus, xmrv, in blood cells of patients with chronic fatigue syndrome. Science 326(5952):585–589Google Scholar
  111. Luque C, Cisternas FA, Araya M (2006) Changes in the patterns of disease after the epidemiological transition in health in Chile, 1950–2003. Rev Med Chil 134(6):703–712PubMedGoogle Scholar
  112. Lutjen-Drecoll E (1992) Morphology of the pars plana region. Dev Ophthalmol 23:50–59PubMedGoogle Scholar
  113. Lykouras D, Sampsonas F, Kaparianos A et al (2008) Human genes in TB infection: their role in immune response. Monaldi Arch Chest Dis 69(1):24–31PubMedGoogle Scholar
  114. Machado AM, Figueiredo C, Touati E et al (2009) Helicobacter pylori infection induces genetic instability of nuclear and mitochondrial DNA in gastric cells. Clin Cancer Res 15(9):2995–3002PubMedGoogle Scholar
  115. Marshall TG (2008) VDR nuclear receptor is key to recovery from cognitive dysfunction. In: Days of molecular medicine. Stockholm, SwedenGoogle Scholar
  116. Marshall TG (2008) Vitamin D discovery outpaces FDA decision making. BioEssays 30(2):173–182PubMedGoogle Scholar
  117. Mattman LH (2000) Cell wall deficient forms: stealth pathogens. CRC Press, Boca Raton, FLGoogle Scholar
  118. Mawer EB, Hayes ME, Still PE et al (1991) Evidence for nonrenal synthesis of 1,25-dihydroxyvitamin D in patients with inflammatory arthritis. J Bone Miner Res 6(7):733–739PubMedGoogle Scholar
  119. Mazmanian SK, Round JL, Kasper DL (2008) A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453(7195):620–625PubMedGoogle Scholar
  120. McIntyre JA (2004) The appearance and disappearance of antiphospholipid autoantibodies subsequent to oxidation–reduction reactions. Thromb Res 114(5–6):579–587PubMedGoogle Scholar
  121. McLean SA, Williams DA, Clauw DJ (2005) Fibromyalgia after motor vehicle collision: evidence and implications. Traffic Inj Prev 6(2):97–104PubMedGoogle Scholar
  122. Mehra NK, Kumar N, Kaur G et al (2007) Biomarkers of susceptibility to type 1 diabetes with special reference to the Indian population. Indian J Med Res 125(3):321–344PubMedGoogle Scholar
  123. Merino G, Carranza-Lira S, Murrieta S et al (1995) Bacterial infection and semen characteristics in infertile men. Arch Androl 35(1):43–47PubMedGoogle Scholar
  124. Merkler D, Horvath E, Bruck W et al (2006) “Viral deja vu” elicits organ-specific immune disease independent of reactivity to self. J Clin Invest 116(5):1254–1263PubMedCentralPubMedGoogle Scholar
  125. Mestas J, Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. J Immunol 172(5):2731–2738PubMedGoogle Scholar
  126. Miller R, Callas DD, Kahn SE et al (2000) Evidence of myocardial infarction in mummified human tissue. JAMA 284(7):831–832PubMedGoogle Scholar
  127. Mitiku K, Mengistu G (2002) Relapsing fever in Gondar, Ethiopia. East Afr Med J 79(2):85–87PubMedGoogle Scholar
  128. Moissl C, Osman S, La Duc MT et al (2007) Molecular bacterial community analysis of clean rooms where spacecraft are assembled. FEMS Microbiol Ecol 61(3):509–521PubMedGoogle Scholar
  129. Monaco C, Mathur A, Martin JF (2005) What causes acute coronary syndromes? Applying Koch’s postulates. Atherosclerosis 179(1):1–15PubMedGoogle Scholar
  130. Muller M (2006) Premature cellular senescence induced by pyocyanin, a redox-active Pseudomonas aeruginosa toxin. Free Radic Biol Med 41(11):1670–1677PubMedGoogle Scholar
  131. Murphy GJ, Reeves BC, Rogers CA et al (2007) Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation 116(22):2544–2552PubMedGoogle Scholar
  132. Nasidze I, Li J, Quinque D et al (2009) Global diversity in the human salivary microbiome. Genome Res 19(4):636–643Google Scholar
  133. Nevado J, Tenbaum SP, Castillo AI et al (2007) Activation of the human immunodeficiency virus type I long terminal repeat by 1 alpha,25-dihydroxyvitamin D3. J Mol Endocrinol 38(6):587–601PubMedGoogle Scholar
  134. Nicolson GL, Gan R, Nicolson NL et al (2007) Evidence for Mycoplasma ssp., Chlamydia pneunomiae, and human herpes virus-6 coinfections in the blood of patients with autistic spectrum disorders. J Neurosci Res 85(5):1143–1148PubMedGoogle Scholar
  135. Nikkari S, McLaughlin IJ, Bi W et al (2001) Does blood of healthy subjects contain bacterial ribosomal DNA? J Clin Microbiol 39(5):1956–1959PubMedCentralPubMedGoogle Scholar
  136. Nuding S, Fellermann K, Wehkamp J et al (2007) Reduced mucosal antimicrobial activity in Crohn’s disease of the colon. Gut 56(9):1240–1247PubMedCentralPubMedGoogle Scholar
  137. O’Connor SM, Taylor CE, Hughes JM (2006) Emerging infectious determinants of chronic diseases. Emerg Infect Dis 12(7):1051–1057PubMedCentralPubMedGoogle Scholar
  138. Padilla ML, Schilero GJ, Teirstein AS (2002) Donor-acquired sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 19(1):18–24PubMedGoogle Scholar
  139. Palmer C, Bik EM, DiGiulio DB et al (2007) Development of the human infant intestinal microbiota. PLoS Biol 5(7):e177PubMedCentralPubMedGoogle Scholar
  140. Pareek SS (1977) Syphilitic alopecia and Jarisch-Herxheimer reaction. Br J Vener Dis 53(6):389–390PubMedCentralPubMedGoogle Scholar
  141. Perez TH (2008) Bacteria induced vitamin D receptor dysfunction in autoimmune disease: theoretical and practical implications for interpretation of serum vitamin D metabolite levels. In: 6th International Congress on Autoimmunity, Porto, Portugal, September 11 2008Google Scholar
  142. Peschard S, Brinkane A, Bergheul S et al (2001) Whipple disease associated with pulmonary arterial hypertension. Jarisch–Herxheimer reaction after antibiotic therapy. Presse Med 30(31 Pt 1):1549–1551PubMedGoogle Scholar
  143. Poolman EM, Galvani AP (2007) Evaluating candidate agents of selective pressure for cystic fibrosis. J R Soc Interface 4(12):91–98PubMedCentralPubMedGoogle Scholar
  144. Pordeus V, Szyper-Kravitz M, Levy RA et al (2008) Infections and autoimmunity: a panorama. Clin Rev Allergy Immunol 34(3):283–299PubMedGoogle Scholar
  145. Posnett DN, Edinger J (1997) When do microbes stimulate rheumatoid factor? J Exp Med 185(10):1721–1723PubMedCentralPubMedGoogle Scholar
  146. Pospechova K, Rozehnal V, Stejskalova L et al (2009) Expression and activity of vitamin D receptor in the human placenta and in choriocarcinoma BeWo and JEG-3 cell lines. Mol Cell Endocrinol 299(2):178–187PubMedGoogle Scholar
  147. Proal AD, Albert PJ, Marshall TG (2009) Dysregulation of the vitamin D nuclear receptor may contribute to the higher prevalence of some autoimmune diseases in women. Ann N Y Acad Sci 1173:252–259PubMedGoogle Scholar
  148. Ramchandran L, Shah NP (2008) Proteolytic profiles and angiotensin-I converting enzyme and alpha-glucosidase inhibitory activities of selected lactic acid bacteria. J Food Sci 73(2):M75–81PubMedGoogle Scholar
  149. Razumov AS (1932) The direct method of calculation of bacteria in water: comparison with the Koch method. Mikrobiologija 1:131–146Google Scholar
  150. Relman DA (1998) Detection and identification of previously unrecognized microbial pathogens. Emerg Infect Dis 4(3):382–389PubMedCentralPubMedGoogle Scholar
  151. Risch NJ (2000) Searching for genetic determinants in the new millennium. Nature 405(6788):847–856PubMedGoogle Scholar
  152. Roesch LF, Lorca GL, Casella G et al (2009) Culture-independent identification of gut bacteria correlated with the onset of diabetes in a rat model. ISME J 3(5):536–548PubMedCentralPubMedGoogle Scholar
  153. Romani B, Engelbrecht S, Glashoff RH (2009) Functions of tat: the versatile protein of human immunodeficiency virus type 1. J Gen VirolGoogle Scholar
  154. Rossman MD, Kreider ME (2007) Lesson learned from ACCESS (A Case Controlled Etiologic Study of Sarcoidosis). Proc Am Thorac Soc 4(5):453–456PubMedGoogle Scholar
  155. Russell MW, Wu HY, White PL et al (1992) Serum antibody responses to Streptococcus mutans antigens in humans systemically infected with oral streptococci. Oral Microbiol Immunol 7(6):321–325PubMedGoogle Scholar
  156. Salazar JC, Duhnam-Ems S, La Vake C et al (2009) Activation of human monocytes by live Borrelia burgdorferi generates TLR2-dependent and -independent responses which include induction of IFN-beta. PLoS Pathog 5(5):e1000444PubMedCentralPubMedGoogle Scholar
  157. Sarkola M, Rintala M, Grenman S et al (2008) Human papillomavirus DNA detected in breast milk. Pediatr Infect Dis J 27(6):557–558PubMedGoogle Scholar
  158. Sauer K, Camper AK, Ehrlich GD et al (2002) Pseudomonas aeruginosa displays multiple phenotypes during development as a biofilm. J Bacteriol 184(4):1140–1154PubMedCentralPubMedGoogle Scholar
  159. Schwocho LR, Masonson HN (2001) Pharmacokinetics of CS-866, a new angiotensin II receptor blocker, in healthy subjects. J Clin Pharmacol 41(5):515–527PubMedGoogle Scholar
  160. Shelburne SA 3rd, Hamill RJ, Rodriguez-Barradas MC et al (2002) Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Baltimore) 81(3):213–227Google Scholar
  161. Siegler RL, Pavia AT, Christofferson RD et al (1994) A 20-year population-based study of postdiarrheal hemolytic uremic syndrome in Utah. Pediatrics 94(1):35–40PubMedGoogle Scholar
  162. Slaughter L, Carson DA, Jensen FC et al (1978) In vitro effects of Epstein–Barr virus on peripheral blood mononuclear cells from patients with rheumatoid arthritis and normal subjects. J Exp Med 148(5):1429–1434PubMedGoogle Scholar
  163. Staley JT (1997) Biodiversity: are microbial species threatened? Curr Opin Biotechnol 8(3):340–345PubMedGoogle Scholar
  164. Stamler J, Elliott P, Dennis B et al (2003) INTERMAP: background, aims, design, methods, and descriptive statistics (nondietary). J Hum Hypertens 17(9):591–608PubMedGoogle Scholar
  165. Swaak T, Smeenk R (1985) Detection of anti-dsDNA as a diagnostic tool: a prospective study in 441 non-systemic lupus erythematosus patients with anti-dsDNA antibody (anti-dsDNA). Ann Rheum Dis 44(4):245–251PubMedCentralPubMedGoogle Scholar
  166. Swidsinski A, Ladhoff A, Pernthaler A et al (2002) Mucosal flora in inflammatory bowel disease. Gastroenterology 122(1):44–54PubMedGoogle Scholar
  167. Tavares-Ratado P, Geraldes A, Simões V et al (2009 of Conference, September 11–13). Prevalence of circulating autoantibodies in portugese blood donors. In: 4th Asian Congress on Autoimmunity, Singapore, September 11–13 2009Google Scholar
  168. Turnbaugh PJ, Ley RE, Mahowald MA et al (2006) An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444(7122):1027–1031PubMedGoogle Scholar
  169. Venter JC, Adams MD, Myers EW et al (2001) The sequence of the human genome. Science 291(5507):1304–1351PubMedGoogle Scholar
  170. Vidal V, Scragg IG, Cutler SJ et al (1998) Variable major lipoprotein is a principal TNF-inducing factor of louse-borne relapsing fever. Nat Med 4(12):1416–1420PubMedGoogle Scholar
  171. Viganò P, Lattuada D, Mangioni S et al (2006) Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system. J Mol Endocrinol 36(3):415–424PubMedGoogle Scholar
  172. Virgin HW, Wherry EJ, Ahmed R (2009) Redefining chronic viral infection. Cell 138(1):30–50PubMedGoogle Scholar
  173. Walker L, Levine H, Jucker M (2006) Koch’s postulates and infectious proteins. Acta Neuropathol 112(1):1–4PubMedGoogle Scholar
  174. Wang TT, Tavera-Mendoza LE, Laperriere D et al (2005) Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol 19(11):2685–2695PubMedGoogle Scholar
  175. Wang Y, Beydoun MA (2007) The obesity epidemic in the United States–gender, age, socioeconomic, racial/ethnic, and geographic characteristics: a systematic review and meta-regression analysis. Epidemiol Rev 29:6–28PubMedGoogle Scholar
  176. Webster Marketon JI, Glaser R (2008) Stress hormones and immune function. Cell Immunol 252(1–2):16–26PubMedGoogle Scholar
  177. Weigt J, Malfertheiner P (2009) Influence of Helicobacter pylori on gastric regulation of food intake. Curr Opin Clin Nutr Metab Care 12(5):522–525PubMedGoogle Scholar
  178. Wikoff WR, Anfora AT, Liu J et al (2009) Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci USA 106(10):3698–3703PubMedCentralPubMedGoogle Scholar
  179. Wilhoite SL, Ferguson DA Jr, Soike DR et al (1993) Increased prevalence of Helicobacter pylori antibodies among nurses. Arch Intern Med 153(6):708–712PubMedGoogle Scholar
  180. Williams RC Jr, Kunkel HG (1962) Rheumatoid factor, complement, and conglutinin aberrations in patients with subacute bacterial endocarditis. J Clin Invest 41:666–675PubMedCentralPubMedGoogle Scholar
  181. Wirostko E, Johnson L, Wirostko B (1987) Crohn’s disease. Rifampin treatment of the ocular and gut disease. Hepatogastroenterology 34(2):90–93PubMedGoogle Scholar
  182. Wirostko E, Johnson L, Wirostko B (1989) Sarcoidosis associated uveitis. Parasitization of vitreous leucocytes by mollicute-like organisms. Acta Ophthalmol (Copenh) 67(4):415–424Google Scholar
  183. Xu Y, Xie J, Li Y et al (2003) Using a cDNA microarray to study cellular gene expression altered by Mycobacterium tuberculosis. Chin Med J 116(7):1070–1073PubMedGoogle Scholar
  184. Yang X, Xie L, Li Y et al (2009) More than 9,000,000 unique genes in human gut bacterial community: estimating gene numbers inside a human body. PLoS One 4(6):e6074PubMedCentralPubMedGoogle Scholar
  185. Yenamandra SP, Lundin A, Arulampalam V et al (2009) Expression profile of nuclear receptors upon Epstein–Barr virus-induced B cell transformation. Exp Oncol 31(2):92–96PubMedGoogle Scholar
  186. Yilmaz O, Yao L, Maeda K et al (2008) ATP scavenging by the intracellular pathogen Porphyromonas gingivalis inhibits P2X7-mediated host-cell apoptosis. Cell Microbiol 10(4):863–875PubMedCentralPubMedGoogle Scholar
  187. Yoshizawa T, Handa Y, Uematsu Y et al (1997) Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet 16(4):391–396PubMedGoogle Scholar
  188. Zanini GM, De Moura Carvalho LJ, Brahimi K et al (2009) Sera of patients with systemic lupus erythematosus react with plasmodial antigens and can inhibit the in vitro growth of Plasmodium falciparum. Autoimmunity 42(6):545–552PubMedGoogle Scholar
  189. Zhang H, DiBaise JK, Zuccolo A et al (2009) Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci USA 106(7):2365–2370PubMedCentralPubMedGoogle Scholar
  190. Zinkernagel MS, Bolinger B, Krebs P et al (2009) Immunopathological basis of lymphocytic choriomeningitis virus-induced chorioretinitis and keratitis. J Virol 83(1):159–166PubMedCentralPubMedGoogle Scholar
  191. Zumla A, James DG (1996) Granulomatous infections: etiology and classification. Clin Infect Dis 23(1):146–158PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Amy D. Proal
    • 1
  • Paul J. Albert
    • 2
  • Trevor G. Marshall
    • 3
  1. 1.Murdoch UniversityMurdochAustralia
  2. 2.Weill Cornell Medical CollegeNew YorkUSA
  3. 3.Murdoch UniversityMurdochAustralia

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