Clinical Reviews in Allergy & Immunology

, Volume 52, Issue 3, pp 333–350 | Cite as

A Review of Autoimmune Disease Hypotheses with Introduction of the “Nucleolus” Hypothesis

  • Wesley H. Brooks


Numerous hypotheses have been proposed in order to explain the complexity of autoimmune diseases. These hypotheses provide frameworks towards understanding the relations between triggers, autoantigen development, symptoms, and demographics. However, testing and refining these hypotheses are difficult tasks since autoimmune diseases have a potentially overwhelming number of variables due to the influence on autoimmune diseases from environmental factors, genetics, and epigenetics. Typically, the hypotheses are narrow in scope, for example, explaining the diseases in terms of genetics without defining detailed roles for environmental factors or epigenetics. Here, we present a brief review of the major hypotheses of autoimmune diseases including a new one related to the consequences of abnormal nucleolar interactions with chromatin, the “nucleolus” hypothesis which was originally termed the “inactive X chromosome and nucleolus nexus” hypothesis. Indeed, the dynamic nucleolus can expand as part of a cellular stress response and potentially engulf portions of chromatin, leading to disruption of the chromatin. The inactive X chromosome (a.k.a. the Barr body) is particularly vulnerable due to its close proximity to the nucleolus. In addition, the polyamines, present at high levels in the nucleolus, are also suspected of contributing to the development of autoantigens.


Epigenetics Nucleolus Inactive X chromosome Polyamines Autoimmune diseases 



SAM decarboxylase, a key, initial enzyme in polyamine synthesis


Decarboxylated S-adenosylmethionine


Epstein–Barr virus


Long interspersed nuclear element 1


Multiple sclerosis


Peptidyl arginine deiminase


Pseudo-autosomal regions of the X chromosome


Rheumatoid arthritis


Scaffold attachment factor


S-adenosylmethionine, the cellular methyl group donor


Spermidine/spermine N1 acetyltransferase, an enzyme in polyamine recycling


Sjӧgren’s syndrome


Systemic lupus erythematosus


Spermine synthase, an enzyme in polyamine synthesis


Spermidine synthase, an enzyme in polyamine synthesis


Signal recognition particle


The active X chromosome


X chromosome inactivation, epigenetic silencing of X chromosomes


The inactive X chromosome


X-inactivation center, locus of genes involved in initiating XCI


Xq, X chromosome short arm and long arm, respectively



The advice of Dr. Yves Renaudineau (University of Brest, France) is greatly appreciated in the development of the preparation of this review.


The author declares no conflicts of interest in this work.


  1. 1.
    Prineas JW, Parratt JDE (2012) Oligodendrocytes and the early multiple sclerosis lesion. Annals Neurol 72(1):18–31CrossRefGoogle Scholar
  2. 2.
    Van Noort JM, Baker D, Amor S (2012) Mechanisms in the development of multiple sclerosis lesions: reconciling autoimmune and neurodegenerative factors. CNS & Neurological Disorders - Drug Targets 11(5):556–69CrossRefGoogle Scholar
  3. 3.
    Anaya JM (2012) Common mechanisms of autoimmune diseases (the autoimmune tautology). Autoimmunity Rev 11(11):781–4CrossRefGoogle Scholar
  4. 4.
    Amador-Patarroyo MJ, Rodriguez-Rodriguez A, Montoya-Ortiz G (2012) How does age at onset influence the outcome of autoimmune diseases? Autoimmune Diseases 2012(art251730):1–7CrossRefGoogle Scholar
  5. 5.
    Brooks WH, Le Dantec C, Pers JO, Youinou P, Renaudineau Y (2010) Epigenetics and autoimmunity. J Autoimmunity 34:J207–19CrossRefGoogle Scholar
  6. 6.
    Le Dantec C, Brooks WH, Renaudineau Y (2015) Epigenomic revolution in autoimmune diseases. World J Immunol 5(2):62–67CrossRefGoogle Scholar
  7. 7.
    Lu Q, Renaudineau Y, Cha S et al (2010) Epigenetics in autoimmune disorders: highlights of the 10th Sjögren’s Syndrome Symposium. Autoimmunity Rev 9(9):627–30CrossRefGoogle Scholar
  8. 8.
    Thabet Y, Canas F, Ghedira I, Youinou P, Mageed RA, Renaudineau Y (2012) Altered patterns of epigenetic changes in systemic lupus erythematosus and auto-antibody production: is there a link? J Autoimmunity 39(3):154–60CrossRefGoogle Scholar
  9. 9.
    Zhang Z, Zhang R (2015) Epigenetics in autoimmune diseases: pathogenesis and prospects for therapy. Autoimmunity Rev 14(10):854–63CrossRefGoogle Scholar
  10. 10.
    Konsta OD, Le Dantec C, Brooks WH, Renaudineau Y (2015) Genetics and epigenetics of autoimmune diseases. eLS. John Wiley & Sons, Ltd, Chichester, pp.1–9.Google Scholar
  11. 11.
    Konsta OD, Le Dantec C, Charras A, Brooks WH, Arleevskaya MI, Bordron A, Renaudineau Y (2015) An in silico approach reveals associations between genetic and epigenetic factors within regulatory elements in B cells from primary Sjögren’s syndrome patients. Front Immunol 6:437PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Thabet Y, Le Dantec C, Ghedira I, Devauchelle V, Cornec D, Pers J-O, Renaudineau Y (2013) Epigenetic dysregulation in salivary glands from patients with primary Sjögren’s syndrome may be ascribed to infiltrating B cells. J Autoimmunity 41:175–81CrossRefGoogle Scholar
  13. 13.
    Invernizzi P, Pasini S, Selmi C et al (2009) Female predominance and X chromosome defects in autoimmune diseases. J Autoimmunity 33(1):12–6CrossRefGoogle Scholar
  14. 14.
    Renaudineau Y, Beauvillard D, Padelli M, Brooks WH, Youinou P (2011) Epigenetic alterations and autoimmune disease. J Dev Orig Health Dis 2(5):258–64PubMedCrossRefGoogle Scholar
  15. 15.
    Barzilai O, Sherer Y, Ram M, Izhaky D, Anaya JM, Shoenfeld Y (2007) Epstein–Barr virus and cytomegalovirus in autoimmune diseases: are they truly notorious? A preliminary report. Ann N Y Acad Sci 1108:567–577PubMedCrossRefGoogle Scholar
  16. 16.
    Arleevskaya MI, Zabotin A, Gabdoulkhakova A, Filina J, Tsibulkin A (2016) A possible interconnection of cholesterol overloading and phagocytic activity of the monocytes in the prone to rheumatoid arthritis individuals. Lupus Open Access 1:112Google Scholar
  17. 17.
    James JA, Harley JB, Scofield RH (2006) Epstein–Barr virus and systemic lupus erythematosus. Curr Opin Rheumatol 18:462–467PubMedCrossRefGoogle Scholar
  18. 18.
    Christensen T (2006) The role of EBV in MS pathogenesis. Intl MS J 13:52–57Google Scholar
  19. 19.
    Fox RI, Luppi M, Pisa P, Kang HI (1992) Potential role of Epstein-Barr virus in Sjogren’s syndrome and rheumatoid arthritis. J Rheumatol Suppl 32:18–24PubMedGoogle Scholar
  20. 20.
    Sibley JT, Lee JS, Decoteau WE (1984) Left-handed “Z” DNA antibodies in rheumatoid arthritis and systemic lupus erythematosus. J Rheumatol 11:633–7PubMedGoogle Scholar
  21. 21.
    Van Helden PD (1985) Potential Z-DNA-forming elements in serum DNA from human systemic lupus erythematosus. J Immunol 134:177–9PubMedGoogle Scholar
  22. 22.
    Krishna P, Fritz MH, van de Sande JH (1993) Interactions of anti-DNA antibodies with Z-DNA. Clin Exp Immunol 92:51–7PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Minota S, Jarour WN, Suzuki N et al (1991) Autoantibodies to nucleolin in systemic lupus erythematosus and other diseases. J Immunol 146:2249–52PubMedGoogle Scholar
  24. 24.
    Harley JB, Scofield RH, Reichlin M (1992) Anti-Ro in Sjogren’s syndrome and systemic lupus erythematosus. Rheum Dis Clin NA 18(2):337–58Google Scholar
  25. 25.
    Renaudineau Y, Hillion S, Saraux A, Youinou P (2014) Autoanticorps dans les maladies systémiques. Traité des maladies et syndromes systémiques. Flammarion Medecine Sciences Ch 6:1–32Google Scholar
  26. 26.
    Baka Z, Gyӧrgy B, Géher P, Buzás EI, Falus A, Nagy G (2012) Citrullination under physiological and pathological conditions. Joint Bone Spine 79:431–6PubMedCrossRefGoogle Scholar
  27. 27.
    Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A et al (2013) NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med 5:178ra40PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Garaud S, Le Dantec C, Jousse-Joulin S, Hanrotel-Saliou C, Saraux A, Mageed RA, Youinou P, Renaudineau Y (2009) IL-6 modulates CD5 expression in B cells from patients with lupus by regulating DNA methylation. J Immunol 182(9):5623–32PubMedCrossRefGoogle Scholar
  29. 29.
    Rojas-Villarraga A, Amaya-Amaya J, Rodriguez-Rodriguez A, Mantilla RD, Anaya JM (2012) Introducing polyautoimmunity: secondary autoimmune diseases no longer exist. Autoimmune Diseases 2012(art254319):1–9CrossRefGoogle Scholar
  30. 30.
    Anaya JM, Castiblanco J, Rojas-Villarraga A et al (2012) The multiple autoimmune syndromes. A clue for the autoimmune tautology. Clin Rev Allerg Immunol 43(3):256–64CrossRefGoogle Scholar
  31. 31.
    Asher MI, Montefort S, Bjorksten B, Lai CK, Strachan DP, Weiland SK et al (2006) Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 368:733–743PubMedCrossRefGoogle Scholar
  32. 32.
    Kuo CH, Kuo H-F, Huang C-H, Yang S-N, Lee M-S, Hung C-H (2013) Early life exposure to antibiotics and the risk of childhood allergic diseases: an update from the perspective of the hygiene hypothesis. J Microbiol Immunol Infect 2013(46):320–329CrossRefGoogle Scholar
  33. 33.
    Strachan DP (1989) Hay fever, hygiene, and household size. BMJ 299(6710):1259–1260PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Rook GAW (2012) Hygiene hypothesis and autoimmune diseases. Clin Rev Allergy Immunol 42(1):5–15PubMedCrossRefGoogle Scholar
  35. 35.
    Stiemsma LT, Reynolds LA, Turvey SE, Finlay BB (2015) The hygiene hypothesis: current perspectives and future therapies. ImmunoTargets and Therapy 4:143–157PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Roduit C, Frei R, von Mutius E, Lauener R (2016) Environmental influences on the immune system. Ed: Esser C. Springer-Verllag Wien. 77-96Google Scholar
  37. 37.
    Maizels RM, McSorley HJ, Smyth DJ (2014) Helminths in the hygiene hypothesis: sooner or later? Clin Exp Immunol 177(1):38–46PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Van Riet E, Hartgers FC, Yazdanbakhsh M (2007) Chronic helminth infections induce immunomodulation: consequences and mechanisms. Immunobiology 212:475–490PubMedCrossRefGoogle Scholar
  39. 39.
    Taher TE, Muhammad HA, Bariller E, Flores-Borja F, Renaudineau Y, Isenberg DA, Mageed RA (2013) B-lymphocyte signalling abnormalities and lupus immunopathology. Int Rev Immunol 32(4):428–44PubMedCrossRefGoogle Scholar
  40. 40.
    Mageed RA, Garaud S, Taher TE, Parikh K, Pers JO, Jamin C, Renaudineau Y, Youinou P (2012) CD5 expression promotes multiple intracellular signaling pathways in B lymphocyte. Autoimmun Rev 11(11):795–8PubMedCrossRefGoogle Scholar
  41. 41.
    Mukherjee S, Brooks WH (2014) Stromal interaction molecules as important therapeutic targets in diseases with dysregulated calcium flux. Biochim Biophysica Acta 1843(10):2307–14CrossRefGoogle Scholar
  42. 42.
    Kidd P (2003) Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev 8(3):223–46PubMedGoogle Scholar
  43. 43.
    Marwaha AK, Leung NJ, McMurchy AN, Levings MK (2012) TH17 cells in autoimmunity and immunodeficiency: protective or pathogenic? Front Immunol 3:129–34PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Burkett PR, zu Horste GM, Kuchroo VK (2015) Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity. J Clin Invest 125(6):2211–2219PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Zambrano-Zaragoza JF, Romo-Martínez EJ, Durán-Avelar M de J et al (2014) Th17 cells in autoimmune and infectious diseases. Intl J Inflamm 2014:651503. doi: 10.1155/2014/651503 CrossRefGoogle Scholar
  46. 46.
    Maddur MS, Miossec P, Kaveri SV, Bayry J (2012) Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies. Am J Pathology 181:8–18CrossRefGoogle Scholar
  47. 47.
    Sharp A, Robinson D, Jacobs P (2000) Age- and tissue-specific variation of X chromosome inactivation ratios in normal women. Hum Genetics 107(4):343–9CrossRefGoogle Scholar
  48. 48.
    Plengel RM, Stevenson RA, Lubs HA, Schwartz CE, Willard HF (2002) Skewed X-chromosome inactivation is a common feature of X-linked mental retardation disorders. Am J Hum Genetics 71(1):168–73CrossRefGoogle Scholar
  49. 49.
    Pegoraro E, Whitaker J, Mowery-Rushton P, Surti U, Lanasa M, Hoffman EP (1997) Familial skewed X inactivation: a molecular trait associated with high spontaneous-abortion rate maps to Xq28. Am J Hum Genetics 61(1):160–70CrossRefGoogle Scholar
  50. 50.
    Brix TH, Knudsen GPS, Kristiansen M et al (2005) High frequency of skewed X-chromosome inactivation in females with autoimmune thyroid disease: a possible explanation for the female predisposition to thyroid autoimmunity. J Clin Endocrinol Metabol 90(11):5949–53CrossRefGoogle Scholar
  51. 51.
    Simmonds MJ, Kavvoura FK, Brand OJ et al (2014) Skewed X chromosome inactivation and female preponderance in autoimmune thyroid disease: an association study and meta-analysis. J Clin Endocrin Metabol 99(1):E127–E131CrossRefGoogle Scholar
  52. 52.
    Broen JCA, Wolvers-Tettero ILM, van Bon LG et al (2010) Skewed X chromosomal inactivation impacts T regulatory cell function in systemic sclerosis. Ann Rheum Dis. doi: 10.1136/ard.2010.129999 PubMedCentralGoogle Scholar
  53. 53.
    Özbalkan Z, Baǧışlar S, Kiraz S et al (2005) Skewed X chromosome inactivation in blood cells of women with scleroderma. Arthritis Rheum 52(5):1564–70PubMedCrossRefGoogle Scholar
  54. 54.
    Knudsen GPS, Harbo HF, Smestad C et al (2007) X chromosome inactivation in females with multiple sclerosis. Eur J Neurol 14(12):1392–6PubMedCrossRefGoogle Scholar
  55. 55.
    Brooks WH (2010) X chromosome inactivation and autoimmunity. Clinic Rev Allerg Immunol 39:20–29CrossRefGoogle Scholar
  56. 56.
    Brooks WH, Renaudineau Y (2015) Epigenetics and autoimmune diseases: the X chromosome-nucleolus nexus. Front Genet 6:22PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Oldstone MBA (2014) Molecular mimicry: its evolution from concept to mechanism as a cause of autoimmune diseases. Monoclonal antibodies in immunodiagnosis and immunotherapy 33:158–165PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Chastain EML, Miller SD (2012) Molecular mimicry as an inducing trigger for CNS autoimmune demyelinating disease. Immunol Rev 245(1):227–238PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Sundar K, Jacques S, Gottlieb P, Villars R, Benito M-E, Taylor DK, Spatz LA (2004) Expression of the Epstein-Barr virus nuclear antigen-1 (EBNA-1) in the mouse can elicit the production of anti-dsDNA and anti-Sm antibodies. J Autoimmunity 23(2):127–140CrossRefGoogle Scholar
  60. 60.
    Cusick MF, Libbey JE, Fujinami RS (2012) Molecular mimicry as a mechanism of autoimmune disease. Clinic Rev Allerg Immunol 42:102–11CrossRefGoogle Scholar
  61. 61.
    Vojdani A (2015) Molecular mimicry as a mechanism for food immune reactivities and autoimmunity. Alternative Therapies in Health and Medicine, suppl 121:34–45Google Scholar
  62. 62.
    Vanderlugt CL, Begolka WS, Neville KL, Katz-Levy Y, Howard LM, Eagar TN, Bluestone JA, Miller SD (1998) The functional significance of epitope spreading and its regulation by co-stimulatory molecules. Immunol Reviews 164(1):63–72CrossRefGoogle Scholar
  63. 63.
    Cornaby C, Gibbons L, Mayhew V et al (2015) B cell epitope spreading: mechanisms and contribution to autoimmune diseases. Immunol Lett 163(1):56–68PubMedCrossRefGoogle Scholar
  64. 64.
    Sokolove J, Bromberg R, Deane KD et al (2012) Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLoS One 7(5), e35296PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Shoenfeld Y, Agmon-Levin N (2011) ‘ASIA’—autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmunity 36:4e8CrossRefGoogle Scholar
  66. 66.
    Agmon-Levin N, Hughes GRV, Shoenfeld Y (2012) The spectrum of ASIA: ‘Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants’. Lupus 21:118–20PubMedCrossRefGoogle Scholar
  67. 67.
    Tervaert JWC, Kappel RM (2013) Silicone implant incompatibility syndrome (SIIS): a frequent cause of ASIA (Shoenfeld’s syndrome). Immunol Res 56:293–98CrossRefGoogle Scholar
  68. 68.
    Toubi E (2012) ASIA—Autoimmune Syndromes Induced by Adjuvants: rare, but worth considering. IMAJ 14:121–4PubMedGoogle Scholar
  69. 69.
    Parks CG, Conrad K, Cooper GS (1999) Occupational exposure to crystalline silica and autoimmune disease. Environ Health Perspect 107(suppl 5):793–802PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Goren I, Segal G, Shoenfeld Y (2015) Autoimmune/inflammatory syndrome induced by adjuvant (ASIA) evolution after silicone implants. Who is at risk? Clin Rheumatol 34:1661–6PubMedCrossRefGoogle Scholar
  71. 71.
    Colafrancesco S, Perriconea C, Prioria R et al (2014) Sjögren’s syndrome: another facet of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). J Autoimmunity 51:10–16CrossRefGoogle Scholar
  72. 72.
    Fasano A (2012) Leaky gut and autoimmune diseases. Clin Rev Allerg Immunol 42(1):71–8CrossRefGoogle Scholar
  73. 73.
    Davis-Richardson AG, Triplett EW (2015) A model for the role of gut bacteria in the development of autoimmunity for type 1 diabetes. Diabetologia 58:1386–93PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Severance EG, Yolken RH, Eaton WW (2014) Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophrenia Research (in press, proofs available online).Google Scholar
  75. 75.
    Brooks WH (2013) Increased polyamines alter chromatin and stabilize autoantigens in autoimmune diseases. Front Immunol 4:91PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    D’Agostino L, Di Luccia A (2002) Polyamines interact with DNA as molecular aggregates. Eur J Biochem 269:4317–4325PubMedCrossRefGoogle Scholar
  77. 77.
    D’Agostino L, Di Pietro M, Di Luccia A (2005) Nuclear aggregates of polyamines are supramolecular structures that play a crucial role in genomic DNA protection and conformation. FEBS J 272:3777–3787PubMedCrossRefGoogle Scholar
  78. 78.
    Iacomino G, Picariello G, Sbrana F, Di Luccia A, Raiteri R, D’Agostino L (2011) DNA is wrapped by the nuclear aggregates of polyamines: the imaging evidence. Biomacromolecules 12:1178–1186PubMedCrossRefGoogle Scholar
  79. 79.
    Iacomino G, Picariello G, D’Agostino L (2012) DNA and nuclear aggregates of polyamines. Biochim Biophys Acta 1823:1745–1755PubMedCrossRefGoogle Scholar
  80. 80.
    Brooks WH (2012) Autoimmune diseases and polyamines. Clinic Rev Allerg Immunol 42:58–70CrossRefGoogle Scholar
  81. 81.
    Su KY, Pisetsky DS (2009) The role of extracellular DNA in autoimmunity in SLE. Scand J Immunol 70:175–83PubMedCrossRefGoogle Scholar
  82. 82.
    Wagner AJ, Meyers C, Laimins LA, Hay N (1993) C-Myc induces the expression and activity of ornithine decarboxylase. Cell Growth Differ 4:879e83Google Scholar
  83. 83.
    Lam YW, Trinkle-Mulcahy L (2015) New insights into nucleolar structure and function. F1000Prime Reports. 7:48.Google Scholar
  84. 84.
    Pederson T (1998) The plurifunctional nucleolus. Nucl Acids Res 26:3871–6PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Rodriguez-Sanchez JL, Gelpi C, Juarez C, Hardin JA (1987) Anti-NOR 90. A new autoantibody in scleroderma that recognizes a 90-kDa component of the nucleolus-organizing region of chromatin. J Immunol 139(8):2579–84PubMedGoogle Scholar
  86. 86.
    Zhang LF, Huynh KD, Lee JT (2007) Perinucleolar targeting of the inactive X during S phase: evidence for a role in the maintenance of silencing. Cell 129:693–706PubMedCrossRefGoogle Scholar
  87. 87.
    Hernandez-Verdun D, Roussel P, Thiry M, Sirri V, Lafontaine DLJ (2010) The nucleolus: structure/function relationship in RNA metabolism. WIREs RNA 1:415–31PubMedCrossRefGoogle Scholar
  88. 88.
    Whelly SM (1991) Role of polyamines in the regulation of RNA synthesis in uterine nucleoli. J Steroid Biochem Mol Biol 39:161–7PubMedCrossRefGoogle Scholar
  89. 89.
    Igarashi K, Kashiwagi K (2010) Modulation of cellular function by polyamines. Intl J Biochem Cell Biol 42:39–51CrossRefGoogle Scholar
  90. 90.
    Shin M, Nakamuta H, Oda-Ueda N, Larsson LI, Fujiwara K (2008) Immunocytochemical demonstration of polyamines in nucleoli and nuclei. Histochem Cell Biol 129:659–65PubMedCrossRefGoogle Scholar
  91. 91.
    Jovine L, Djordjevic S, Rhodes D (2002) The crystal structure of yeast phenylalanine tRNA at 2.0 A resolution: cleavage by Mg(2+) in 15-year old crystals. J Mol Biol 301:401–14CrossRefGoogle Scholar
  92. 92.
    Pegg AE (2009) Mammalian polyamine metabolism and function. IUBMB Life 61:880–94PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Bale S, Lopez MM, Makhatadze GI, Fang Q, Pegg AE, Ealick SE (2008) Structural basis for putrescine activation of human S-adenosylmethionine decarboxylase. Biochemistry 47:13404–13417PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Neidhart M, Karouzakis E, Jüngel A, Gay RE, Gay S (2014) Inhibition of spermidine/spermine N1-acetyltransferase activity: a new therapeutic concept in rheumatoid arthritis. Arthritis Rheum 66(7):1723–33CrossRefGoogle Scholar
  95. 95.
    Karouzakis E, Gay RE, Gay S, Neidhart M (2012) Increased recycling of polyamines is associated with global DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 64:1809–1817PubMedCrossRefGoogle Scholar
  96. 96.
    Bajaj BG, Murakami M, Cai Q et al (2008) Epstein–Barr virus nuclear antigen 3C interacts with and enhances the stability of the c-Myc oncoprotein. J Virol 82:4082–90PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Bello-Fernandez C, Packham G, Cleveland JL (1993) The ornithine decarboxylase gene is a transcriptional target of c-Myc. Proc Natl Acad Sci U S A 90:7804–8PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Dang CV (1999) c-Myc targets genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol 19:1–11PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Nilsson JA, Keller UB, Baudino TA et al (2005) Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation. Cancer Cell 7:433–44PubMedCrossRefGoogle Scholar
  100. 100.
    Gfeller E, Stern DN, Russell DH, Levy CC, Taylor RL (1972) Ultrastructural changes in vitro of rat liver nucleoli in response to polyamines. Z Zellforsch Mikrosk Anat 129(4):447–54PubMedCrossRefGoogle Scholar
  101. 101.
    Gomez-Roman N, Grandori C, Eisenman RN, White RJ (2003) Direct activation of RNA polymerase III transcription by c-Myc. Nature 421:290–4PubMedCrossRefGoogle Scholar
  102. 102.
    Felton-Edkins ZA, Kondrashov A, Karali D et al (2006) Epstein-Barr virus induces cellular transcription factors to allow active expression of EBER genes by RNA polymerase III. J Biol Chem 281:33871–80PubMedCrossRefGoogle Scholar
  103. 103.
    Toussirot E, Roudier J (2008) Epstein-Barr virus in autoimmune diseases. Best Pract Res Clin Rheum 22(5):883–96CrossRefGoogle Scholar
  104. 104.
    Sharma V, Tekwani BL, Saxena JK, Gupta S, Katiyar JC, Chatterjee RK et al (1991) Polyamine metabolism in helminth parasites. ExpParasitol 72:15–23Google Scholar
  105. 105.
    Finlay CM, Stefanska AM, Walsh KP, Kelly PJ, Boon L, Lavelle EC, Walsh PT, Mills KH (2016) Helminth products protect against autoimmunity via innate type 2 cytokines IL-5 and IL-33, which promote eosinophilia. J Immunol 196(2):703–14PubMedCrossRefGoogle Scholar
  106. 106.
    Ross MT, Graham DV, Coffey AJ et al (2005) The DNA sequence of the human X chromosome. Nature 434:325–37PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Ross MT, Bentley DR, Tyler-Smith C (2006) The sequences of the human sex chromosomes. Curr Op Genetics & Develop 2006(16):213–18CrossRefGoogle Scholar
  108. 108.
    Barr ML, Carr DH (1962) Correlations between sex chromatin and sex chromosomes. Acta Cytol 6:34–45PubMedGoogle Scholar
  109. 109.
    Blaschke JR, Rappold G (2006) The pseudoautosomal regions, SHOX and disease. Curr Op Genetics Dev 16:233–239CrossRefGoogle Scholar
  110. 110.
    Carrel L, Willard HF (2005) X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434:400–4PubMedCrossRefGoogle Scholar
  111. 111.
    Carrel L, Cottle AA, Goglin KC, Willard HF (1999) A first-generation X-inactivation profile of the human X chromosome. Proc Natl Acad Sci U S A 96:14440–4PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Cotton AM, Ge B, Light N, Pastinen T, Brown CJ (2013) Analysis of expressed SNPs identifies variable extents of expression from the human inactive X chromosome. Genome Biol 14:R122PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Higashi K, Yoshida M, Igarashi A et al (2009) Intense correlation between protein-conjugated acrolein and primary Sjӧgren’s syndrome. Clin Chim Acta 411:359–63PubMedCrossRefGoogle Scholar
  114. 114.
    Agostinelli E (2014) Polyamines and transglutaminases: biological, clinical and biotechnological perspectives. Amino Acids 46:475–85PubMedCrossRefGoogle Scholar
  115. 115.
    WangY LM, Stadler S et al (2009) Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J Cell Biol 184:205–13CrossRefGoogle Scholar
  116. 116.
    Arita K, Hashimoto H, Shimizu T et al (2004) Structural basis for Ca(2+)-induced activation of human PAD4. Nat Struct Mol Biol 11:777–783PubMedCrossRefGoogle Scholar
  117. 117.
    Slade DJ, Fang P, Dreyton CJ et al (2015) Protein arginine deiminase 2 binds calcium in an ordered fashion: implications for inhibitor design. ACS Chem Biol 10:1043–53PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Zhu H, Luo H, Yan M, Zuo X, Li QZ (2015) Autoantigen microarray for high-throughput autoantibody profiling in systemic lupus erythematosus. Genomics Proteomics Bioinformatics 13:210–8PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Yaniv G, Twig G, Shor DB et al (2015) A volcanic explosion of autoantibodies in systemic lupus erythematosus: a diversity of 180 different antibodies found in SLE patients. Autoimmunity Rev 14:75–9CrossRefGoogle Scholar
  120. 120.
    Reichlin M (1991) Systemic lupus erythematosus. In: Bigazzi PE (ed) Systemic Autoimmunity. Marcel Dekker Inc., New York, pp 163–200Google Scholar
  121. 121.
    Lartigue A, Drouot L, Jouen F et al (2005) Association between anti-nucleophosmin and anti-cardiolipin antibodies in (NZW × BXSB)F1 mice and human systemic lupus erythematosus. Arthritis Res Therapy 57:R1394CrossRefGoogle Scholar
  122. 122.
    Brown CJ, Greally JM (2003) A stain upon the silence: genes escaping X inactivation. Trends 810 Genet 19:432–38CrossRefGoogle Scholar
  123. 123.
    Kim C, Rubin CM, Schmid CW (2001) Genome-wide chromatin remodeling modulates the Alu 919 heat shock response. Gene 276:127–33PubMedCrossRefGoogle Scholar
  124. 124.
    Wise AL, Gyi L, Manolio TA (2013) eXclusion: toward integrating the X chromosome in genome-wide association analyses. Am J Hum Genet 92:643–7PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Cooney CM, Bruner GR, Aberle T et al (2009) 46, X, del(X)(q13) Turner’s syndrome female with systemic lupus erythematosus in a pedigree multiplex for SLE. Genes Immun 10:478–81PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Slae M, Heshin-Bekenstein M, Sinckes A, Heimer G, Engelhard D, Eisenstein EM (2014) Female polysomy-X and systemic lupus erythematosus. Sem Arthritis Rheum 43(4):508–512CrossRefGoogle Scholar
  127. 127.
    Rook GAW (2009) Review series on helminths, immune modulation and the hygiene hypothesis: the broader implications of the hygiene hypothesis. Immunol 126(1):3–11CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of ChemistryUniversity of South FloridaTampaUSA

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