Fresh Insights into Disease Etiology and the Role of Microbial Pathogens

  • Antonella Farina
  • G. Alessandra FarinaEmail author
Scleroderma (J Varga, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Scleroderma


Pathogens have been implicated in the initiation and/or promotion of systemic sclerosis (scleroderma, SSc); however, no evidence was found to substantiate the direct contribution to this disease in past years. Recently, significant advances have been made in understanding the role of the innate immune system in SSc pathogenesis, supporting the idea that pathogens might interact with host innate immune-regulatory responses in SSc. In light of these findings, we review the studies that identified the presence of pathogens in SSc, along with studies on pathogens implicated in driving the innate immune dysregulation in SSc. The goal of this review is to illustrate how these pathogens, specifically viruses, may play important role both as triggers of the innate immune system, and critical players in the development of SSc disease.


Scleroderma Systemic sclerosis EBV CMV Innate immunity Fibrosis 



We wish to thank Paul Haines for the critical proofreading of the manuscript.

Compliance with Ethical Standards

Conflict of Interest

Antonella Farina and G. Alessandra Farina declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


This study was supported by the NIH-NIAMS grant 1R03AR062721-01 and Scleroderma Foundation Established investigator (G.A.F).


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Kumar H, Kawai T, Akira S. Pathogen recognition by the innate immune system. Int Rev Immunol. 2011;30(1):16–34. doi: 10.3109/08830185.2010.529976.CrossRefPubMedGoogle Scholar
  2. 2.
    Milano A, Pendergrass SA, Sargent JL, George LK, McCalmont TH, Connolly MK, et al. Molecular subsets in the gene expression signatures of scleroderma skin. PLoS One. 2008;3(7):e2696. doi: 10.1371/journal.pone.0002696.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Farina G, Lafyatis D, Lemaire R, Lafyatis R. A four-gene biomarker predicts skin disease in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 2010;62(2):580–8. doi: 10.1002/art.27220.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Schreiber G, Piehler J. The molecular basis for functional plasticity in type I interferon signaling. Trends Immunol. 2015;36(3):139–49. doi: 10.1016/ Scholar
  5. 5.
    Takeuchi O, Akira S. Innate immunity to virus infection. Immunol Rev. 2009;227(1):75–86. doi: 10.1111/j.1600-065X.2008.00737.x.CrossRefPubMedGoogle Scholar
  6. 6.
    Christmann RB, Sampaio-Barros P, Stifano G, Borges CL, de Carvalho CR, Kairalla R, et al. Association of Interferon- and transforming growth factor beta-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis. Arthritis Rheumatol. 2014;66(3):714–25. doi: 10.1002/art.38288.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Christmann RB, Hayes E, Pendergrass S, Padilla C, Farina G, Affandi AJ, et al. Interferon and alternative activation of monocyte/macrophages in systemic sclerosis-associated pulmonary arterial hypertension. Arthritis Rheum. 2011;63(6):1718–28. doi: 10.1002/art.30318.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Johnson ME, Mahoney JM, Taroni J, Sargent JL, Marmarelis E, Wu MR, et al. Experimentally-derived fibroblast gene signatures identify molecular pathways associated with distinct subsets of systemic sclerosis patients in three independent cohorts. PLoS One. 2015;10(1):e0114017. doi: 10.1371/journal.pone.0114017.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Assassi S, Swindell WR, Wu M, Tan FD, Khanna D, Furst DE, et al. Dissecting the heterogeneity of skin gene expression patterns in systemic sclerosis. Arthritis Rheumatol. 2015. doi: 10.1002/art.39289.PubMedCentralGoogle Scholar
  10. 10.
    York MR, Nagai T, Mangini AJ, Lemaire R, van Seventer JM, Lafyatis R. A macrophage marker, Siglec-1, is increased on circulating monocytes in patients with systemic sclerosis and induced by type I interferons and toll-like receptor agonists. Arthritis Rheum. 2007;56(3):1010–20. doi: 10.1002/art.22382.CrossRefPubMedGoogle Scholar
  11. 11.
    van Roon JA, Tesselaar K, Radstake TR. Proteome-wide analysis and CXCL4 in systemic sclerosis. N Engl J Med. 2014;370(16):1563–4. doi: 10.1056/NEJMc1402401.PubMedGoogle Scholar
  12. 12.
    Farina GA, York MR, Di Marzio M, Collins CA, Meller S, Homey B, et al. Poly(I:C) drives type I IFN- and TGFbeta-mediated inflammation and dermal fibrosis simulating altered gene expression in systemic sclerosis. J Investig Dermatol. 2010;130(11):2583–93. doi: 10.1038/jid.2010.200.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Farina G, York M, Collins C, Lafyatis R. dsRNA activation of endothelin-1 and markers of vascular activation in endothelial cells and fibroblasts. Ann Rheum Dis. 2011;70(3):544–50. doi: 10.1136/ard.2010.132464.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Chrobak I, Lenna S, Stawski L, Trojanowska M. Interferon-gamma promotes vascular remodeling in human microvascular endothelial cells by upregulating endothelin (ET)-1 and transforming growth factor (TGF) beta2. J Cell Physiol. 2013;228(8):1774–83. doi: 10.1002/jcp.24337.PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Agarwal SK, Wu M, Livingston CK, Parks DH, Mayes MD, Arnett FC, et al. Toll-like receptor 3 upregulation by type I interferon in healthy and scleroderma dermal fibroblasts. Arthritis Res Ther. 2011;13(1):R3. doi: 10.1186/ar3221.PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Bhattacharyya S, Kelley K, Melichian DS, Tamaki Z, Fang F, Su Y, et al. Toll-like receptor 4 signaling augments transforming growth factor-beta responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma. Am J Pathol. 2013;182(1):192–205. doi: 10.1016/j.ajpath.2012.09.007.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Salazar G, Mayes MD. Genetics, Epigenetics, and Genomics of Systemic Sclerosis. Rheum Dis Clin N Am. 2015;41(3):345–66. doi: 10.1016/j.rdc.2015.04.001.CrossRefGoogle Scholar
  18. 18.
    Tracy SI, Kakalacheva K, Lunemann JD, Luzuriaga K, Middeldorp J, Thorley-Lawson DA. Persistence of Epstein-Barr virus in self-reactive memory B cells. J Virol. 2012;86(22):12330–40. doi: 10.1128/JVI.01699-12.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Paludan SR, Bowie AG, Horan KA, Fitzgerald KA. Recognition of herpesviruses by the innate immune system. Nat Rev Immunol. 2011;11(2):143–54. doi: 10.1038/nri2937.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.•
    Taylor GS, Long HM, Brooks JM, Rickinson AB, Hislop AD. The immunology of Epstein-Barr virus-induced disease. Annu Rev Immunol. 2015;33:787–821. Excellent review on the interplay between cellular immune responses to EBV infection and the various disease states, inlcuding autoimmune diseases. CrossRefPubMedGoogle Scholar
  21. 21.
    Fattal I, Shental N, Molad Y, Gabrielli A, Pokroy-Shapira E, Oren S, et al. Epstein-Barr virus antibodies mark systemic lupus erythematosus and scleroderma patients negative for anti-DNA. Immunology. 2014;141(2):276–85. doi: 10.1111/imm.12200.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.•
    Farina A, Cirone M, York M, Lenna S, Padilla C, McLaughlin S, et al. Epstein-Barr virus infection induces aberrant TLR activation pathway and fibroblast-myofibroblast conversion in scleroderma. J Investig Dermatol. 2014;134(4):954–64. doi: 10.1038/jid.2013.423. Important study on the role of EBV in SSc fibroblasts. The study showes the evidence of EBV in scleroderma skin, and proves that EBV infects fibroblasts and activates the innate immune system in infected cells. PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Lunardi C, Dolcino M, Peterlana D, Bason C, Navone R, Tamassia N, et al. Antibodies against human cytomegalovirus in the pathogenesis of systemic sclerosis: a gene array approach. PLoS Med. 2006;3(1):e2. doi: 10.1371/journal.pmed.0030002.PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Munz C, Lunemann JD, Getts MT, Miller SD. Antiviral immune responses: triggers of or triggered by autoimmunity? Nat Rev Immunol. 2009;9(4):246–58. doi: 10.1038/nri2527.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Arnson Y, Amital H, Guiducci S, Matucci-Cerinic M, Valentini G, Barzilai O, et al. The role of infections in the immunopathogensis of systemic sclerosis--evidence from serological studies. Ann N Y Acad Sci. 2009;1173:627–32. doi: 10.1111/j.1749-6632.2009.04808.x.CrossRefPubMedGoogle Scholar
  26. 26.
    Shore A, Klock R, Lee P, Snow KM, Keystone EC. Impaired late suppression of Epstein-Barr virus (EBV)-induced immunoglobulin synthesis: a common feature of autoimmune disease. J Clin Immunol. 1989;9(2):103–10.CrossRefPubMedGoogle Scholar
  27. 27.
    Kahan A, Menkes CJ, Amor B. Defective Epstein-Barr virus specific suppressor T cell function in progressive systemic sclerosis. Ann Rheum Dis. 1986;45(7):553–60.PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Yamamoto H, Miwa H, Kato Y, Nakamura S, Hara K, Nitta M. Angioimmunoblastic T cell lymphoma with an unusual proliferation of Epstein-Barr virus-associated large B cells arising in a patient with progressive systemic sclerosis. Acta Haematol. 2005;114(2):108–12. doi: 10.1159/000086585.CrossRefPubMedGoogle Scholar
  29. 29.
    Vaughan JH, Shaw PX, Nguyen MD, Medsger Jr TA, Wright TM, Metcalf JS, et al. Evidence of activation of 2 herpesviruses, Epstein-Barr virus and cytomegalovirus, in systemic sclerosis and normal skins. J Rheumatol. 2000;27(3):821–3.PubMedGoogle Scholar
  30. 30.
    Pender MP. Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol. 2003;24(11):584–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Niller HH, Wolf H, Minarovits J. Regulation and dysregulation of Epstein-Barr virus latency: implications for the development of autoimmune diseases. Autoimmunity. 2008;41(4):298–328. doi: 10.1080/08916930802024772.CrossRefPubMedGoogle Scholar
  32. 32.
    Sugimoto M, Tahara H, Ide T, Furuichi Y. Steps involved in immortalization and tumorigenesis in human B-lymphoblastoid cell lines transformed by Epstein-Barr virus. Cancer Res. 2004;64(10):3361–4. doi: 10.1158/0008-5472.CAN-04-0079.CrossRefPubMedGoogle Scholar
  33. 33.
    Thorley-Lawson DA, Gross A. Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med. 2004;350(13):1328–37. doi: 10.1056/NEJMra032015.CrossRefPubMedGoogle Scholar
  34. 34.
    Wagner HJ, Scott RS, Buchwald D, Sixbey JW. Peripheral blood lymphocytes express recombination-activating genes 1 and 2 during Epstein-Barr virus-induced infectious mononucleosis. J Infect Dis. 2004;190(5):979–84. doi: 10.1086/423211.CrossRefPubMedGoogle Scholar
  35. 35.
    Dreyfus DH. Immune system: success owed to a virus? Science. 2009;325(5939):392–3. doi: 10.1126/science.325_392c.CrossRefPubMedGoogle Scholar
  36. 36.
    Dreyfus DH. Paleo-immunology: evidence consistent with insertion of a primordial herpes virus-like element in the origins of acquired immunity. PLoS One. 2009;4(6):e5778. doi: 10.1371/journal.pone.0005778.PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Kuhn-Hallek I, Sage DR, Stein L, Groelle H, Fingeroth JD. Expression of recombination activating genes (RAG-1 and RAG-2) in Epstein-Barr virus-bearing B cells. Blood. 1995;85(5):1289–99.PubMedGoogle Scholar
  38. 38.
    Jankovic M, Casellas R, Yannoutsos N, Wardemann H, Nussenzweig MC. RAGs and regulation of autoantibodies. Annu Rev Immunol. 2004;22:485–501. doi: 10.1146/annurev.immunol.22.012703.104707.CrossRefPubMedGoogle Scholar
  39. 39.
    Hu PQ, Fertig N, Medsger Jr TA, Wright TM. Molecular recognition patterns of serum anti-DNA topoisomerase I antibody in systemic sclerosis. J Immunol. 2004;173(4):2834–41.CrossRefPubMedGoogle Scholar
  40. 40.
    Moroncini G, Mori S, Tonnini C, Gabrielli A. Role of viral infections in the etiopathogenesis of systemic sclerosis. Clin Exp Rheumatol. 2013;31(2 Suppl 76):3–7.PubMedGoogle Scholar
  41. 41.
    Thorley-Lawson DA. Epstein-Barr virus: exploiting the immune system. Nat Rev Immunol. 2001;1(1):75–82. doi: 10.1038/35095584.CrossRefPubMedGoogle Scholar
  42. 42.
    Kenney SC. Reactivation and lytic replication of EBV. In: Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, Whitley R et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge 2007.Google Scholar
  43. 43.
    Ning S. Innate immune modulation in EBV infection. Herpesviridae. 2011;2(1):1. doi: 10.1186/2042-4280-2-1.PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    Hislop AD, Taylor GS, Sauce D, Rickinson AB. Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu Rev Immunol. 2007;25:587–617. doi: 10.1146/annurev.immunol.25.022106.141553.CrossRefPubMedGoogle Scholar
  45. 45.
    Woellmer A, Arteaga-Salas JM, Hammerschmidt W. BZLF1 governs CpG-methylated chromatin of Epstein-Barr Virus reversing epigenetic repression. PLoS Pathog. 2012;8(9):e1002902. doi: 10.1371/journal.ppat.1002902.PubMedCentralCrossRefPubMedGoogle Scholar
  46. 46.
    Yasuda K, Richez C, Uccellini MB, Richards RJ, Bonegio RG, Akira S, et al. Requirement for DNA CpG content in TLR9-dependent dendritic cell activation induced by DNA-containing immune complexes. J Immunol. 2009;183(5):3109–17. doi: 10.4049/jimmunol.0900399.PubMedCentralCrossRefPubMedGoogle Scholar
  47. 47.
    Fiola S, Gosselin D, Takada K, Gosselin J. TLR9 contributes to the recognition of EBV by primary monocytes and plasmacytoid dendritic cells. J Immunol. 2010;185(6):3620–31. doi: 10.4049/jimmunol.0903736.CrossRefPubMedGoogle Scholar
  48. 48.
    Martin HJ, Lee JM, Walls D, Hayward SD. Manipulation of the toll-like receptor 7 signaling pathway by Epstein-Barr virus. J Virol. 2007;81(18):9748–58. doi: 10.1128/JVI.01122-07.PubMedCentralCrossRefPubMedGoogle Scholar
  49. 49.
    Iwakiri D, Zhou L, Samanta M, Matsumoto M, Ebihara T, Seya T, et al. Epstein-Barr virus (EBV)-encoded small RNA is released from EBV-infected cells and activates signaling from Toll-like receptor 3. J Exp Med. 2009;206(10):2091–9. doi: 10.1084/jem.20081761.PubMedCentralCrossRefPubMedGoogle Scholar
  50. 50.
    Iwakiri D. Epstein-Barr virus-encoded RNAs: key molecules in viral pathogenesis. Cancers. 2014;6(3):1615–30. doi: 10.3390/cancers6031615.PubMedCentralCrossRefPubMedGoogle Scholar
  51. 51.
    Malizia AP, Keating DT, Smith SM, Walls D, Doran PP, Egan JJ. Alveolar epithelial cell injury with Epstein-Barr virus upregulates TGFbeta1 expression. Am J Physiol Lung Cell Mol Physiol. 2008;295(3):L451–60. doi: 10.1152/ajplung.00376.2007.CrossRefPubMedGoogle Scholar
  52. 52.
    Kenney SC, Mertz JE. Regulation of the latent-lytic switch in Epstein-Barr virus. Semin Cancer Biol. 2014;26:60–8. doi: 10.1016/j.semcancer.2014.01.002.CrossRefPubMedGoogle Scholar
  53. 53.
    Grogan E, Jenson H, Countryman J, Heston L, Gradoville L, Miller G. Transfection of a rearranged viral DNA fragment, WZhet, stably converts latent Epstein-Barr viral infection to productive infection in lymphoid cells. Proc Natl Acad Sci U S A. 1987;84(5):1332–6.PubMedCentralCrossRefPubMedGoogle Scholar
  54. 54.
    Guenther JF, Cameron JE, Nguyen HT, Wang Y, Sullivan DE, Shan B, et al. Modulation of lung inflammation by the Epstein-Barr virus protein Zta. Am J Physiol Lung Cell Mol Physiol. 2010;299(6):L771–84. doi: 10.1152/ajplung.00408.2009.PubMedCentralCrossRefPubMedGoogle Scholar
  55. 55.
    Cayrol C, Flemington EK. Identification of cellular target genes of the Epstein-Barr virus transactivator Zta: activation of transforming growth factor beta igh3 (TGF-beta igh3) and TGF-beta 1. J Virol. 1995;69(7):4206–12.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Chang Y, Lee HH, Chen YT, Lu J, Wu SY, Chen CW, et al. Induction of the early growth response 1 gene by Epstein-Barr virus lytic transactivator Zta. J Virol. 2006;80(15):7748–55. doi: 10.1128/JVI.02608-05.PubMedCentralCrossRefPubMedGoogle Scholar
  57. 57.
    Tsai SC, Lin SJ, Chen PW, Luo WY, Yeh TH, Wang HW, et al. EBV Zta protein induces the expression of interleukin-13, promoting the proliferation of EBV-infected B cells and lymphoblastoid cell lines. Blood. 2009;114(1):109–18. doi: 10.1182/blood-2008-12-193375.PubMedCentralCrossRefPubMedGoogle Scholar
  58. 58.
    Adamson AL, Kenney S. The Epstein-Barr virus BZLF1 protein interacts physically and functionally with the histone acetylase CREB-binding protein. J Virol. 1999;73(8):6551–8.PubMedCentralPubMedGoogle Scholar
  59. 59.
    Naiki Y, Komatsu T, Koide N, Dagvadorj J, Yoshida T, Arditi M, et al. TGF-beta1 inhibits the production of IFN in response to CpG DNA via ubiquitination of TNF receptor-associated factor (TRAF) 6. Innate Immun. 2015;21(7):770–7. doi: 10.1177/1753425915596844.CrossRefPubMedGoogle Scholar
  60. 60.
    Savard M, Gosselin J. Epstein-Barr virus immunossuppression of innate immunity mediated by phagocytes. Virus Res. 2006;119(2):134–45. doi: 10.1016/j.virusres.2006.02.008.CrossRefPubMedGoogle Scholar
  61. 61.
    Kashiwagi S, Kumasaka T, Bunsei N, Fukumura Y, Yamasaki S, Abe K, et al. Detection of Epstein-Barr virus-encoded small RNA-expressed myofibroblasts and IgG4-producing plasma cells in sclerosing angiomatoid nodular transformation of the spleen. Virchows Arch Int J Pathol. 2008;453(3):275–82. doi: 10.1007/s00428-008-0648-z.CrossRefGoogle Scholar
  62. 62.
    Weinreb I, Bailey D, Battaglia D, Kennedy M, Perez-Ordonez B. CD30 and Epstein-Barr virus RNA expression in sclerosing angiomatoid nodular transformation of spleen. Virchows Arch Int J Pathol. 2007;451(1):73–9. doi: 10.1007/s00428-007-0422-7.CrossRefGoogle Scholar
  63. 63.
    Lee ES, Locker J, Nalesnik M, Reyes J, Jaffe R, Alashari M, et al. The association of Epstein-Barr virus with smooth-muscle tumors occurring after organ transplantation. N Engl J Med. 1995;332(1):19–25. doi: 10.1056/NEJM199501053320104.CrossRefPubMedGoogle Scholar
  64. 64.
    Koide J, Takada K, Sugiura M, Sekine H, Ito T, Saito K, et al. Spontaneous establishment of an Epstein-Barr virus-infected fibroblast line from the synovial tissue of a rheumatoid arthritis patient. J Virol. 1997;71(3):2478–81.PubMedCentralPubMedGoogle Scholar
  65. 65.
    Adachi H, Saito I, Horiuchi M, Ishii J, Nagata Y, Mizuno F, et al. Infection of human lung fibroblasts with Epstein-Barr virus causes increased IL-1beta and bFGF production. Exp Lung Res. 2001;27(2):157–71.CrossRefPubMedGoogle Scholar
  66. 66.
    Probert M, Epstein MA. Morphological transformation in vitro of human fibroblasts by Epstein-Barr virus: preliminary observations. Science. 1972;175(4018):202–3.CrossRefPubMedGoogle Scholar
  67. 67.
    Janz A, Oezel M, Kurzeder C, Mautner J, Pich D, Kost M, et al. Infectious Epstein-Barr virus lacking major glycoprotein BLLF1 (gp350/220) demonstrates the existence of additional viral ligands. J Virol. 2000;74(21):10142–52.PubMedCentralCrossRefPubMedGoogle Scholar
  68. 68.
    Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–9. doi: 10.1038/ncb1596.CrossRefPubMedGoogle Scholar
  69. 69.
    Zomer A, Vendrig T, Hopmans ES, van Eijndhoven M, Middeldorp JM, Pegtel DM. Exosomes: fit to deliver small RNA. Commun Integr Biol. 2010;3(5):447–50. doi: 10.4161/cib.3.5.12339.PubMedCentralCrossRefPubMedGoogle Scholar
  70. 70.
    Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van Eijndhoven MA, Hopmans ES, Lindenberg JL, et al. Functional delivery of viral miRNAs via exosomes. Proc Natl Acad Sci U S A. 2010;107(14):6328–33. doi: 10.1073/pnas.0914843107.PubMedCentralCrossRefPubMedGoogle Scholar
  71. 71.
    Wurdinger T, Gatson NN, Balaj L, Kaur B, Breakefield XO, Pegtel DM. Extracellular vesicles and their convergence with viral pathways. Advances Virol. 2012;2012:767694. doi: 10.1155/2012/767694.CrossRefGoogle Scholar
  72. 72.•
    Pegtel DM. Oncogenic herpesviruses sending mixed signals. Proc Natl Acad Sci U S A. 2013;110(31):12503–4. doi: 10.1073/pnas.1310928110. Excellent review on mechanisms used by several cell types, including fibroblasts, to internalize EBV-infected-exosom. PubMedCentralCrossRefPubMedGoogle Scholar
  73. 73.
    Lunardi C, Bason C, Navone R, Millo E, Damonte G, Corrocher R, et al. Systemic sclerosis immunoglobulin G autoantibodies bind the human cytomegalovirus late protein UL94 and induce apoptosis in human endothelial cells. Nat Med. 2000;6(10):1183–6. doi: 10.1038/80533.CrossRefPubMedGoogle Scholar
  74. 74.
    Neidhart M, Kuchen S, Distler O, Bruhlmann P, Michel BA, Gay RE, et al. Increased serum levels of antibodies against human cytomegalovirus and prevalence of autoantibodies in systemic sclerosis. Arthritis Rheum. 1999;42(2):389–92. doi: 10.1002/1529-0131(199902)42:2<389::AID-ANR23>3.0.CO;2-P.CrossRefPubMedGoogle Scholar
  75. 75.
    Muryoi T, Kasturi KN, Kafina MJ, Cram DS, Harrison LC, Sasaki T, et al. Antitopoisomerase I monoclonal autoantibodies from scleroderma patients and tight skin mouse interact with similar epitopes. J Exp Med. 1992;175(4):1103–9.CrossRefPubMedGoogle Scholar
  76. 76.
    Cohen Y, Stern-Ginossar N. Manipulation of host pathways by human cytomegalovirus: insights from genome-wide studies. Semin Immunopathol. 2014;36(6):651–8. doi: 10.1007/s00281-014-0443-7.CrossRefPubMedGoogle Scholar
  77. 77.
    Wujcicka W, Wilczynski J, Nowakowska D. Alterations in TLRs as new molecular markers of congenital infections with Human cytomegalovirus? Pathog Dis. 2014;70(1):3–16. doi: 10.1111/2049-632X.12083.CrossRefPubMedGoogle Scholar
  78. 78.
    Markiewicz M, Smith EA, Rubinchik S, Dong JY, Trojanowska M, LeRoy EC. The 72-kilodalton IE-1 protein of human cytomegalovirus (HCMV) is a potent inducer of connective tissue growth factor (CTGF) in human dermal fibroblasts. Clin Exp Rheumatol. 2004;22(3 Suppl 33):S31–4.PubMedGoogle Scholar
  79. 79.
    Hamamdzic D, Harley RA, Hazen-Martin D, LeRoy EC. MCMV induces neointima in IFN-gammaR−/− mice: intimal cell apoptosis and persistent proliferation of myofibroblasts. BMC Musculoskelet Disord. 2001;2:3.PubMedCentralCrossRefPubMedGoogle Scholar
  80. 80.
    Gamadia LE, Remmerswaal EB, Weel JF, Bemelman F, van Lier RA, Ten Berge IJ. Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease. Blood. 2003;101(7):2686–92. doi: 10.1182/blood-2002-08-2502.CrossRefPubMedGoogle Scholar
  81. 81.
    Ohtsuka T, Yamazaki S. Altered prevalence of human parvovirus B19 component genes in systemic sclerosis skin tissue. Br J Dermatol. 2005;152(5):1078–80. doi: 10.1111/j.1365-2133.2005.06567.x.CrossRefPubMedGoogle Scholar
  82. 82.
    Ferri C, Zakrzewska K, Longombardo G, Giuggioli D, Storino FA, Pasero G, et al. Parvovirus B19 infection of bone marrow in systemic sclerosis patients. Clin Exp Rheumatol. 1999;17(6):718–20.PubMedGoogle Scholar
  83. 83.
    Arron ST, Dimon MT, Li Z, Johnson ME, A Wood T, Feeney L, et al. High Rhodotorula sequences in skin transcriptome of patients with diffuse systemic sclerosis. J Investig Dermatol. 2014;134(8):2138–45. doi: 10.1038/jid.2014.127.PubMedCentralCrossRefPubMedGoogle Scholar
  84. 84.•
    Joseph CG, Darrah E, Shah AA, Skora AD, Casciola-Rosen LA, Wigley FM, et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science. 2014;343(6167):152–7. doi: 10.1126/science.1246886. Important study indicating a link between malignancy and scleroderma. PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Arthritis Center, Department of RheumatologyBoston UniversityBostonUSA
  2. 2.Institute Pasteur-Fondazione Cenci Bolognetti, Department of Experimental Medicine“Sapienza”, University of RomeRomeItaly

Personalised recommendations