Skip to main content

Advertisement

SpringerLink
Log in

Gene expression profiling offers insights into the role of innate immune signaling in SSc

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Systemic sclerosis (SSc) is characterized by inflammation, vascular dysfunction, and ultimately fibrosis. Progress in understanding disease pathogenesis and developing effective disease treatments has been hampered by an incomplete understanding of SSc heterogeneity. To clarify this, we have used genomic approaches to identify distinct patient subsets based on gene expression patterns in SSc skin and other end-target organs. Here, we review what is known about the gene expression-based subsets in SSc, currently defined as the inflammatory, fibroproliferative, limited, and normal-like subsets. The inflammatory subset of patients is characterized by infiltrating immune cells that include T cells, macrophages, and possibly dendritic cells, although little is known about the mediators these cells secrete and the pathways that govern cell activation. Prior studies have suggested a role for pathogens as a trigger of immune responses in SSc, and recent data have identified viral and mycobiome components as potential environmental triggers. We present a model based on analyses of gene expression data and a review of the literature, which suggests that the gene expression subsets observed in patients possibly represent distinct, interconnected molecular states of disease, to which an innate immune response is central that results in the generation of clinical disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Milano A et al (2008) Molecular subsets in the gene expression signatures of scleroderma skin. PLoS One 3:e2696

    Article  PubMed Central  PubMed  Google Scholar 

  2. Pendergrass SA, Lemaire R, Francis IP, Mahoney JM, Lafyatis R, Whitfield ML (2012) Intrinsic gene expression subsets of diffuse cutaneous systemic sclerosis are stable in serial skin biopsies. J Invest Dermatol 132:1363–1373

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Hinchcliff M et al (2013) Molecular signatures in skin associated with clinical improvement during mycophenolate treatment in systemic sclerosis. J Invest Dermatol 133:1979–1989

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Mahoney JM et al (2015) Systems level analysis of systemic sclerosis shows a network of immune and profibrotic pathways connected with genetic polymorphisms. PLoS Comput Biol 11:e1004005

    Article  PubMed Central  PubMed  Google Scholar 

  5. Hsu E, Shi H, Jordan RM, Lyons-Weiler J, Pilewski JM, Feghali-Bostwick CA (2011) Lung tissues in patients with systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension. Arthritis Rheum 63:783–794

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Christmann RB et al (2014) Association of interferon- and transforming growth factor beta-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis. Arthritis Rheumatol 66:714–725

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Whitfield ML et al (2003) Systemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci U S A 100:12319–12324

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Gardner H et al (2006) Gene profiling of scleroderma skin reveals robust signatures of disease that are imperfectly reflected in the transcript profiles of explanted fibroblasts. Arthritis Rheum 54:1961–1973

    Article  CAS  PubMed  Google Scholar 

  9. Perou CM et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752

    Article  CAS  PubMed  Google Scholar 

  10. Alizadeh AA et al (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503–511

    Article  CAS  PubMed  Google Scholar 

  11. Garber ME et al (2001) Diversity of gene expression in adenocarcinoma of the lung. Proc Natl Acad Sci U S A 98:13784–13789

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Bhattacharjee A et al (2001) Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci U S A 98:13790–13795

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Sorlie T et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100:8418–8423

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Lafyatis R et al (2009) B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum 60:578–583

    Article  PubMed Central  PubMed  Google Scholar 

  15. Chakravarty EF et al (2015). A pilot randomized placebo-controlled study of abatacept for the treatment of diffuse cutaneous systemic sclerosis. Arthritis Res Ther. In press.

  16. Gordon JK et al (2015). Nilotinib in the treatment of early diffuse systemic sclerosis: an open-label, pilot clinical trial. Arthritis Res Ther. Submitted.

  17. Assassi S et al (2015). Dissecting the heterogeneity of skin gene expression patterns in systemic sclerosis. Arthritis Rheum. In Press.

  18. Wong AK, Park CY, Greene CS, Bongo LA, Guan Y, Troyanskaya OG (2012) IMP: a multi-species functional genomics portal for integration, visualization and prediction of protein functions and networks. Nucleic Acids Res 40:W484–W490

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Assassi S, Radstake TR, Mayes MD, Martin J (2013) Genetics of scleroderma: implications for personalized medicine? BMC Med 11:9

    Article  PubMed Central  PubMed  Google Scholar 

  20. Taroni J et al (2015). Genome-wide gene expression analysis of systemic sclerosis esophageal biopsies identifies disease-specific molecular subsets. Arthritis Res Ther. In press.

  21. Chung L et al (2009) Molecular framework for response to imatinib mesylate in systemic sclerosis. Arthritis Rheum 60:584–591

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Sargent JL et al (2009) A TGFbeta-responsive gene signature is associated with a subset of diffuse scleroderma with increased disease severity. J Invest Dermatol 130:694–705

    Article  PubMed  Google Scholar 

  23. Greenblatt MB et al (2012) Interspecies comparison of human and murine scleroderma reveals IL-13 and CCL2 as disease subset-specific targets. Am J Pathol 180:1080–1094

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Johnson ME et al (2015) Experimentally-derived fibroblast gene signatures identify molecular pathways associated with distinct subsets of systemic sclerosis patients in three independent cohorts. PLoS One 10:e0114017

    Article  PubMed Central  PubMed  Google Scholar 

  25. Bhattacharyya S, Wei J, Tourtellotte WG, Hinchcliff M, Gottardi CG, Varga J (2012) Fibrosis in systemic sclerosis: common and unique pathobiology. Fibrogenesis Tissue Repair 5:S18

    Article  PubMed Central  PubMed  Google Scholar 

  26. Farina A et al (2014) Epstein-Barr virus infection induces aberrant TLR activation pathway and fibroblast-myofibroblast conversion in scleroderma. J Invest Dermatol 134:954–964

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. van Bon L et al (2010) Distinct evolution of TLR-mediated dendritic cell cytokine secretion in patients with limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis 69:1539–1547

    Article  PubMed  Google Scholar 

  28. Artlett CM, Sassi-Gaha S, Rieger JL, Boesteanu AC, Feghali-Bostwick CA, Katsikis PD (2011) The inflammasome activating caspase 1 mediates fibrosis and myofibroblast differentiation in systemic sclerosis. Arthritis Rheum 63:3563–3574

    Article  CAS  PubMed  Google Scholar 

  29. Arron ST et al (2014) High Rhodotorula sequences in skin transcriptome of patients with diffuse systemic sclerosis. J Invest Dermatol 134:2138–2145

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Christmann RB et al (2011) Interferon and alternative activation of monocyte/macrophages in systemic sclerosis-associated pulmonary arterial hypertension. Arthritis Rheum 63:1718–1728

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Mathes AL et al (2014) Global chemokine expression in systemic sclerosis (SSc): CCL19 expression correlates with vascular inflammation in SSc skin. Ann Rheum Dis 73:1864–1872

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Higashi-Kuwata N et al (2010) Characterization of monocyte/macrophage subsets in the skin and peripheral blood derived from patients with systemic sclerosis. Arthritis Res Ther 12:R128

    Article  PubMed Central  PubMed  Google Scholar 

  34. Atamas SP, White B (2003) Cytokine regulation of pulmonary fibrosis in scleroderma. Cytokine Growth Factor Rev 14:537–550

    Article  CAS  PubMed  Google Scholar 

  35. Chen ZY et al (1984) Immune complexes and antinuclear, antinucleolar, and anticentromere antibodies in scleroderma. J Am Acad Dermatol 11:461–467

    Article  CAS  PubMed  Google Scholar 

  36. Seibold JR, Medsger TA Jr, Winkelstein A, Kelly RH, Rodnan GP (1982) Immune complexes in progressive systemic sclerosis (scleroderma). Arthritis Rheum 25:1167–1173

    Article  CAS  PubMed  Google Scholar 

  37. Hasegawa M, Fujimoto M, Kikuchi K, Takehara K (1997) Elevated serum levels of interleukin 4 (IL-4), IL-10, and IL-13 in patients with systemic sclerosis. J Rheumatol 24:328–332

    CAS  PubMed  Google Scholar 

  38. Leask A, Abraham DJ (2004) TGF-beta signaling and the fibrotic response. Faseb J 18:816–827

    Article  CAS  PubMed  Google Scholar 

  39. Varga J, Pasche B (2009) Transforming growth factor beta as a therapeutic target in systemic sclerosis. Nat Rev Rheumatol 5:200–206

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35

    Article  CAS  PubMed  Google Scholar 

  41. Li MO, Sanjabi S, Flavell RA (2006) Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25:455–471

    Article  CAS  PubMed  Google Scholar 

  42. Reizis B, Bunin A, Ghosh HS, Lewis KL, Sisirak V (2011) Plasmacytoid dendritic cells: recent progress and open questions. Annu Rev Immunol 29:163–183

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Assassi S et al (2010) Systemic sclerosis and lupus: points in an interferon-mediated continuum. Arthritis Rheum 62:589–598

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Eloranta ML et al (2010) Type I interferon system activation and association with disease manifestations in systemic sclerosis. Ann Rheum Dis 69:1396–1402

    Article  CAS  PubMed  Google Scholar 

  45. Kim D et al (2008) Induction of interferon-alpha by scleroderma sera containing autoantibodies to topoisomerase I: association of higher interferon-alpha activity with lung fibrosis. Arthritis Rheum 58:2163–2173

    Article  CAS  PubMed  Google Scholar 

  46. van Bon L et al (2014) Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. NEJM 370:433–443

    Article  PubMed Central  PubMed  Google Scholar 

  47. Luzina IG, Atamas SP, Wise R, Wigley FM, Xiao HQ, White B (2002) Gene expression in bronchoalveolar lavage cells from scleroderma patients. Am J Respir Cell Mol Biol 26:549–557

    Article  CAS  PubMed  Google Scholar 

  48. Falanga V, Gerhardt CO, Dasch JR, Takehara K, Ksander GA (1992) Skin distribution and differential expression of transforming growth factor β1 and β2. J Dermatol Sci 3:131–136

    Article  CAS  PubMed  Google Scholar 

  49. Sfikakis PP, McCune BK, Tsokos M, Aroni K, Vayiopoulos G, Tsokos GC (1993) Immunohistological demonstration of transforming growth factor-β isoforms in the skin of patients with systemic sclerosis. Clin Immunol Immunopathol 69:199–204

    Article  CAS  PubMed  Google Scholar 

  50. Higashi-Kuwata N, Makino T, Inoue Y, Takeya M, Ihn H (2009) Alternatively activated macrophages (M2 macrophages) in the skin of patient with localized scleroderma. Exp Dermatol 18:727–729

    Article  PubMed  Google Scholar 

  51. Pechkovsky DV et al (2010) Alternatively activated alveolar macrophages in pulmonary fibrosis—mediator production and intracellular signal transduction. Clin Immunol 137:89–101

    Article  CAS  PubMed  Google Scholar 

  52. Truchetet M-E, Brembilla NC, Montanari E, Allanore Y, Chizzolini C (2011) Increased frequency of circulating Th22 in addition to Th17 and Th2 lymphocytes in systemic sclerosis: association with interstitial lung disease. Arth Res Ther 13:R166

    Article  CAS  Google Scholar 

  53. Kessel A et al (2004) Increased CD8+ T cell apoptosis in scleroderma is associated with low levels of NF-kappa B. J Clin Immunol 24:30–36

    Article  CAS  PubMed  Google Scholar 

  54. Mathian A et al (2012) Activated and resting regulatory T cell exhaustion concurs with high levels of interleukin-22 expression in systemic sclerosis lesions. Ann Rheum Dis 71:1227–1234

    Article  CAS  PubMed  Google Scholar 

  55. Murata M et al (2008) Clinical association of serum interleukin-17 levels in systemic sclerosis: is systemic sclerosis a Th17 disease? J Dermatol Sci 50:240–242

    Article  CAS  PubMed  Google Scholar 

  56. Radstake TR et al (2009) The pronounced Th17 profile in systemic sclerosis (SSc) together with intracellular expression of TGFβ and IFNγ distinguishes SSc phenotypes. PLoS One 4:e5903

    Article  PubMed Central  PubMed  Google Scholar 

  57. Rodríguez-Reyna TS et al (2012) Th17 peripheral cells are increased in diffuse cutaneous systemic sclerosis compared with limited illness: a cross-sectional study. Rheumatol Int 32:2653–2660

    Article  PubMed  Google Scholar 

  58. Deleuran B, Abraham DJ (2007) Possible implication of the effector CD4+ T-cell subpopulation TH17 in the pathogenesis of systemic scleroderma. Nat Clin Pract Rheum 3:682–683

    Article  CAS  Google Scholar 

  59. Axtell RC, Raman C (2012) Janus-like effects of type I interferon in autoimmune diseases. Immunol Rev 248:23–35

    Article  PubMed Central  PubMed  Google Scholar 

  60. Brand S (2009) Crohn’s disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn’s disease. Gut 58:1152–1167

    Article  CAS  PubMed  Google Scholar 

  61. Camporeale A (2012) IL-6, IL-17, and STAT3: a holy trinity in auto-immunity? Front Biosci 17:2306–2326

    Article  Google Scholar 

  62. Kimura A, Kishimoto T (2011) Th17 cells in inflammation. Int Immunopharmacol 11:319–322

    Article  CAS  PubMed  Google Scholar 

  63. Zheng SG (2013) Regulatory T cells versus Th17: differentiation of Th17 versus Treg, are they mutually exclusive? In: IL-17, IL-22 and their producing cells: role in inflammation and autoimmunity: springer., pp 91–107

    Chapter  Google Scholar 

  64. Steinman L (2007) A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell-mediated tissue damage. Nat Med 13:139–145

    Article  CAS  PubMed  Google Scholar 

  65. Marangoni RG et al (2015) Myofibroblasts in murine cutaneous fibrosis originate from adiponectin-positive intradermal progenitors. Arthritis Rheumatol 67:1062–1073

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Genetics, Geisel School of Medicine at Dartmouth, 7400 Remsen, Hanover, NH, 03755, USA

    Michael E. Johnson & Michael L. Whitfield

  2. Department of Obstetrics and Gynecology, Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, 03756, USA

    Patricia A. Pioli

  3. Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, 03756, USA

    Patricia A. Pioli

Authors
  1. Michael E. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patricia A. Pioli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael L. Whitfield
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael L. Whitfield.

Additional information

This article is a contribution to the Special Issue on Immunopathology of Systemic Sclerosis - Guest Editors: Jacob M. van Laar and John Varga

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Johnson, M.E., Pioli, P.A. & Whitfield, M.L. Gene expression profiling offers insights into the role of innate immune signaling in SSc. Semin Immunopathol 37, 501–509 (2015). https://doi.org/10.1007/s00281-015-0512-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-015-0512-6

Keywords

Search

Navigation