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Innate Immunity

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Scleroderma

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Abstract

The human immune system is designed to appropriately respond to both self and foreign antigens. This complex system is effective at elimination of microbes because specialized cellular components exert both an immediate broad protection (innate immunity) as well as delayed, finely tuned (adaptive) responses. The primary cellular components of innate immunity are cells capable of phagocytosis (neutrophils, macrophages, and dendritic cells) – all of which are able to sense ingested material and send signals to recruit and activate other immune cells. Cell types and cytokines associated with innate immunity have been implicated in the pathogenesis of scleroderma. Analysis of both peripheral blood cells as well as skin biopsies from Scleroderma patients revealed signatures of both TGF-β as well as type 1 IFN. Several studies have provided evidence for increased expression of proteins or genes responsive to type 1 IFN in patients with Scleroderma, and also support IFN-α as causal in scleroderma vasculopathy. It is likely that immune complexes trigger IFN-α through activation of toll-like receptors (TLR). Evidence suggests that, as in SLE, immune complexes in scleroderma are internalized via Fc-gamma receptors into pDCs, followed by endosomal stimulation of TLRs. Other evidence supports a link between TLR activation and the fibrosis (as well as autoimmunity) associated with scleroderma. Specifically, increased expression of TLR3 in the skin of scleroderma patients and enhanced dermal expression of TLR3 following bleomycin or PIC stimulation in animal models of fibrosis suggest an important relationship between TLR activation and fibrosis. Clinically, increased IFN activity was associated with lung fibrosis and / or digital ulcers indicating important correlates between activation of the type 1 IFN system and clinical expression of disease.

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References

  1. Redecke V, Hacker H, Datta SK, et al. Cutting edge: activation of Toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma. J Immunol. 2004;172:2739–43.

    PubMed  CAS  Google Scholar 

  2. Hugle T, Hogan V, White K, van Laar JM. Mast cells are a source of transforming growth factor (TGF) beta in systemic sclerosis. Arthritis Rheum. 2011;63:795–9.

    Google Scholar 

  3. Aliprantis AO, Wang J, Fathman JW, et al. Transcription factor T-bet regulates skin sclerosis through its function in innate immunity and via IL-13. Proc Natl Acad Sci USA. 2007;104:2827–30.

    Article  PubMed  CAS  Google Scholar 

  4. Kraling BM, Maul GG, Jimenez SA. Mononuclear cellular infiltrates in clinically involved skin from patients with systemic sclerosis of recent onset predominantly consist of monocytes/macrophages. Pathobiology. 1995;63:48–56.

    Article  PubMed  CAS  Google Scholar 

  5. Higashi-Kuwata N, Jinnin M, Makino T, et al. Characterization of monocyte/macrophage subsets in the skin and peripheral blood derived from patients with systemic sclerosis. Arthritis Res Ther. 2010;12:R128.

    Article  PubMed  Google Scholar 

  6. Seibold JR, Giorno RC, Claman HN. Dermal mast cell degranulation in systemic sclerosis. Arthritis Rheum. 1990;33:1702–9.

    Article  PubMed  CAS  Google Scholar 

  7. Horikawa M, Hasegawa M, Komura K, et al. Abnormal natural killer cell function in systemic sclerosis: altered cytokine production and defective killing activity. J Invest Dermatol. 2005;125:731–7.

    Article  PubMed  CAS  Google Scholar 

  8. Theofilopoulos AN, Gonzalez-Quintial R, Lawson BR, et al. Sensors of the innate immune system: their link to rheumatic diseases. Nat Rev Rheumatol. 2010;6:146–56.

    Article  PubMed  CAS  Google Scholar 

  9. Rock KL, Latz E, Ontiveros F, Kono H. The sterile inflammatory response. Annu Rev Immunol. 2010;28:321–42.

    Article  PubMed  CAS  Google Scholar 

  10. Du Clos TW. The interaction of C-reactive protein and serum amyloid P component with nuclear antigens. Mol Biol Rep. 1996;23:253–60.

    Article  PubMed  Google Scholar 

  11. Zitvogel L, Kepp O, Kroemer G. Decoding cell death signals in inflammation and immunity. Cell. 2010;140:798–804.

    Article  PubMed  CAS  Google Scholar 

  12. Honda K, Takaoka A, Taniguchi T. Type I interferon gene induction by the interferon regulatory factor family of transcription factors. Immunity. 2006;25:349–60.

    Article  PubMed  CAS  Google Scholar 

  13. Theofilopoulos AN, Baccala R, Beutler B, Kono DH. Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol. 2005;23:307–36.

    Article  PubMed  CAS  Google Scholar 

  14. 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;56:1010–20.

    Article  PubMed  CAS  Google Scholar 

  15. Tan FK, Zhou X, Mayes MD, et al. Signatures of differentially regulated interferon gene expression and vasculotrophism in the peripheral blood cells of systemic sclerosis patients. Rheumatology (Oxford). 2006;45:694–702.

    Article  CAS  Google Scholar 

  16. Duan H, Fleming J, Pritchard DK, et al. Combined analysis of monocyte and lymphocyte messenger RNA expression with serum protein profiles in patients with scleroderma. Arthritis Rheum. 2008;58:1465–74.

    Article  PubMed  CAS  Google Scholar 

  17. Assassi S, Mayes MD, Arnett FC, et al. Systemic sclerosis and lupus: points in an interferon-mediated continuum. Arthritis Rheum. 2010;62:589–98.

    Article  PubMed  CAS  Google Scholar 

  18. Sargent JL, Milano A, Bhattacharyya S, et al. A TGFbeta-responsive gene signature is associated with a subset of diffuse scleroderma with increased disease severity. J Invest Dermatol. 2010;130:694–705.

    Article  PubMed  CAS  Google Scholar 

  19. Rönnblom L, Eloranta ML, Alm GV. The type I interferon system in systemic lupus erythematosus. Arthritis Rheum. 2006;54:408–20.

    Article  PubMed  Google Scholar 

  20. Kirou KA, Lee C, George S, Louca K, Peterson MG, Crow MK. Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheum. 2005;52:1491–503.

    Article  PubMed  CAS  Google Scholar 

  21. Kim D, Peck A, Santer D, et al. Induction of interferon-alpha by scleroderma sera containing autoantibodies to topoisomerase I: association of higher interferon-alpha activity with lung fibrosis. Arthritis Rheum. 2008;58:2163–73.

    Article  PubMed  CAS  Google Scholar 

  22. Means TK, Latz E, Hayashi F, Murali MR, Golenbock DT, Luster AD. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J Clin Invest. 2005;115:407–17.

    PubMed  CAS  Google Scholar 

  23. Eloranta ML, Franck-Larsson K, Lovgren T, et al. Type I interferon system activation and association with disease manifestations in systemic sclerosis. Ann Rheum Dis. 2010;69:1396–402.

    Article  PubMed  CAS  Google Scholar 

  24. Fleming JN, Nash RA, McLeod DO, et al. Capillary regeneration in scleroderma: stem cell therapy reverses phenotype? PLoS One. 2008;3:e1452.

    Article  PubMed  Google Scholar 

  25. Thacker SG, Berthier CC, Mattinzoli D, Rastaldi MP, Kretzler M, Kaplan MJ. The detrimental effects of IFN-a on vasculogenesis in lupus are mediated by repression of IL-1 pathways: potential role in atherogenesis and renal vascular rarefaction. J Immunol. 2010;185:4457–69.

    Article  PubMed  CAS  Google Scholar 

  26. Fleming JN, Shulman HM, Nash RA, et al. Cutaneous chronic graft-versus-host disease does not have the abnormal endothelial phenotype or vascular rarefaction characteristic of systemic sclerosis. PLoS One. 2009;4:e6203.

    Article  PubMed  Google Scholar 

  27. van Bon L, Popa C, Huijbens R, et al. Distinct evolution of TLR-mediated dendritic cell cytokine secretion in patients with limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2010;69:1539–47.

    Article  PubMed  Google Scholar 

  28. Farina GA, York MR, Di Marzio M, et al. Poly(I:C) drives type I IFN- and TGFbeta-mediated inflammation and dermal fibrosis simulating altered gene expression in systemic sclerosis. J Invest Dermatol. 2010;130:2583–93.

    Article  PubMed  CAS  Google Scholar 

  29. Yamamoto T, Takagawa S, Katayama I, et al. Animal model of sclerotic skin. I: local injections of bleomycin induce sclerotic skin mimicking scleroderma. J Invest Dermatol. 1999;112:456–62.

    Article  PubMed  CAS  Google Scholar 

  30. Agarwal SK, Wu M, Livingston CK, et al. Toll-like receptor 3 upregulation by type I interferon in healthy and scleroderma dermal fibroblasts. Arthritis Res Ther. 2011;13:R3.

    Article  PubMed  CAS  Google Scholar 

  31. 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;62:580–8.

    Article  PubMed  CAS  Google Scholar 

  32. Seki E, De Minicis S, Osterreicher CH, et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med. 2007;13:1324–32.

    Article  PubMed  CAS  Google Scholar 

  33. Sugiura H, Ichikawa T, Koarai A, et al. Activation of Toll-like receptor 3 augments myofibroblast differentiation. Am J Respir Cell Mol Biol. 2009;40:654–62.

    Article  PubMed  CAS  Google Scholar 

  34. Meneghin A, Choi ES, Evanoff HL, et al. TLR9 is expressed in idiopathic interstitial pneumonia and its activation promotes in vitro myofibroblast differentiation. Histochem Cell Biol. 2008;130:979–92.

    Article  PubMed  CAS  Google Scholar 

  35. Fineschi S, Goffin L, Rezzonico R, et al. Antifibroblast antibodies in systemic sclerosis induce fibroblasts to produce profibrotic chemokines, with partial exploitation of toll-like receptor 4. Arthritis Rheum. 2008;58:3913–23.

    Article  PubMed  CAS  Google Scholar 

  36. Demaria O, Pagni PP, Traub S, et al. TLR8 deficiency leads to autoimmunity in mice. J Clin Invest. 2010;120:3651–62.

    PubMed  CAS  Google Scholar 

  37. Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature. 2002;416:603–7.

    Article  PubMed  CAS  Google Scholar 

  38. Lau CM, Broughton C, Tabor AS, et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J Exp Med. 2005;202:1171–7.

    Article  PubMed  CAS  Google Scholar 

  39. Christensen SR, Shupe J, Nickerson K, Kashgarian M, Flavell RA, Shlomchik MJ. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity. 2006;25:417–28.

    Article  PubMed  CAS  Google Scholar 

  40. Pisitkun P, Deane JA, Difilippantonio MJ, Tarasenko T, Satterthwaite AB, Bolland S. Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science. 2006;312:1669–72.

    Article  PubMed  CAS  Google Scholar 

  41. Subramanian S, Tus K, Li QZ, et al. A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. Proc Natl Acad Sci USA. 2006;103:9970–5.

    Article  PubMed  CAS  Google Scholar 

  42. Kawaguchi Y, Hara M, Kamatani N, Wright TM. Identification of an IL1A gene segment that determines aberrant constitutive expression of interleukin-1 alpha in systemic sclerosis. Arthritis Rheum. 2003;48:193–202.

    Article  PubMed  CAS  Google Scholar 

  43. Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140:821–32.

    Article  PubMed  CAS  Google Scholar 

  44. Cai P, Khan MF, Kaphalia BS, Ansari GA. Immunotoxic response of oleic acid anilide and its hydrolysis products in female MRL (+/+) mice. J Immunotoxicol. 2005;2:231–6.

    Article  PubMed  CAS  Google Scholar 

  45. Wermuth PJ, Del Galdo F, Jimenez SA. Induction of the expression of profibrotic cytokines and growth factors in normal human peripheral blood monocytes by gadolinium contrast agents. Arthritis Rheum. 2009;60:1508–18.

    Article  PubMed  Google Scholar 

  46. Rönnblom L, Elkon KB. Cytokines as therapeutic targets in SLE. Nat Rev Rheumatol. 2010;6:339–47.

    Article  PubMed  Google Scholar 

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Acknowledgment

The authors wish to thank Vivian Vlamakis, M.D., for her careful reading and constructive criticism of the manuscript.

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Authors and Affiliations

  1. Medicine, Division of Rheumatology, University of Washington, Seattle, WA, USA

    Keith B. Elkon MD

  2. Department of Internal Medicine, Division of Rheumatology, Harborview and the University of Washington Medical Centers, Seattle, WA, USA

    Julia J. Rhiannon MD, MSW

Authors
  1. Keith B. Elkon MD
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  2. Julia J. Rhiannon MD, MSW
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Correspondence to Keith B. Elkon MD .

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Editors and Affiliations

  1. Feinberg School of Medicine, Northwestern University, E. Huron Street 240, Chicago, 60611-2909, Illinois, USA

    John Varga

  2. Royal Free and University College, Medical School, University College London, Rowland Street, London, NW3 2PF, United Kingdom

    Christopher P. Denton

  3. School of Medicine, Div. Rheumatology, Johns Hopkins University, Eastern Avenue 5200, Baltimore, 21224, Maryland, USA

    Fredrick M. Wigley

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Elkon, K.B., Rhiannon, J.J. (2012). Innate Immunity. In: Varga, J., Denton, C., Wigley, F. (eds) Scleroderma. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-5774-0_16

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  • DOI: https://doi.org/10.1007/978-1-4419-5774-0_16

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