Type I Interferon in Rheumatoid Arthritis, Systemic Lupus Erythematosus, Myositis and Systemic Scleroderma – A Review of Transcript Profiling Studies in the Blood

Brandon W Higgs, Zheng Liu, Wei Zhu, Wendy I White, Laura Richman, Bahija Jallal, Yihong Yao
European Musculoskeletal Review, 2012;7(1):22-8
pdf icon download pdf ejournal view ejournal

Abstract

Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), myositis and systemic sclerosis (SSc) are complex rheumatic diseases with heterogeneous clinical features. Though the are not completely understood for these diseases, recent work has revealed type I interferon (IFN) as a shared pathway that is overexpressed in patient subgroups of each disease. This commonality of an activated type I IFN pathway is robust and consistently present in both affected tissue and peripheral blood of patients with these diseases. Transcript profiling technology has greatly enabled such discoveries, allowing one to survey the dysregulation of numerous biological pathways simultaneously and identify those most associated with both disease severity and activity, increasing understanding of the underlying mechanisms at play. In this review, we examine how transcript profiling is used to characterise the activation of the type I IFN pathway in the diseases of RA, SLE, myositis and SSc, as measured in the blood, and report how this activation pattern associates with measures of disease pathogenesis, activity and/or treatment response.

Acknowledgements: We would like to acknowledge Jonathan Hirsch, Chris Morehouse and Philip Brohawn for their contributions to this work.
Keywords
Type I interferon (IFN), systemic lupus erythematosus (SLE), myositis, rheumatoid arthritis (RA), systemic sclerosis (SSc), type I IFN-inducible genes
Disclosure The work described in this article was supported by MedImmune, LLC. MedImmune develops anti-type I interferon therapy for autoimmune diseases. The authors are all full-time employees of MedImmune.
Received: August 05, 2011 Accepted September 27, 2011
Correspondence: Brandon W Higgs, MedImmune, One MedImmune Way, Gaithersburg, MD 20878, US. E: HiggsB@medimmune.com
Type I Interferons

The type I interferon (IFN) family consists of multiple members including 14 IFN-α subtypes, −β, −ε, −κ, −ω, −δ and -τ. They bear a variety of biological functions, such as defending against viral or bacterial infection, immunomodulation and anti-proliferation. Due to their pluripotent function, type I IFNs, more specifically IFN-α/β, have been intensively studied for decades for their important roles in immunity/autoimmunity and cancers. Although IFN-α/β can be produced by many types of cells when exposed to environmental threats such as viral or bacterial infections, the most potent source of IFN-α/β is plasmacytoid dendritic cells (PDCs), which produce more than 1,000-fold more IFN-α/β than any other cell type.1–3

IFN-α/β composition, receptors and pathways have been thoroughly reviewed;4–6 therefore, we only provide a brief description here. The type I IFN receptor (IFNAR), a heterodimer of IFNAR-1 and IFNAR-2, is activated by the binding of IFN-α or –β, resulting in the conformational changes of IFNAR and activation of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signalling pathway (see Figure 1). JAK1 and tyrosine kinase2 (TYK2) are intracellular kinases associated with type I IFN receptors that recruit and phosphorylate STAT1 and STAT2, which form IFN-stimulated gene factor (ISGF3), a heterotrimeric transcription complex with IFN regulatory factor 9 (IRF-9). This complex (ISGF3) then binds to an upstream regulatory sequence, IFN-stimulated response element (ISRE), to initiate transcription of IFN-inducible genes. This pathway is a classic type I IFN signalling pathway that is active in almost all cell types (see Figure 1A). Other than STAT1 and STAT2, there are other STATs that have been found to be activated by type I IFN, and such activation is generally cell type-specific7–10 Accumulating evidence indicates that there are other signalling pathways necessary for diverse responses to type I IFN. These pathways are independent of the classic JAK/STAT pathway (see Figure 1B and 1C) or somehow co-operate with the JAK/STAT pathway to adjust in association with type I IFN. In response to type I IFN activation, the phosphoinositide-3 kinase (PI3K) pathway can activate AKT (see Figure 1B), which in turn activates nuclear factor-kappa B (NF-κB). Alternatively, PI3K/AKT can activate NF-κB through protein kinase Cθ (PKCθ), which can also be activated by VAV, a component of the p38 mitogen-activated protein kinase (MAPK) pathway in response to type I IFN activation.

References:
  1. Borden EC, Sen GC, Uze G, et al., Interferons at age 50: past, current and future impact on biomedicine, Nat Rev Drug Discov, 2007;6:975–90.
  2. Ronnblom L, Alm GV, A pivotal role for the natural interferon alpha-producing cells (plasmacytoid dendritic cells) in the pathogenesis of lupus, J Exp Med, 2001;194:F59–63.
  3. Siegal FP, Kadowaki N, Shodell M, et al., The nature of the principal type 1 interferon-producing cells in human blood, Science, 1999;284:1835–7.
  4. Pestka S, The human interferon alpha species and receptors, Biopolymers, 2000;55:254–87.
  5. Theofilopoulos AN, Baccala R, Beutler B, et al., Type I interferons (alpha/beta) in immunity and autoimmunity, Annu Rev Immunol, 2005;23:307–36.
  6. Stark GR, Kerr IM, Williams BR, et al., How cells respond to interferons, Annu Rev Biochem, 1998;67:227–64.
  7. Farrar JD, Smith JD, Murphy TL, et al., Recruitment of Stat4 to the human interferon-alpha/beta receptor requires activated Stat2, J Biol Chem, 2000;275:2693–7.
  8. Fasler-Kan E, Pansky A, Wiederkehr M, et al., Interferon-alpha activates signal transducers and activators of transcription 5 and 6 in Daudi cells, Eur J Biochem, 1998;254:514–9.
  9. Matikainen S, Sareneva T, Ronni T, et al., Interferon-alpha activates multiple STAT proteins and upregulates proliferation-associated IL-2Ralpha, c-myc, and pim-1 genes in human T cells, Blood, 1999;93:1980–91.
  10. Torpey N, Maher SE, Bothwell AL, et al., Interferon alpha but not interleukin 12 activates STAT4 signaling in human vascular endothelial cells, J Biol Chem, 2004;279:26789–96.
  11. Wong LH, Hatzinisiriou I, Devenish RJ, et al., IFN-gamma priming up-regulates IFN-stimulated gene factor 3 (ISGF3) components, augmenting responsiveness of IFN-resistant melanoma cells to type I IFNs, J Immunol, 1998;160:5475–84.
  12. Sakamoto S, Qin J, Navarro A, et al., Cells previously desensitized to type 1 interferons display different mechanisms of activation of stat-dependent gene expression from naive cells, J Biol Chem, 2004;279:3245–53.
  13. Tian Z, Shen X, Feng H, et al., IL-1 beta attenuates IFN-alpha beta-induced antiviral activity and STAT1 activation in the liver: involvement of proteasome-dependent pathway, J Immunol, 2000;165:3959–65.
  14. Platanias LC, Mechanisms of type-I- and type-II-interferon-mediated signalling, Nat Rev Immunol, 2005;5:375-86.
  15. van Boxel-Dezaire AH, Rani MR, Stark GR, Complex modulation of cell type-specific signaling in response to type I interferons, Immunity, 2006;25:361–72.
  16. Hervas-Stubbs S, Perez-Gracia JL, Rouzaut A, et al., Direct effects of type I interferons on cells of the immune system, Clin Cancer Res, 2011;17:2619–27.
  17. Tannous BA, Kim DE, Fernandez JL, et al., Codon-optimized Gaussia luciferase cDNA for mammalian gene expression in culture and in vivo, Mol Ther, 2005;11:435–43.
  18. Bengtsson AA, Sturfelt G, Truedsson L, et al., Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies, Lupus, 2000;9:664–71.
  19. Dall'era MC, Cardarelli PM, Preston BT, et al., Type I interferon correlates with serological and clinical manifestations of SLE, Ann Rheum Dis, 2005;64:1692–7.
  20. von Wussow P, Jakschies D, Hartung K, et al., Presence of interferon and anti-interferon in patients with systemic lupus erythematosus, Rheumatol Int, 1988;8:225–30.
  21. Kirou KA, Lee C, George S, et al., Coordinate overexpression of interferon-alpha-induced genes in systemic lupus erythematosus, Arthritis Rheum, 2004;50:3958–67.
  22. Der SD, Zhou A, Williams BR, et al., Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays, Proc Natl Acad Sci U S A, 1998;95:15623–8.
  23. Bennett L, Palucka AK, Arce E, et al., Interferon and granulopoiesis signatures in systemic lupus erythematosus blood, J Exp Med, 2003;197:711–23.
  24. Baechler EC, Batliwalla FM, Karypis G, et al., Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus, Proc Natl Acad Sci U S A, 2003;100:2610–5.
  25. van der Pouw Kraan TC, Wijbrandts CA, van Baarsen LG, et al., Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients, Ann Rheum Dis, 2007;66:1008–14.
  26. van Baarsen LG, Bos WH, Rustenburg F, et al., Gene expression profiling in autoantibody-positive patients with arthralgia predicts development of arthritis, Arthritis Rheum, 2010;62:694–704.
  27. Coelho LF, de Oliveira JG, Kroon EG, Interferons and scleroderma-a new clue to understanding the pathogenesis of scleroderma? Immunol Lett, 2008;118:110–5.
  28. 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.
  29. Han GM, Chen SL, Shen N, et al., Analysis of gene expression profiles in human systemic lupus erythematosus using oligonucleotide microarray, Genes Immun, 2003;4:177–86.
  30. Walsh RJ, Kong SW, Yao Y, et al., Type I interferon-inducible gene expression in blood is present and reflects disease activity in dermatomyositis and polymyositis, Arthritis Rheum, 2007;56:3784–92.
  31. Bilgic H, Ytterberg SR, Amin S, et al., Interleukin-6 and type I interferon-regulated genes and chemokines mark disease activity in dermatomyositis, Arthritis Rheum, 2009;60:3436–46.
  32. Feng X, Wu H, Grossman JM, et al., Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus, Arthritis Rheum, 2006;54:2951–62.
  33. Baechler EC, Bauer JW, Slattery CA, et al., An interferon signature in the peripheral blood of dermatomyositis patients is associated with disease activity, Mol Med, 2007;13:59–68.
  34. Weckerle CE, Franek BS, Kelly JA, et al., Network analysis of associations between serum interferon-alpha activity, autoantibodies, and clinical features in systemic lupus erythematosus, Arthritis Rheum, 2010;63:1044–53.
  35. Yao Y, Richman L, Higgs BW, et al., Neutralization of interferon-alpha/beta-inducible genes and downstream effect in a phase I trial of an anti-interferon-alpha monoclonal antibody in systemic lupus erythematosus, Arthritis Rheum, 2009;60:1785–96.
  36. Yao Y, Higgs BW, Morehouse C, et al., Development of Potential Pharmacodynamic and Diagnostic Markers for Anti- IFN-alpha Monoclonal Antibody Trials in Systemic Lupus Erythematosus, Hum Genomics Proteomics, 2009;2009.
  37. Crow MK, Interferon-alpha: a therapeutic target in systemic lupus erythematosus, Rheum Dis Clin North Am, 2010;36:173–86, x.
  38. Sekiguchi N, Kawauchi S, Furuya T, et al., Messenger ribonucleic acid expression profile in peripheral blood cells from RA patients following treatment with an anti-TNF-alpha monoclonal antibody, infliximab, Rheumatology (Oxford), 2008;47:780–8.
  39. van Baarsen LG, Wijbrandts CA, Rustenburg F, et al., Regulation of IFN response gene activity during infliximab treatment in rheumatoid arthritis is associated with clinical response to treatment, Arthritis Res Ther, 2010;12:R11.
  40. Thurlings RM, Boumans M, Tekstra J, et al., Relationship between the type I interferon signature and the response to rituximab in rheumatoid arthritis patients, Arthritis Rheum, 2010;62:3607–14.
  41. Schlaak JF, Hilkens CM, Costa-Pereira AP, et al., Cell-type and donor-specific transcriptional responses to interferon-alpha. Use of customized gene arrays, J Biol Chem, 2002;277:49428–37.
  42. Hilkens CM, Schlaak JF, Kerr IM, Differential responses to IFN-alpha subtypes in human T cells and dendritic cells, J Immunol, 2003;171:5255–63.
  43. Farkas L, Beiske K, Lund-Johansen F, et al., Plasmacytoid dendritic cells (natural interferon- alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions, Am J Pathol, 2001;159:237–43.
  44. Lande R, Gafa V, Serafini B, et al., Plasmacytoid dendritic cells in multiple sclerosis: intracerebral recruitment and impaired maturation in response to interferon-beta, J Neuropathol Exp Neurol, 2008;67:388–401.
  45. Blomberg S, Eloranta ML, Cederblad B, et al., Presence of cutaneous interferon-alpha producing cells in patients with systemic lupus erythematosus, Lupus, 2001;10:484–90.
  46. van Holten J, Smeets TJ, Blankert P, et al., Expression of interferon beta in synovial tissue from patients with rheumatoid arthritis: comparison with patients with osteoarthritis and reactive arthritis, Ann Rheum Dis, 2005;64:1780–2.
  47. Fleming JN, Nash RA, McLeod DO, et al., Capillary regeneration in scleroderma: stem cell therapy reverses phenotype? PLoS One, 2008;3:e1452.
  48. Van Krinks CH, Matyszak MK, Gaston JS, Characterization of plasmacytoid dendritic cells in inflammatory arthritis synovial fluid, Rheumatology (Oxford), 2004;43:453–60.
  49. Greenberg SA, Pinkus JL, Pinkus GS, et al., Interferon-alpha/beta-mediated innate immune mechanisms in dermatomyositis, Ann Neurol, 2005;57:664–78.
  50. Greenberg SA, A gene expression approach to study perturbed pathways in myositis, Curr Opin Rheumatol, 2007;19:536–41.
  51. Wenzel J, Schmidt R, Proelss J, et al., Type I interferon-associated skin recruitment of CXCR3+ lymphocytes in dermatomyositis, Clin Exp Dermatol, 2006;31:576–82.
  52. Cederblad B, Blomberg S, Vallin H, et al., Patients with systemic lupus erythematosus have reduced numbers of circulating natural interferon-alpha- producing cells, J Autoimmun, 1998;11:465–70.
  53. Gill MA, Blanco P, Arce E, et al., Blood dendritic cells and DC-poietins in systemic lupus erythematosus, Hum Immunol, 2002;63:1172–80.
  54. Hooks JJ, Moutsopoulos HM, Geis SA, et al., Immune interferon in the circulation of patients with autoimmune disease, N Engl J Med, 1979;301:5–8.
  55. Wailoo AJ, Bansback N, Brennan A, et al., Biologic drugs for rheumatoid arthritis in the Medicare program: a cost-effectiveness analysis, Arthritis Rheum, 2008;58:939–46.
  56. Fong KY, Boey ML, Koh WH, et al., Cytokine concentrations in the synovial fluid and plasma of rheumatoid arthritis patients: correlation with bony erosions, Clin Exp Rheumatol, 1994;12:55–8.
  57. Hopkins SJ, Meager A, Cytokines in synovial fluid: II. The presence of tumour necrosis factor and interferon, Clin Exp Immunol, 1988;73:88–92.
  58. Shiozawa S, Chihara K, Shiozawa K, et al., A sensitive radioimmunoassay for alpha-interferon: circulating alpha-interferon-like substance in the plasma of healthy individuals and rheumatoid arthritis patients, Clin Exp Immunol, 1986;66:77–87.
  59. Yarilina A, Ivashkiv LB, Type I interferon: a new player in TNF signaling, Curr Dir Autoimmun, 2010;11:94–104.
  60. van der Pouw Kraan TC, van Baarsen LG, Wijbrandts CA, et al., Expression of a pathogen-response program in peripheral blood cells defines a subgroup of rheumatoid arthritis patients, Genes Immun, 2008;9:16–22.
  61. Cantaert T, Baeten D, Tak PP, et al., Type I IFN and TNF-alpha cross-regulation in immune-mediated inflammatory disease: basic concepts and clinical relevance, Arthritis Res Ther, 2010;12:219.
  62. Pascual V, Farkas L, Banchereau J, Systemic lupus erythematosus: all roads lead to type I interferons, Curr Opin Immunol, 2006;18:676–82.
  63. Quartier P, Allantaz F, Cimaz R, et al., A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial), Ann Rheum Dis, 2010;70:747–54.
  64. Lahita RG, Systemic Lupus Erythematosus, 3rd edn, San Diego, CA: Academic Press, 1999.
  65. Kammer GM, Tsokos GC, Lupus: Molecular and Cellular Pathogenesis. Totowa, NJ: Humana Press, 1999.
  66. Blanco P, Palucka AK, Gill M, et al., Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus, Science, 2001;294:1540–3.
  67. Nzeusseu Toukap A, Galant C, Theate I, et al., Identification of distinct gene expression profiles in the synovium of patients with systemic lupus erythematosus, Arthritis Rheum, 2007;56:1579–88.
  68. Kirou KA, Lee C, George S, et al., 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.
  69. Landolt-Marticorena C, Bonventi G, Lubovich A, et al., Lack of association between the interferon-alpha signature and longitudinal changes in disease activity in systemic lupus erythematosus, Ann Rheum Dis, 2009;68:1440–6.
  70. MacDermott EJ, Cherian J, Santiago AG, et al., Type I interferon pathway activation predicts flares of disease activity in SLE, Arthritis Rheumatism, 2008;58(Abstract).
  71. Rus V, Atamas SP, Shustova V, et al., Expression of cytokine-and chemokine-related genes in peripheral blood mononuclear cells from lupus patients by cDNA array, Clin Immunol, 2002;102:283–90.
  72. Fu Q, Chen X, Cui H, et al., Association of elevated transcript levels of interferon-inducible chemokines with disease activity and organ damage in systemic lupus erythematosus patients, Arthritis Res Ther, 2008;10:R112.
  73. Higgs BW, Liu Z, White B, et al., Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway, Ann Rheum Dis, 2011;ARD Online First.
  74. Yao Y, Higgs BW, Richman L, et al., Use of type I interferon-inducible mRNAs as pharmacodynamic markers and potential diagnostic markers in trials with sifalimumab, an anti-IFNalpha antibody, in systemic lupus erythematosus, Arthritis Res Ther, 2010;12(Suppl 1):S6.
  75. Crow MK, Kirou KA, Interferon-induced versus chemokine transcripts as lupus biomarkers, Arthritis Res Ther, 2008;10:126.
  76. McBride JM, Wallace DJ, Yao Z, et al., Dose-dependent modulation of interferon regulated genes with administration of single and repeat doses of Rontalizumab in a phase I, placebo controlled, double blind, dose escalation study in SLE, Arthritis Rheum, 2009;60.
  77. Greenberg SA, Type 1 interferons and myositis, Arthritis Res Ther, 2010;12 Suppl 1:S4.
  78. Isenberg DA, Rowe D, Shearer M, et al., Localization of interferons and interleukin 2 in polymyositis and muscular dystrophy, Clin Exp Immunol, 1986;63:450–8.
  79. Dietrich LL, Bridges AJ, Albertini MR, Dermatomyositis after interferon alpha treatment, Med Oncol, 2000;17:64–9.
  80. Somani AK, Swick AR, Cooper KD, et al., Severe dermatomyositis triggered by interferon beta-1a therapy and associated with enhanced type I interferon signaling, Arch Dermatol, 2008;144:1341–9.
  81. Gota C, Calabrese L, Induction of clinical autoimmune disease by therapeutic interferon-alpha, Autoimmunity, 2003;36:511–8.
  82. Duncan MR, Berman B, Differential regulation of glycosaminoglycan, fibronectin, and collagenase production in cultured human dermal fibroblasts by interferon-alpha, - beta, and -gamma, Arch Dermatol Res, 1989;281:11–8.
  83. Duncan MR, Berman B, Persistence of a reduced-collagen-producing phenotype in cultured scleroderma fibroblasts after short-term exposure to interferons, J Clin Invest, 1987;79:1318–24.
  84. 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.
  85. Black CM, Silman AJ, Herrick AI, et al., Interferon-alpha does not improve outcome at one year in patients with diffuse cutaneous scleroderma: results of a randomized, double-blind, placebo-controlled trial, Arthritis Rheum, 1999;42:299–305.
  86. Stevens W, Vancheeswaran R, Black CM, Alpha interferon-2a (Roferon-A) in the treatment of diffuse cutaneous systemic sclerosis: a pilot study. UK Systemic Sclerosis Study Group, Br J Rheumatol, 1992;31:683–9.
  87. Beretta L, Caronni M, Vanoli M, et al., Systemic sclerosis after interferon-alfa therapy for myeloproliferative disorders, Br J Dermatol, 2002;147:385–6.
  88. Ioannou Y, Isenberg DA, Current evidence for the induction of autoimmune rheumatic manifestations by cytokine therapy, Arthritis Rheum, 2000;43:1431–42.
  89. Solans R, Bosch JA, Esteban I, et al., Systemic sclerosis developing in association with the use of interferon alpha therapy for chronic viral hepatitis, Clin Exp Rheumatol, 2004;22:625–8.
  90. Coelho LF, de Oliveira JG, de Oliveira DB, et al., Increased expression of 2'5'oligoadenylate synthetase and double-stranded RNA dependent protein kinase messenger RNAs on affected skin of systemic sclerosis patients, Arch Dermatol Res, 2007;299:259–62.
  91. 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.
  92. York MR, Nagai T, Mangini AJ, et al., 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.
  93. Storey JD, A direct approach to false discovery rates, J Royal Statistical Society, Series B, 2002;64:479–98.
  94. Sweeney S, Hematopoietic stem cell transplant for systemic lupus erythematosus: Interferon regulatory factor 7 activation correlates with the IFN signature and recurrent disease, Lupus, 2011;20:975–80.
  95. Petri M, Singh S, Tesfasyone H, et al., Longitudinal expression of type I interferon responsive genes in systemic lupus erythematosus, Lupus, 2009;18:980–9.
  96. Tezak Z, Hoffman EP, Lutz JL, et al., Gene expression profiling in DQA1*0501+ children with untreated dermatomyositis: a novel model of pathogenesis, J Immunol, 2002;168:4154–63.
close

This content is copyright protected

However, if you would like to share the information on this webpage, you may use the headline and link below:

Type I Interferon in Rheumatoid Arthritis, Systemic Lupus Erythematosus, Myositis and Systemic Scleroderma – A Review of Transcript Profiling Studies in the Blood

Read more: Type I Interferon in Rheumatoid Arthritis, Systemic Lupus Erythematosus, Myositis and Systemic Scleroderma – A Review of Transcript Profiling Studies in the Blood