Skip to main content

Advertisement

SpringerLink
Log in

Type I Interferons: Beneficial in Th1 and Detrimental in Th17 Autoimmunity

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

In relapsing remitting multiple sclerosis (RRMS), type I interferon (IFN) is considered immuno-modulatory, and recombinant forms of IFN-β are the most prescribed treatment for this disease. However, within the RRMS population, 30–50% of MS patients are nonresponsive to this treatment, and it consistently worsens neuromyelitis optica (NMO), a disease once considered to be a form of RRMS. In contrast to RRMS, type I IFNs have been shown to have properties that drive the inflammatory pathologies in many other autoimmune diseases. These diseases include Sjögren's syndrome, system lupus erythematosus (SLE), neuromyelitis optica (NMO), rheumatoid arthritis (RA) and psoriasis. Historically, autoimmune diseases were thought to be driven by a TH1 response to auto-antigens. However, since the discovery of the TH17 in experimental autoimmune encephalomyelitis (EAE), it is now generally thought that TH17 plays an important role in MS and all other autoimmune diseases. In this article, we will discuss recent clinical and basic research advances in the field of autoimmunity and argue that IFN-β and other type I IFNs are immuno-modulatory in diseases driven predominantly by TH1 but in contrast are inflammatory in diseases that have a predominant Th17 response.

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. Arnason BG (1999) Immunologic therapy of multiple sclerosis. Annu Rev Med 50:291–302

    Article  PubMed  CAS  Google Scholar 

  2. Pena-Rossi C et al. (2008) Clinical trial: a multicentre, randomized, double-blind, placebo-controlled, dose-finding, phase II study of subcutaneous interferon-beta-1a in moderately active ulcerative colitis. Aliment Pharmacol Ther

  3. Benveniste EN and Qin H (2007) Type I interferons as anti-inflammatory mediators. Sci STKE 2007 (416), pe70

  4. Guo B et al (2008) The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice. J Clin Invest 118(5):1680–1690

    Article  PubMed  CAS  Google Scholar 

  5. Prinz M et al (2008) Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity 28(5):675–686

    Article  PubMed  CAS  Google Scholar 

  6. Bennett L et al (2003) Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 197(6):711–723

    Article  PubMed  CAS  Google Scholar 

  7. van der Fits L et al (2004) In psoriasis lesional skin the type I interferon signaling pathway is activated, whereas interferon-alpha sensitivity is unaltered. J Invest Dermatol 122(1):51–60

    Article  PubMed  Google Scholar 

  8. van der Pouw Kraan TC et al (2007) 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 66(8):1008–1014

    Article  PubMed  Google Scholar 

  9. Stromnes IM et al (2008) Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells. Nat Med 14(3):337–342

    Article  PubMed  CAS  Google Scholar 

  10. McRae BL et al (1998) Type I IFNs inhibit human dendritic cell IL-12 production and Th1 cell development. J Immunol 160(9):4298–4304

    PubMed  CAS  Google Scholar 

  11. Nagai T et al (2007) Interferon-beta mediates opposing effects on interferon-gamma-dependent interleukin-12 p70 secretion by human monocyte-derived dendritic cells. Scand J Immunol 65(2):107–117

    Article  PubMed  CAS  Google Scholar 

  12. Harrington LE et al (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6(11):1123–1132

    Article  PubMed  CAS  Google Scholar 

  13. Martin-Saavedra FM et al (2008) Beta interferon restricts the inflammatory potential of CD4+ cells through the boost of the Th2 phenotype, the inhibition of Th17 response and the prevalence of naturally occurring T regulatory cells. Mol Immunol 45(15):4008–4019

    Article  PubMed  CAS  Google Scholar 

  14. Ramgolam VS et al (2009) IFN-beta inhibits human Th17 cell differentiation. J Immunol 183(8):5418–5427

    Article  PubMed  CAS  Google Scholar 

  15. Durelli L et al (2009) T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta. Ann Neurol 65(5):499–509

    Article  PubMed  CAS  Google Scholar 

  16. Axtell RC et al (2010) T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med 16(4):406–412

    Article  PubMed  CAS  Google Scholar 

  17. Hesse D, Sorensen PS (2007) Using measurements of neutralizing antibodies: the challenge of IFN-beta therapy. Eur J Neurol 14(8):850–859

    Article  PubMed  CAS  Google Scholar 

  18. Rani MR et al (2009) Heterogeneous, longitudinally stable molecular signatures in response to interferon-beta. Ann N Y Acad Sci 1182:58–68

    Article  PubMed  CAS  Google Scholar 

  19. Boniface K et al (2010) Human Th17 cells comprise heterogeneous subsets including IFN-gamma-producing cells with distinct properties from the Th1 lineage. J Immunol 185(1):679–687

    Article  PubMed  CAS  Google Scholar 

  20. Haak S et al (2009) IL-17A and IL-17 F do not contribute vitally to autoimmune neuro-inflammation in mice. J Clin Invest 119(1):61–69

    PubMed  CAS  Google Scholar 

  21. Comabella M et al (2009) A type I interferon signature in monocytes is associated with poor response to interferon-beta in multiple sclerosis. Brain 132(Pt 12):3353–3365

    Article  PubMed  CAS  Google Scholar 

  22. Nestle FO et al (2005) Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J Exp Med 202(1):135–143

    Article  PubMed  CAS  Google Scholar 

  23. Hida S et al (2000) CD8(+) T cell-mediated skin disease in mice lacking IRF-2, the transcriptional attenuator of interferon-alpha/beta signaling. Immunity 13(5):643–655

    Article  PubMed  CAS  Google Scholar 

  24. Scavo S et al (2004) Verrucous psoriasis in a patient with chronic C hepatitis treated with interferon. Clin Drug Investig 24(7):427–429

    Article  PubMed  Google Scholar 

  25. Horev A, Halevy S (2009) New-onset psoriasis following treatment with pegylated interferon-alpha 2b and ribavirin for chronic hepatitis C. Isr Med Assoc J 11(12):760–761

    PubMed  Google Scholar 

  26. La Mantia L, Capsoni F (2010) Psoriasis during interferon beta treatment for multiple sclerosis. Neurol Sci 31(3):337–339

    Article  PubMed  Google Scholar 

  27. Lopez-Lerma I et al (2009) New-onset psoriasis in a patient treated with interferon beta-1a. Br J Dermatol 160(3):716–717

    Article  PubMed  CAS  Google Scholar 

  28. Webster GF et al (1996) Cutaneous ulcerations and pustular psoriasis flare caused by recombinant interferon beta injections in patients with multiple sclerosis. J Am Acad Dermatol 34(2 Pt 2):365–367

    Article  PubMed  CAS  Google Scholar 

  29. Seckin D et al (2004) Concomitant vitiligo and psoriasis in a patient treated with interferon alfa-2a for chronic hepatitis B infection. Pediatr Dermatol 21(5):577–579

    Article  PubMed  Google Scholar 

  30. Imafuku S et al (2007) Ciclosporin treatment of psoriasis in a patient with chronic hepatitis C. Br J Dermatol 156(6):1367–1369

    Article  PubMed  CAS  Google Scholar 

  31. Downs AM, Dunnill MG (2000) Exacerbation of psoriasis by interferon-alpha therapy for hepatitis C. Clin Exp Dermatol 25(4):351–352

    Article  PubMed  CAS  Google Scholar 

  32. Kimball AB et al. (2008) Efficacy and safety of ABT-874, a monoclonal anti-interleukin 12/23 antibody, for the treatment of chronic plaque psoriasis: 36-week observation/retreatment and 60-week open-label extension phases of a randomized phase II trial. J Am Acad Dermatol

  33. Cargill M et al (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80(2):273–290

    Article  PubMed  CAS  Google Scholar 

  34. Nair RP et al (2008) Polymorphisms of the IL12B and IL23R genes are associated with psoriasis. J Invest Dermatol 128(7):1653–1661

    Article  PubMed  CAS  Google Scholar 

  35. Krueger GG et al (2007) A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 356(6):580–592

    Article  PubMed  CAS  Google Scholar 

  36. Hueber W et al (2010) Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med 2(52):52–72

    Article  Google Scholar 

  37. Lucchinetti CF et al (2002) A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica. Brain 125(Pt 7):1450–1461

    Article  PubMed  Google Scholar 

  38. Hengstman GJ et al (2007) Neuromyelitis optica with clinical and histopathological involvement of the brain. Mult Scler 13(5):679–682

    Article  PubMed  CAS  Google Scholar 

  39. Ishizu T et al (2005) Intrathecal activation of the IL-17/IL-8 axis in opticospinal multiple sclerosis. Brain 128(Pt 5):988–1002

    Article  PubMed  Google Scholar 

  40. Smith E et al (2007) IL-23 is required for neutrophil homeostasis in normal and neutrophilic mice. J Immunol 179(12):8274–8279

    PubMed  CAS  Google Scholar 

  41. Zhang Z et al (2009) Interleukin-17 causes neutrophil mediated inflammation in ovalbumin-induced uveitis in DO11.10 mice. Cytokine 46(1):79–91

    Article  PubMed  CAS  Google Scholar 

  42. Palace J et al (2010) Interferon beta treatment in neuromyelitis optica: increase in relapses and aquaporin 4 antibody titers. Arch Neurol 67(8):1016–1017

    Article  PubMed  Google Scholar 

  43. Shimizu J et al (2010) IFNbeta-1b may severely exacerbate Japanese optic-spinal MS in neuromyelitis optica spectrum. Neurology 75(16):1423–1427

    Article  PubMed  CAS  Google Scholar 

  44. Shimizu Y et al (2008) Development of extensive brain lesions following interferon beta therapy in relapsing neuromyelitis optica and longitudinally extensive myelitis. J Neurol 255(2):305–307

    Article  PubMed  Google Scholar 

  45. Uzawa A et al (2010) Different responses to interferon beta-1b treatment in patients with neuromyelitis optica and multiple sclerosis. Eur J Neurol 17(5):672–676

    Article  PubMed  CAS  Google Scholar 

  46. Warabi Y et al (2007) Interferon beta-1b exacerbates multiple sclerosis with severe optic nerve and spinal cord demyelination. J Neurol Sci 252(1):57–61

    Article  PubMed  CAS  Google Scholar 

  47. Genovese MC et al (2004) A randomized, controlled trial of interferon-beta-1a (Avonex(R)) in patients with rheumatoid arthritis: a pilot study [ISRCTN03626626]. Arthritis Res Ther 6(1):R73–R77

    Article  PubMed  CAS  Google Scholar 

  48. Mannon PJ et al (2010) Suppression of inflammation in ulcerative colitis by interferon-{beta}-1a is accompanied by inhibition of IL-13 production. Gut 60(4):449–455

    Article  PubMed  Google Scholar 

  49. Martinelli S et al (2004) Induction of genes mediating interferon-dependent extracellular trap formation during neutrophil differentiation. J Biol Chem 279(42):44123–44132

    Article  PubMed  CAS  Google Scholar 

  50. Krumbholz M et al (2008) Interferon-beta increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity. Brain 131(Pt 6):1455–1463

    Article  PubMed  CAS  Google Scholar 

  51. Vaknin-Dembinsky A et al (2010) Preferential increase of B-cell activating factor in the cerebrospinal fluid of neuromyelitis optica in a white population. Mult Scler 16(12):1453–1457

    Article  PubMed  CAS  Google Scholar 

  52. Xie S et al (2010) IL-17 activates the canonical NF-kappaB signaling pathway in autoimmune B cells of BXD2 mice to upregulate the expression of regulators of G-protein signaling 16. J Immunol 184(5):2289–2296

    Article  PubMed  CAS  Google Scholar 

  53. Hsu HC et al (2008) Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol 9(2):166–175

    Article  PubMed  CAS  Google Scholar 

  54. Meinl E et al (2011) Humoral autoimmunity in multiple sclerosis. J Neurol Sci 306(1–2):180–182

    Article  PubMed  CAS  Google Scholar 

  55. Lee LF et al (2011) IL-7 promotes T(H)1 development and serum IL-7 predicts clinical response to interferon-beta in multiple sclerosis. Sci Transl Med 3(93):93–68

    Article  CAS  Google Scholar 

  56. Lundmark F et al (2007) Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis. Nat Genet 39(9):1108–1113

    Article  PubMed  CAS  Google Scholar 

  57. Gregory SG et al (2007) Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 39(9):1083–1091

    Article  PubMed  CAS  Google Scholar 

  58. von Freeden-Jeffry U et al (1995) Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J Exp Med 181(4):1519–1526

    Article  Google Scholar 

  59. Seddon B et al (2003) Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells. Nat Immunol 4(7):680–686

    Article  PubMed  CAS  Google Scholar 

  60. Puel A et al (1998) Defective IL7R expression in T(−)B(+)NK(+) severe combined immunodeficiency. Nat Genet 20(4):394–397

    Article  PubMed  CAS  Google Scholar 

  61. Gao X et al (2010) Adjuvant treatment suppresses IL-17 production by T cell-independent myeloid sources in nonobese diabetic mice. Mol Immunol 47(14):2397–2404

    Article  PubMed  CAS  Google Scholar 

  62. Walline CC et al (2011) IL-7Ralpha confers susceptibility to experimental autoimmune encephalomyelitis. Genes Immun 12(1):1–14

    Article  PubMed  CAS  Google Scholar 

  63. Lee LF et al. IL-7 promotes T(H)1 development and serum IL-7 predicts clinical response to interferon-beta in multiple sclerosis. Sci Transl Med 3 (93): 93ra68

  64. Liu X et al. Crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease. Nat Med 16 (2): 191–197

  65. Davis CC et al (2011) Interleukin-7 permits Th1/Tc1 maturation and promotes ex vivo expansion of cord blood T cells: a critical step toward adoptive immunotherapy after cord blood transplantation. Cancer Res 70(13):5249–5258

    Article  Google Scholar 

  66. Oshima S et al (2004) Interferon regulatory factor 1 (IRF-1) and IRF-2 distinctively up-regulate gene expression and production of interleukin-7 in human intestinal epithelial cells. Mol Cell Biol 24(14):6298–6310

    Article  PubMed  CAS  Google Scholar 

  67. Ariizumi K et al (1995) IFN-gamma-dependent IL-7 gene regulation in keratinocytes. J Immunol 154(11):6031–6039

    PubMed  CAS  Google Scholar 

  68. Nanjappa SG et al (2011) Immunotherapeutic effects of IL-7 during a chronic viral infection in mice. Blood 117(19):5123–5132

    Article  PubMed  CAS  Google Scholar 

  69. Gregersen PK, Olsson LM (2009) Recent advances in the genetics of autoimmune disease. Annu Rev Immunol 27:363–391

    Article  PubMed  CAS  Google Scholar 

  70. Bellesi M et al (2006) CNS demyelination during anti-tumor necrosis factor alpha therapy. J Neurol 253(5):668–669

    Article  PubMed  Google Scholar 

  71. Segal BM et al (2008) Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol 7(9):796–804

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA

    Robert C. Axtell & Lawrence Steinman

  2. Division of Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Chander Raman

Authors
  1. Robert C. Axtell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chander Raman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lawrence Steinman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert C. Axtell.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Axtell, R.C., Raman, C. & Steinman, L. Type I Interferons: Beneficial in Th1 and Detrimental in Th17 Autoimmunity. Clinic Rev Allerg Immunol 44, 114–120 (2013). https://doi.org/10.1007/s12016-011-8296-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-011-8296-5

Keywords

Search

Navigation