Interferon-gamma and immune system

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Interferon-gamma and immune system

Presented by Wat Mitthamsiri, M.D.

April4, 2014

Published in: Health & Medicine, Technology
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Interferon-gamma and immune system

  1. 1. By Wat Mitthamsiri, MD. Allergy and Clinical Immunology Fellow King Chulalongkorn Memorial Hospital Interferon-Gamma And Immune System
  2. 2. Outline • Introduction • What is interferon (IFN) • Classification of IFN • Interferon gamma (IFN-γ) – History and biology – Roles with other immune components – Roles in infection defense – Roles in autoimmunity – Roles in allergy and hypersensitivity
  3. 3. INTRODUCTION
  4. 4. What is interferon (IFN) • Interferons are proteins which produce antiviral and antiproliferative responses in cells. • On the basis of their sequence interferons are classified into five groups: α, α-II (or omega), β, delta (or trophoblast) and γ. • Except for γ-interferon, the sequence of all the others are related PROSITE documentation PDOC00225, Swiss Institute of Bioinformatics, http://prosite.expasy.org/cgi-bin/prosite/prosite-search-ac?PDOC00225#ref1 InterPro: protein sequence analysis & classification, EMBL-EBI, http://www.ebi.ac.uk/interpro/entry/IPR000471
  5. 5. What is interferon (IFN) • Roles of IFN: – Decrease tumor growth, inflammation, and angiogenesis – Innate immunity (IFN-α and IFN-β) – Adaptive immunity (IFN-γ) O Meyer, Joint Bone Spine 76 (2009) 464–473
  6. 6. Classification of IFN • 3 main classes: K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
  7. 7. Classification of IFN • Type I IFNs – Encoded by 17 nonallelic genes • Lack introns • Located on chromosome 9 in humans – Glycosylated proteins,160-200 amino acids – Sharing 30% to 55% homology • Type II IFN – 140 amino acids and shares no homology with type I IFNs O Meyer, Joint Bone Spine 76 (2009) 464–473
  8. 8. Classification of IFN • Type III IFNs: 3 IFN molecules – IL-28A, IL-28B, and IL-29 – Co-produced with IFN-β – But act by binding to a different receptor from type I IFN receptors O Meyer, Joint Bone Spine 76 (2009) 464–473
  9. 9. O Meyer, Joint Bone Spine 76 (2009) 464–473
  10. 10. INTERFERON-GAMMA History and biology
  11. 11. Interferon-gamma (IFN-γ) • Sole type II IFN • Made primarily by T cells and NK cells • More of an interleukin than an interferon? – Modest antiviral activity – Prominent derivation from T lymphocytes – Wide-ranging functions • Play roles in cellular and allergic immunity J W Steinke, et al., Middleton’s Allergy 8th edition, 2013, 65-82.
  12. 12. IFN-γ: General history A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113 1965 Induction of an IFN activity in human PBMC by phytohemagglutinin 1966 Ag-specific induction of IFN activity during virus infections 1972 New IFN was named ‘immune IFN’ 1973 IFN produced during DTH reactions  named ‘Type II IFN’ 1980 Nomenclature Committee: definitive name ‘IFN-γ’ 1982 Dimeric structure of IFN- γ suggested, Cloning of IFN- γ from cDNA
  13. 13. IFN-γ: Structure • Dimeric in solution • Each subunit – 6 α-helices, that comprise 62% of the structure – No β-sheet – Composed of 140 amino acids – No homology with type I IFNs S E. Ealick, et al., Science, New Series, Vol. 252, No. 5006 (May 3, 1991), pp. 698-702 O Meyer, Joint Bone Spine 76 (2009) 464–473
  14. 14. IFN-γ: Sources • During innate immune responses – Natural killer (NK) cells – Natural killer T (NKT) cells – Macrophages – Dendritic cells K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
  15. 15. IFN-γ: Sources • In adaptive immunity – CD8+ T cells – Control of infection, – CD4+ T helper 1 (Th1) subset • Promotes inflammatory responses • Clearance of intracellular pathogens • Class-switching to IgG2a, IgG2b, and IgG3 K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
  16. 16. IFN-γ: Gene • Human chromosome 12 • Cytogenetic Location: 12q14 • Molecular Location on chromosome 12: – Base pairs 68,154,769 to 68,159,740 National Library of Medicine (US). Genetics Home Reference [Internet]. Bethesda (MD): The Library; 2013 Sep 16 [cited 2014 April 3]. Available from: http://ghr.nlm.nih.gov/gene/IFNG.
  17. 17. IFN-γ: Expression regulation • In innate immunity – IFN-γ production response to constitutive expression of transcription factors • Eomes and T-bet (NK cells) • T-bet (NKT) – These transcription factors bind to regulatory elements that are already accessible within the Ifng locus, leading to activation of Ifng transcription K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
  18. 18. IFN-γ: Expression regulation • In adaptive immunity – Expression by CD4+and CD8+ T cells – Differentiation process of naïve CD4+ or CD8+ T cells to Th1 or cytotoxic T effector cells requires: • T cell receptor (TCR) stimulation • Multiple rounds of cell division • Induction of T-bet • Epigenetic modifications within the Ifng gene K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
  19. 19. IFN-γ: Expression regulation • Epigenetic regulation: long non-coding RNAs (lncRNAs) Tmevpg1 (also known as NeST) – Positively contribute to IFN-γ production by CD4+ and CD8+ T cells – Tmevpg1 is adjacent to the Ifng gene – Encoded on the DNA strand opposite to that coding IFN-γ K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
  20. 20. IFN-γ: Expression regulation • Epigenetic regulation: long non-coding RNAs (lncRNAs) Tmevpg1 (also known as NeST) – Tmevpg1 transcription is dependent upon transcription factors, Stat4 and T-bet • Which also influence Ifng transcription in CD4+ Th1 T cells – Tmevpg1 transgenic mice: • Increased IFN-γ • Immune to salmonella infection K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
  21. 21. IFN-γ: Signalling pathways X Hu, et al., Immunity 31, October 16, 2009, 539-550.
  22. 22. IFN-γ: Signalling pathways X Hu, et al., Immunity 31, October 16, 2009, 539-550.
  23. 23. IFN-γ: Signalling pathways X Hu, et al., Immunity 31, October 16, 2009, 539-550. • IFN-γ enhances TLR- induced TNF production by disrupting an IL-10- mediated inhibitory loop • Increased activity of GSK3 • Negatively regulates IL-10 expression by suppressing activation of transcription factors CREB and AP-1
  24. 24. IFN-γ: Signalling pathways X Hu, et al., Immunity 31, October 16, 2009, 539-550. • IFN-γ enhances TLR-induced IL-6 and IL-12 production • Disrupts inhibitory loop mediated by Notch target genes Hes1 and Hey1 • Downregulates intracellular NICD2 amounts • Inhibits expression of Hes1 and Hey1
  25. 25. IFN-γ: Signalling pathways X Hu, et al., Immunity 31, October 16, 2009, 539-550.
  26. 26. IFN-γ: Signalling pathways X Hu, et al., Immunity 31, October 16, 2009, 539-550. • Via regulation of IL-1R and TLR signaling • Inhibits IL-1 signaling in macrophages by downregulating IL-1RI expression • Blocks induction of MMP downstream of TLR signaling by • Superinduce transcription repressor ATF3 • Inhibit transcription activators CREB and AP-1 • Inhibits CREB activity by suppressing its serine phosphorylation • Inhibits AP-1 by downregulating nuclear protein levels of its subunits
  27. 27. IFN-γ: Signalling pathways X Hu, et al., Immunity 31, October 16, 2009, 539-550. • Inhibits osteoclastogenesis and bone resorption • Suppress expression and signal transduction of RANK, CSF-1R, and TREM2 • (Receptors critical for the process of osteoclastogenesis)
  28. 28. IFN-γ: Signalling pathways X Hu, et al., Immunity 31, October 16, 2009, 539-550. • Attenuates fibrosis by: • Suppresses TGF-βR signaling by • Induction of inhibitory SMAD (SMAD7) • Direct inhibition of SMAD3 by STAT1 • Inhibits IL-4R signaling by induction of SOCS1
  29. 29. IFN-γ: Signalling pathways X Hu, et al., Immunity 31, October 16, 2009, 539-550.
  30. 30. IFN-γ: Signalling pathways X Hu, et al., Immunity 31, October 16, 2009, 539-550. • In Th1 cell differentiation • IFN-γ-STAT1 signaling is critical for induction of T-bet and thus for sustaining the positive feedback loop • Leads to heightened production of IFN-γ.
  31. 31. IFN-γ: Signalling pathways X Hu, et al., Immunity 31, October 16, 2009, 539-550. • IFN-γ blocks Th2 cell differentiation • By inhibiting IL-4-STAT6 signaling
  32. 32. IFN-γ: Signalling pathways X Hu, et al., Immunity 31, October 16, 2009, 539-550. • IFN-γ and STAT1 can block Th17 cell differentiation • Mechanism of action is not clear • Possibly suppresses Th17 cell by targeting STAT3 (shown by dotted lines) • Inhibit aryl hydrocarbon nuclear receptor (AHR) • Suppression of TGF-β and IL-1 signaling by IFN-γ may contributes to inhibition of Th17 cell differentiation (not depicted)
  33. 33. IFN-γ: Signalling pathways X Hu, et al., Immunity 31, October 16, 2009, 539-550. • Regulates Treg cell differentiation and function. • Block TGFβ-mediated Treg cell differentiation • Upregulates expression of T-bet in Foxp3+ Treg cells • Promotes expression of CXCR3 that regulates homing of T-bet+ FoxP3+ Treg cells to sites of Th1 cell inflammation
  34. 34. INTERFERON-GAMMA Roles with other immune components
  35. 35. IFN-γ and macrophages A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113 1969 Lymphocyte-mediated activation of macrophagesMIF responsible? 1979 Several macrophage-activating factor (MAF) assays established 1983 Anti-IFN-γ antibody neutralizes MAF preparations 1985 Cloned IFN-γ possesses MAF activity
  36. 36. IFN-γ and macrophages • Driving differentiation from inactive monocytes into potent effector M1 activated macrophages – Enhanced adherence, phagocytosis, degranulation, and production of reactive oxygen and nitrogen molecules • Responsible for their accumulation at the site of CMIR as cells newly capable of killing intracellular pathogens and cancers J W Steinke, et al., Middleton’s Allergy 8th edition, 2013, 65-82.
  37. 37. IFN-γ and macrophages • Activated M1 macrophages – Induced by IFN-γ – High producers of IL-1β, TNF-α, IL-6, IL-12, and IL-23 – but not IL-10 – =>Proinflammatory and participate in Th1 polarization J W Steinke, et al., Middleton’s Allergy 8th edition, 2013, 65-82.
  38. 38. IFN-γ and NK cells A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113 1980 IFN-γ upregulates NK activity 1983 IL-2 may induce IFN-γ in NK cells 1993 Novel IFN-γ-coinducing factor  IGIF/IL-18 1995 IL-18 induces IFN-γ in NK cells 1991 IL-12 induces IFN-γ in NK cells
  39. 39. IFN-γ and NK cells+PMN • Stimulates killing by NK cells and neutrophils • Stimulates adherence of leukocytes to endothelial cells through induction of ICAM-1 J W Steinke, et al., Middleton’s Allergy 8th edition, 2013, 65-82.
  40. 40. IFN-γ and APCs + DCs A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113 1982 IFN-γ enhances MHC Class II expression in mononuclear phagocytes 1984 IFN-γ induces enzymatic breakdown of tryptophan 2000 IFN-γ optimizes IL-12 production by DCs IFN-γ-induced IDO conditions DCs to become tolerogenic 1990 IFN-γ induces IDO in vivo 1996 IFN -γ enhances MHC Class II expression in DCs
  41. 41. IFN-γ and APCs + DCs • Directly stimulates Ag processing • Stimulates antigen presentation via increased MHC class I and II expression • Stimulates cytokine production J W Steinke, et al., Middleton’s Allergy 8th edition, 2013, 65-82.
  42. 42. IFN-γ and Treg cells A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113 1995 CD4+CD25+ Treg cells defined 2005 Defective functioning of Treg cells in IFN -γR KO mice with collagen-induced arthritis (CIA) 2006 IFN-γ can convert CD4+CD25 cells into CD4+ Treg cells able to suppress experimental autoimmune encephalomyelitis (EAE) Release of IFN-γ by Treg cells
  43. 43. IFN-γ and T-helper cells A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113 1973 T cell-replacing factor (TRF, T cell help for B cells) described 1977 Type II IFN inhibits antibody production in vitro 2005 Th17 cell lineage defined in mice IFN-γ inhibits differentiation of Th17 cells and IL-17 production by activated Th memory cells 1984 IFN-γ proposed as a TRF 1988 Th1 and Th2 clones described Role of IFN-g in Th1/Th2 paradigm
  44. 44. INTERFERON-GAMMA Roles in infection defense
  45. 45. IFN-γ and infection defense • Most important in vivo role • Establishing effective response towards pathogens whose elimination from the body depends on phagocytosis and intracellular killing • Weakly inhibits viral replication A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113 J W Steinke, et al., Middleton’s Allergy 8th edition, 2013, 65-82.
  46. 46. IFN-γ and infection defense A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113 Pathogen entry NK cells produce IFN-γ  primes mononuclear phagocytes for production of monokines: TNF-a and IL-12 IFN-γ & TNF-a augment bacteriostatic potential of phagocytes Guided by IL-12, Th1 response is mounted Additional IFN-γ production by activated CD4+ and CD8+ T cells
  47. 47. IFN-γ and infection defense • In Listeria infection, IFN-γ can: – Augment normal resistance – Restore compromised resistance – Rx with neutralizing Ab to IFN-γ abrogated resistance – IFN-γ production during the first 2 days of infection was critical for development of protective Ag-specific T cells A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
  48. 48. IFN-γ and infection defense • In Mycobacterial infections – Application of IFN-γ on skin lesions of lepromatous leprosy patients caused increased infiltration with lymphocytes and reduction in the local bacterial load – Mice with a disrupted gene for the IFN-γ receptor were found to fail controlling infection with M. bovis. A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
  49. 49. IFN-γ and infection defense • Mycobacterial infections in IFN-γ deficient mice – Unable to control sublethal doses M. tuberculosis or M. bovis – Bacteria multiplied more extensively and caused more widespread damage in affected tissues. – Compromised in both innate resistance in early phase of infection, and also later development of protective immunity A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
  50. 50. IFN-γ and infection defence • Important factor in directing the immune response towards the Th1 pathway • Mitigates excessive extramedullary myelopoiesis • Responsible for apoptosis of CD4+ T cells in the later phases of the immune response to mycobacteria • Responsible for the appearance of ‘immunosuppressive’ macrophages A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
  51. 51. INTERFERON-GAMMA Roles in autoimmunity
  52. 52. K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
  53. 53. IFN-γ and autoimmunity • Mechanism is remain unclear • Epidermal transgenic expression of IFN-γ leads to – Anti-dsDNA, – Anti-histone autoAb – Glomerulonephritis • Transgenic IFN-γ expression in other sites does not lead to systemic autoimmunity?? K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
  54. 54. IFN-γ and autoimmunity • Possibly supporting evidence – Ability of IFN-γ to • Promote B cell IgG class switching to more pathogenic autoAb • Activation of IgG Fc receptors and complement • Contributes to disease severity – In end organ damage, infiltration of IFN-γ secreting T cells resulting in macrophage activation, inflammation, and tissue damage K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
  55. 55. IFN-γ and autoimmunity • Possibly supporting evidence – Mutated mice with reduced decay of IFN-γ mRNA • Increased IFN-γ signaling and accumulation of follicular helper T (Tfh) cells • Increased germinal center B cells and autoAb • IFN -γR-deficiency in these mice can prevent the development of lupus K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
  56. 56. IFN-γ and autoimmunity • Possibly contradict evidence – The experimental autoimmune diseases, EAE, EAU and CIA, = Th17-driven – Conditions for optimal in vitro induction of naive T cells differentiation into Th17 cells by IL-23 were found to include neutralization of endogenous IFN-γ A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
  57. 57. IFN-γ and autoimmunity • Possibly contradict evidence – Ablation of IFN-γ resulted in increased numbers of IL-17-producing T cells – Conclusion: Endogenous IFN-γ inhibits differentiation of Th17 cells – Ablation of endogenous IFN-g should boost disease in EAE and CIA. A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
  58. 58. IFN-γ and autoimmunity • Possibly contradict evidence – Blocking of autoimmune diseases can be done by injection of syngeneic Treg cells – In vitro treatment of CD4+CD25 cells with IFN-γ cause their conversion into CD4+ Treg cells – Evidence exists for induced Treg cells to rapidly release IFN-γ, that may be important for their suppressive activity A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
  59. 59. IFN-γ and autoimmunity K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
  60. 60. IFN-γ as a therapeutic target? • Fontolizumab, – Humanized monoclonal Ab against IFN-γ – Showed some efficacy in patients with Crohn’s disease – Phase II clinical trial investigating its use in rheumatoid arthritis was terminated because the first phase did not meet the endpoint K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
  61. 61. IFN-γ as a therapeutic target? • Amgen’s AMG 811 – Human monoclonal Ab – Being evaluated in safety trials with subjects with DLE and subjects with SLE with and without glomerulonephritis K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
  62. 62. IFN-γ as a therapeutic target? • Non-specific targeting of IFN-γ – Impact both innate and adaptive immunity – Deficiency of IFN-γ is associated with severe infection • Targeting to cellular components regulating IFN-γ expression, such as lncRNA Tmevpg1, may provide greater therapeutic benefit without adverse effect on responses to infection K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
  63. 63. INTERFERON-GAMMA Roles in allergy and hypersensitivity
  64. 64. IFN-γ and allergy • Allergic inflammatory tissue has prominent presence of IFN-γ • IFN-γ exacerbates allergic inflammation through its ability to – Activate accessory cell function – Stimulate cytokine secretion – Induce adhesion molecule expression – Activate eosinophils and neutrophils J W Steinke, et al., Middleton’s Allergy 8th edition, 2013, 65-82.
  65. 65. IFN-γ and allergy • IFN-γ promotes allergic inflammation – IFN-γ–producing Th1 lymphocytes exacerbate murine asthma – Th1-like processes are particularly prevalent in patients with severe asthma, especially those with irreversible obstruction and neutrophilic inflammation J W Steinke, et al., Middleton’s Allergy 8th edition, 2013, 65-82.
  66. 66. IFN-γ and allergy • It is frequently stated that the immune response to allergens in non-allergic subjects is characterized by Th1-like lymphocyte responses • …But without CMIR and cellular inflammation J W Steinke, et al., Middleton’s Allergy 8th edition, 2013, 65-82.
  67. 67. IFN-γ and DTH A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113 • Exogenous IFN-γ was found to reverse inhibition of the DTH response by anti- CD4 or anti-IL-2R Ab in mouse model •  supporting the concept that production of IFN-γ by TH1 cells is essential for the reaction • There was report of IFN-γ potentiates contact sensitivity
  68. 68. IFN-γ and DTH A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113 • There were ambiguity in reports analyzing the role of IFN-γ in DTH reactions • This reflects the pathogenic complexity of the systems under study • Effects may differ depending on • Ag used (protein or hapten) • Route of exposure (injection or contact with the skin) • Time point during the reaction (during the sensitization or the elicitation phase)
  69. 69. IFN-γ and DTH A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113 • DTH reactions rely on both natural and acquired immune response mechanisms • IFN-γ may act differently on these components
  70. 70. IFN-γ and Shwartzman reaction A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113 • 2 varients: • Localized • Generalized • Both are two-stage phenomena • Preparative (sensitizing) injection of endotoxin • Eliciting (provoking) injection followed after about 24 h
  71. 71. IFN-γ and Shwartzman reaction A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113 • Example of human model: • Thrombohemorrhagic shock that sometimes occurs in humans with meningococcal sepsis • In mouse model with Pre-treatment with neutralizing anti-IFN-γ • Completely protected against this reaction • Reduced production of circulating TNF following the eliciting dose
  72. 72. TAKE HOME MESSAGE
  73. 73. Take home message • IFN-γ is the only type II IFN • It’s a cytokine that is critical for innate and adaptive immunity • Its action mainly via JAK-STAT pathway • It has multifaceted roles: Infection defense (esp. intracellular pathogens) , CMIR, autoimmunity, allergy and hypersensitivity

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