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Immune Mechanisms of Inflamation in SJIA


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Immune mechanisms of inflammation in SJIA

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Immune Mechanisms of Inflamation in SJIA

  1. 1. Immune mechanisms of inflammation in sJIA Claudia Macaubas, PhD Stanford University Feb 7 2015
  2. 2. Inflammation in sJIA Arthritis Rash Pericarditis
  3. 3. Pathogens, Cell damage Other irritants Inflammation: Body’s response to injury M Blood Tissue Monocyte Macrophage Inflammation ‘goal’ is to be protective But potentially harmful – resolution mechanisms Tissue repair Anti- inflammatory response MM Resolvins Apoptotic neutrophil M Neutrophil ‘danger’ signals
  4. 4. Activity Neutrophils Monocytes/ macrophages Lymphocytes Inflammation: Body’s response to injury Part of innate immunity: one of 2 arms of the immune response
  5. 5. Pathogens Monocyte
  6. 6. Inflammation: Body’s response to injury IL-1b IL-6 Systemic effects Key cytokines in sJIA Local effects Recruitment and activation of inflammatory cells M Blood Tissue Monocyte Macrophage Monocytes and macrophages produce
  7. 7. IL-1β is Responsible for Many of the Systemic Features of SJIA Induces expression of adhesion molecules by EC cells, leading to increased recruitment of inflammatory cells + osteoclasts
  8. 8. Production of IL-1b requires 2 signals Signal 1 Signal 2
  9. 9. IL-1β Signaling is Highly Regulated IL-1b IL-1a IL-1RI IL-1RacP IL-1RI IL-1RacP IL-1Ra IL-1b IL-1a IL-1RII IL-1a IL-1b No signal No signal No signal
  10. 10. IL-1b overproduction in sJIA Trigger(s): unknown Neutrophil serine proteases pro-IL1b pro-IL18 IL1b IL18 The mechanism(s) involved in overproduction of IL-1b in sJIA is/are unknown
  11. 11. sJIA is not only about IL-1
  12. 12. IL-6 Levels Correlate with Arthritic Features • IL-6 levels are easily measured in serum and are increased in patients with SJIA • Levels correlate with – Presence of arthritis – Degree of joints affected De Benedetti F, Massa M, Robbioni P, et al. Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis. Arthritis Rheum. 1991;34(9):1158-1163.
  13. 13. Joint damage is associated with distinct monocyte phenotypes during SJIA flare %CD14hiCD16lowmonocytes Frequency of CD14+ Monocytes in SJIA Patients with Flare IL-1b Production During Flare 150 *** * * LPS Control Control 100 50 0 Brefeldin QuantityofIL-6(MFI) *P<0.05 ***P<0.001LPS, lipopolysaccharide; MFI, mean fluorescence intensity IL-6 Production During Flare 250 *** *** QuantityofIL-1β(MFI) 200 150 100 50 0 LPSBrefeldin 100 * 90 80 70 60 + - Control Joint Damage + - Joint Damage Joint Damage + -+ - Joint Damage Joint Damage + -Control Control From Macaubas et al, 2012
  14. 14. IL-6 signaling Expression of membrane-bound IL-6Rα - mainly cells of the immune system and hepatocytes Many other cells can respond to IL-6 Inhibitor Inhibitor Inhibitor
  15. 15. Human T cells require IL-1b and IL-6 for Th17 differentiation Th17 CD4+ T cells: central role in eliminating harmful microbes; promote chronic inflammation Reports of increased frequency of Th17 cells in blood and in synovial fluid in sJIA Lasiglie et al, 2011 Omoyinmi et al, 2012
  16. 16. IL-18 in sJIA IL-18 Potent activator of neutrophils Promotes Th1-type response (IFNg - MAS) Arthritis High circulating levels of IL-18 have been described in sJIA Correlation with several measures of articular inflammation and disease severity; potential biomarker of disease activity in sJIA Lotito et al, 2007 plasma Synovial fluid
  17. 17. IL-6 and IL-18 Distinct subsets of patients with systemic juvenile idiopathic arthritis based on their cytokine profiles - Shimizu et al, 2013 IL-18-dominant subset: more likely to develop macrophage activation syndrome (MAS) IL-6-dominant subset: greater number of joints with active disease and higher serum levels of MMP-3
  18. 18. Anti-inflammatory mechanisms IL-1RI IL-1RacP IL-1b IL-1ra Increase in endogenous IL-1ra Increase in ‘anti-inflammatory’ (M2) monocyte/macrophage response sJIA plasma (SAA) induces control Treg proliferation CD4+ T regulatory cells (Treg) Nguyen et al, 2011, 2014 Macaubas et al, 2012 Shimizu & Yachie, 2012 De Benedetti et al, 1995
  19. 19. IL-18 in sJIA remission Shimizu et al, 2014 Patients in remission: IL18 still high during inactive phase, decreasing only in remission Patients with relapse: increase in IL-18 levels
  20. 20. Inactive sJIA responses are not like healthy control CD14+ CD16+ Monocytes IL-1b 0 1 0 0 2 0 0 3 0 0 4 0 0 5 0 0 *** *** IL-1bMFI S J IA Q S J IA F C tl S J IA Q S J IA F C tl 0 1 0 0 2 0 0 3 0 0 4 0 0 5 0 0 ** ** IL-1bMFI Q: quiescence F: flare Macaubas et al, 2012 Compensated inflammation
  21. 21. sJIA ? Other mediators (S100P) Potential resolving mechanisms IL-1b IL-6 IL-18 Th17 IL-1Ra Anti-inflammatory monocytes CD4+ T regulatory cells IL-10 Complex IL-1-mediated disease, with contributions from IL-6, possibly IL-18 and other mediators sJIA can also be seen as a defect of immune regulation Unknown trigger(s)
  22. 22. Some questions • What is/are the trigger(s) in sJIA? • Disease heterogeneity • Mechanistic basis of disease heterogeneity? • Cellular source of IL-1b? • What is the role of IL-18? • How treatment changes patterns of inflammation? • Is there an ‘immunological remission’, and could it help to guide therapy?