Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Immune Mechanisms of Inflamation in SJIA

4,689 views

Published on

Immune mechanisms of inflammation in SJIA

Published in: Healthcare
  • Sex in your area is here: ♥♥♥ http://bit.ly/2F90ZZC ♥♥♥
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
  • Dating direct: ❤❤❤ http://bit.ly/2F90ZZC ❤❤❤
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here

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?

×