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Immune mechanisms of
inflammation in sJIA
Claudia Macaubas, PhD
Stanford University
Feb 7 2015
Inflammation in sJIA
Arthritis Rash Pericarditis
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
Activity
Neutrophils
Monocytes/
macrophages
Lymphocytes
Inflammation: Body’s response to injury
Part of innate immunity: one of 2 arms of the immune response
Pathogens
Monocyte
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
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
Production of IL-1b requires 2 signals
Signal 1
Signal 2
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
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
sJIA is not only about IL-1
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.
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
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
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
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
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
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
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
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
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)
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?
Immune Mechanisms of Inflamation in SJIA

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Immune Mechanisms of Inflamation in SJIA

  • 1. Immune mechanisms of inflammation in sJIA Claudia Macaubas, PhD Stanford University Feb 7 2015
  • 2. Inflammation in sJIA Arthritis Rash Pericarditis
  • 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. Activity Neutrophils Monocytes/ macrophages Lymphocytes Inflammation: Body’s response to injury Part of innate immunity: one of 2 arms of the immune response
  • 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. 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. Production of IL-1b requires 2 signals Signal 1 Signal 2
  • 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. 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. sJIA is not only about IL-1
  • 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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?

Notas del editor

  1. IL-18 is a member of the IL-1 cytokine family and shares similarities in genetic sequence, protein processing, receptor signalling and intracellular pathways with the IL-1β pathway Signal 1 and 2 are unknown in sJIA
  2. IL-1a: produced by the calpain pathway; role in sJIA is unknown IL-1RacP: The interleukin-1 receptor accessory protein IL-1ra: Interleukin 1 receptor antagonist