This document summarizes the immune mechanisms involved in systemic juvenile idiopathic arthritis (sJIA). It discusses how sJIA is characterized by excessive inflammation driven by cytokines like interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and interleukin-18 (IL-18). These cytokines promote inflammation by recruiting and activating immune cells. While the triggers for overproduction of these cytokines in sJIA are unknown, they lead to systemic symptoms and joint damage. The document also reviews efforts to understand disease heterogeneity and developing anti-inflammatory treatments targeting these cytokines.

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

5. Pathogens
Monocyte

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?