immune mechanisms of inflamation in sjia
TRANSCRIPT
Immune mechanisms of inflammation in sJIA
Claudia Macaubas, PhD
Stanford University
Feb 7 2015
Inflammation in sJIA
Arthritis Rash Pericarditis
Pathogens,Cell damageOther 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
Apoptoticneutrophil
MNeutrophil
‘danger’ signals
Act
ivit
y
Neutrophils
Monocytes/macrophagesLymphocytes
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-1bIL-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
%C
D1
4h
i CD
16lo
w m
on
ocy
tes
Frequency of CD14+ Monocytes in SJIA Patients with Flare
IL-1b Production During Flare150
***
*
*
LPS
Control Control
100
50
0
Brefeldin
Qu
anti
ty o
f IL
-6(M
FI)
*P<0.05***P<0.001LPS, lipopolysaccharide; MFI, mean fluorescence intensity
IL-6 Production During Flare250 ***
***
Qu
anti
ty o
f IL
-1β
(MFI
) 200
150
100
50
0LPSBrefeldin
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 sJIALasiglie et al, 2011Omoyinmi 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-18Distinct 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, 2012Shimizu & 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-1
b M
FI
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-1
b M
FI
Q: quiescenceF: flare
Macaubas et al, 2012
Compensated inflammation
sJIA?
Other mediators (S100P)
Potentialresolving mechanisms
IL-1b
IL-6IL-18
Th17
IL-1RaAnti-inflammatory monocytes
CD4+ T regulatory cellsIL-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?
