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SLE pathogenesis updateChristian Lood, PhDAssistant Professor
Division of Rheumatology, UW
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Lupus pathogenesis - overview
5. Immune cellactivation
pDC
1. Cell death
Apoptosis
2. Antigen presentation
4. Tissue damage
PMN
3. IC formation
DC B
T
6. Inflammation/Type I IFNs
PMN
LE cell
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Neutrophil effector functions
Lu T et al 2012 Front. Immunol.
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Neutrophil extracellular traps
• Release of chromatin as well as granular and cytoplasmic anti-microbial molecules in an attempt to trap and kill pathogens.
Brinkmann 2004, Science
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NETs contain autoantigens
ANCA Vasculitis
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Cocaine-mediated NETosis
No stimulation Cocaine
DNA
NE
Lood C et al Rheum 2016
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NETs contain autoantigens
ANCA Vasculitis
SLE
PAD2/4
cit
citrullination
RA
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IC-mediated NETosis
FcgRIIA
NETosis
TLR7/8
RNP-IC
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Mitochondria are oxidized and extruded by activated neutrophils
TLR8
ROS
PI3K
NADPHoxidase
FcgRIIA
Phagocytosis
Lood C et al Nat Med 2016, Caielli S JEM 2016
NETs
mitochondria
8-OHdG mtDNA
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NET formation may be a useful clinical biomarker in SLE
HC
SL
E
0 .0 0
0 .0 5
0 .1 0
0 .1 5
0 .2 0
0 .2 5
MP
O-D
NA
co
mp
lex
es
(AU
45
0 n
m)
*
Lood C et al Nat Med 2016
HC
SL
E
0 .0 0 0 0
0 .0 0 0 5
0 .0 0 1 0
0 .0 0 1 5
0 .0 0 2 0
0 .0 0 2 5
mtD
NA
(p
g/u
L p
las
ma
)
*
HC
SL
E
0 .0
0 .5
1 .0
1 .5
2 .0
2 .5
8-O
Hd
G
DN
A (
ng
/mL
)
* *
NETs mtDNA 8-OHdG DNA
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Lupus pathogenesis - update
5. Immune cellactivation
pDC
1. Cell death
Apoptosis
2. Antigen presentation
4. Tissue damage
PMN
3. IC formation
DC B
T
6. Inflammation/Type I IFNs
PMN
NETosis?
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Is oxidized mitochondrial DNA inflammatory?8-OHdG -
DNA
8-OHdG +DNA
PBMCs
Inflammatory Cytokines (qPCR)
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Oxidized mtDNA is highly inflammatory
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How is 8-OHdG+ mtDNA inducing inflammation?
Lood C et al Nat Med 2016
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cGAS/STING pathway may be activated in SLE
An J et al A&R 2017
cGAS mRNA cGAMP levels
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Lupus pathogenesis - update
5. Immune cellactivation
pDC
1. Cell death
Apoptosis
2. Antigen presentation
4. Tissue damage
PMN
3. IC formation
DC B
T
6. Inflammation/Type I IFNs
PMN
NETosiscGAS/STING
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Activated neutrophils are the main source of B cell-activating BAFF
Parsa R 2016 JEM
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Lupus pathogenesis - update
5. Immune cellactivation
pDC
1. Cell death
Apoptosis
2. Antigen presentation
4. Tissue damage
PMN
3. IC formation
DC B
T
6. Inflammation/Type I IFNs
PMN
NETosiscGAS/STING
BAFF
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Lupus pathogenesis - update
5. Immune cellactivation
pDC
1. Cell death
Apoptosis
2. Antigen presentation
4. Tissue damage
PMN
3. IC formation
DC B
T
6. Inflammation/Type I IFNs
PMN
NETosiscGAS/STING
BAFF
DNase1L3 RNase
Belimumab
Anti-malarials
mtROSinhibitor
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Highlighted papers
• An J et al. Expression of cyclic GMP-AMP synthase in patients with systemic lupus erythematosus. Arthritis Rheum. 69, 800-807 (2017).
• An J et al. Cutting edge: Antimalarial drugs inhibit IFN-B production through blockade of cyclic GMP-AMP synthase-DNA interaction. JI Cutting Edge. 194, 4089-4093 (2015).
• Caielli S et al. Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. JEM. 213, 697-713 (2016).
• Lood C et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med. 22, 146-153 (2016).
• Parsa R et al. BAFF-secreting neutrophils drive plasma cell responses during emergency granulopoiesis. JEM. 213, 1537-1553 (2016).
• Sisirak V et al. Digestion of chromatin in apoptotic cell microparticles prevents autoimmunity. Cell. 166, 88-101 (2016).