SLE pathogenesis updateChristian Lood, PhDAssistant Professor

Division of Rheumatology, UW

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

Neutrophil effector functions

Lu T et al 2012 Front. Immunol.

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

NETs contain autoantigens

ANCA Vasculitis

Cocaine-mediated NETosis

No stimulation Cocaine

DNA

NE

Lood C et al Rheum 2016

NETs contain autoantigens

ANCA Vasculitis

SLE

PAD2/4

cit

citrullination

RA

IC-mediated NETosis

FcgRIIA

NETosis

TLR7/8

RNP-IC

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

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

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?

Is oxidized mitochondrial DNA inflammatory?8-OHdG -

DNA

8-OHdG +DNA

PBMCs

Inflammatory Cytokines (qPCR)

Oxidized mtDNA is highly inflammatory

How is 8-OHdG+ mtDNA inducing inflammation?

Lood C et al Nat Med 2016

cGAS/STING pathway may be activated in SLE

An J et al A&R 2017

cGAS mRNA cGAMP levels

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

Activated neutrophils are the main source of B cell-activating BAFF

Parsa R 2016 JEM

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

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

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).