Advances in the pathogenesis and management of SLE

Anne Davidson MBBSFeinstein Institute for Medical Research,

Manhasset NY

Disease causation- the big picture

Disease phenotypeAmplification

Target organ damage

Genetic risk Environment

Chance/Fate

Innate and adaptive immune responses

Systemic autoimmunity

SLE is associated with aberrant clearance of nucleic acid containing debris

Plasmacytoid DC

Myeloid DC

T Cell

Type I IFN Cytokines

IgG immune complexes

Antigen presentation Costimulation

Proliferation and Memory

Autoantibodies

BCR

FCR

TLR

TLR

BAFF/APRIL

Cytokines

Apoptotic cell debris, NETs, microparticles

TCR

Plasmacytoid DC

Myeloid DC

T Cell

Type I IFN Cytokines

IgG immune complexes

Antigen presentation Costimulation

Proliferation and Memory

Autoantibodies

BCR

FCR

TLR

TLR

BAFF/APRIL

Cytokines

Apoptotic cell debris, NETs, microparticles

TCR

Neut and BasophInnate

Adaptive

FCR

Virus

The source of nucleic acids in SLE

J Exp Med. 1994;179:1317-30

DNA

Ro

DNA LL37

Genetic defects can cause an overload of IC or apoptotic particles

– Fc receptor polymorphisms

– Altered nuclease digestion • eg Trex1 mutation

– Inefficient clearance • eg complement deficiencies

– Excess cell death

SLE is associated with aberrant clearance of nucleic acid containing debris

Plasmacytoid DC

Myeloid DC

T Cell

Type I IFN Cytokines

IgG immune complexes

Antigen presentation Costimulation

Proliferation and Memory

Autoantibodies

BCR

FCR

TLR

TLR

BAFF/APRIL

Cytokines

Apoptotic cell debris, NETs, microparticles

TCR

Plasmacytoid DC

Myeloid DC

T Cell

Type I IFN Cytokines

IgG immune complexes

Antigen presentation Costimulation

Proliferation and Memory

Autoantibodies

BCR

FCR

TLR

TLR

BAFF/APRIL

Cytokines

Apoptotic cell debris, NETs, microparticles

TCR

Neut and BasophInnate

Adaptive

FCR

Virus

Immunity. 2010 Mar 26;32(3):305-15

Endosome

Nucleus

SLE associated genes with definitive statistical evidence on GWAS

Many lupus associated genes are involved with both the induction, and response to, type 1 IFNs

Recognition of intracellular nucleic acids by innate receptors is pro-inflammatory

Nat Rev Rheum 6:146 2010

Tissue damage

FcγRC4, C1q

MHCBANKBLK

PTPN22IL10

PCDCD1FcRIIBTLR7

IRF5IRAK1ITGAMTLR7

TNFAIP3

DNAseI TREX1

Plasmacytoid DC

Myeloid DC

T Cell

Type I IFN Cytokines

IgG immune complexes

Antigen presentation Costimulation

Proliferation and Memory

Autoantibodies

BCR

FCR

TLR

TLR

BAFF/APRIL

Cytokines

Apoptotic cell debris, NETs, microparticles

TCR

Nucleic acid digestion

Plasmacytoid DC

Myeloid DC

T Cell

Type I IFN Cytokines

IgG immune complexes

Antigen presentation Costimulation

Proliferation and Memory

Autoantibodies

BCR

FCR

TLR

TLR

BAFF/APRIL

Cytokines

Apoptotic cell debris, NETs, microparticles

TCR

Nucleic acid digestion

Other genetic contributors to SLE

Knowledge gained from genetic studies

• Pathogenic pathways identified (TLRs, IFNs, lymphocyte activation).

• May pave the way to personalized interventions – e.g. can be used to identify those at risk of drug

toxicity

• Only a small contribution to genetic risk has been identified using GWAS.

• Other approaches will be required to identify rare alleles with a higher degree of susceptibility risk.

B cell fate decisions

Naive

Extrafollicular

Short-lived PC

GC

Short-lived PC

Long-lived PC

Memory

High

affini

ty

Low affinity Low affinity

High affinityIL-1

2, C

D40,

TLR9

IFNa,TLR4 (MyD88)IRF4, B

limp1

Complement

Receptor

IFNa

BAFF

BAFF/APRIL

EBI2Bcl6

Blimp1

BAFF/APRIL Stromal factors

PCTolerance

checkpoints

The germinal center is a specialized microenvironment

1

2

EF focus

3

4

(CD4 T cells)

Effector T cell subset differentiation and plasticity

Science. 2010 Feb 26;327(5969):1098-102.

Abnormal T cell signaling in SLE

NEJM 365: 2110. 2012

IL-2 IL-17

Ca2+

Replacement of with Fc

Use of Syk instead of

ZAP70

Preformed rafts

Local organ damage

Soluble inflammatory mediators, autoantibodies

Complement and Fc receptor mediated inflammatory cascades

Vascular injuryDamage to blood brain barrier allows antibody entry

Stress, other environmental factors damage BBB

Inflammatory cell infiltrates, hypoxia, fibrosis

Atherosclerosis Parenchymal toxicity

Genetic risk for tissue injury

Traditional risk factors

Thromboses

Soluble inflammatory mediators, autoantibodies

Complement and Fc receptor mediated inflammatory cascades

Vascular injuryDamage to blood brain barrier allows antibody entry

Stress, other environmental factors damage BBB

Inflammatory cell infiltrates, hypoxia, fibrosis

Atherosclerosis Parenchymal toxicity

Genetic risk for tissue injury

Traditional risk factors

Thromboses

SLE is associated with damage to multiple organs

Endothelial dysfunction occurs in SLE

• Reduced circulating progenitors

• Increased circulating endothelial microparticles

• Anti-endothelial antibodies

• Differentiation and repair defects in mice

• Increased cardiovascular risk – a major cause of mortality

– 10 yr risk for a coronary event or stroke is 7.5-17 fold increased

Tissue injury is due to inflammation, hypertension, stress, hypoxia and

tissue remodeling/fibrosis

Mesangial cell activation

Endothelial cell activation

Antibody

ComplementThrombosis

Lymphocytic and DC infiltration

Intrinsic macrophage activation

Endothelial cell activation/death

Hypoxia

Tubular atrophy

Fibrosis

PP

Podocyte injury

Soluble mediators

M

Mesangial cell activation

Endothelial cell activation

Antibody

ComplementThrombosis

Lymphocytic and DC infiltration

Intrinsic macrophage activation

Endothelial cell activation/death

Hypoxia

Tubular cell activationTubular atrophy

Fibrosis

PP

Podocyte injury

Soluble mediators

M

Mesangial cell activation

Endothelial cell activation

Antibody

ComplementThrombosis

Lymphocytic and DC infiltration

Intrinsic macrophage activation

Endothelial cell activation/death

Hypoxia

Tubular atrophy

Fibrosis

PP

Podocyte injury

Soluble mediators

M

Mesangial cell activation

Endothelial cell activation

Antibody

ComplementThrombosis

Lymphocytic and DC infiltration

Intrinsic macrophage activation

Endothelial cell activation/death

Hypoxia

Tubular cell activationTubular atrophy

Fibrosis

PP

Podocyte injury

Soluble mediators

M

Heterogeneity among different models

Inflammation

Hypoxia, ER-Stress, Apoptosis

Cytokine, T-cell, macrophages

NZB/NZW NZM2410NZW/BXSBpos reg. cytokine biosynthetic process immune response-activating signal transduction cellular response to unfolded protein

immune system process immune system process endoplasmic reticulum unfolded protein response

regulation of cytokine production immune response response to biotic stimulus

cytokine production immune response-regulating signal transduction positive regulation of NF-kappaB activity

regulation of cytokine biosynthetic process cytokine production positive regulation of cell migration

immune response response to molecule of bacterial origin response to molecule of bacterial origin

glycerol ether metabolic process immune response-cell surface receptor signaling response to organic substance

T cell activation regulation of peptidyl-tyrosine phosphorylation response to chemical stimulushemopoietic or lymphoid organ development lymphocyte proliferation positive regulation of cell motion

response to bacterium mononuclear cell proliferation response to other organism

Top ten Biological processes enriched in the shared network (Z-score >10)

CD45

CCL5

Fn1

EGF

C Berthier and M Kretzler

Proteinuric mice vs human SLE nephritis

ITGAM

CD68

CXCL10

IL1

VCAM-1

Treatment

Therapeutic targets suggested by an enhanced understanding of biology

Genetics + Trigger

Anti-IL-21/IL-17

Anti-TNF

INNATE

ADAPTIVE

Bas

Neut

Success in SLE has been limited

DNAse I – failed

Anti-IFN - ongoing

LJP toleragen – failed

Rituxan - failed

Atacicept – toxicity

Belimumab – modest success

Anti-CD22 - ongoing

Anti-CD40L – failed (toxicity)

Abatacept – failed?

Anti-IL6 – toxicity

Anti-TNF - toxicity

Innate

B cell

Costimulation

Cytokines

Challenges in developing therapies for SLE

• Stage– New cell types– New pathways– Recruitment of

multiple inflammatory molecules

– Irreversible tissue injury/fibrosis

• Heterogeneity• Homeostatic

mechanisms

0 10 20 30 40 500

25

50

75

100

Ad-LacZAd-BAFF-R-IgAd-TACI-Ig

Age (weeks)

Per

cen

t su

rviv

al

Ramanujam, M. A&R 62(5):1457-68. 2010.

Response to remission induction is strain and context dependent

0 25 50 75 100 125 1500

25

50

75

100

Control

TACI-Ig Day 21

Days after adenovirus

Per

cen

t Su

rviv

al

NZB/W IFNα induced NZM2410

Liu, J. Immunol 187;1506-13. 2011.

Conclusions – the biology of SLE is complex

• SLE is a multigenic disease that involves loss of tolerance involving both innate and adaptive immune pathways.

• Multiple triggers are likely to be involved in disease initiation and perpetuation.

• Continuous exposure to excess nucleic acid containing material amplifies the disease process.

• Chronic inflammation can set up aberrant activation pathways and maintain the inflammatory phenotype of long-lived effector cells.

The future looks bright

• There are many new therapeutic opportunities directed at both systemic autoimmunity and local inflammation.

• Improvements in clinical trial design together with integration of genetic and biomarker information are being addressed using large patient cohorts.

• These strategies, together with discovery based approaches using appropriate animal models should translate into a decrease in morbidity and mortality in SLE patients in the coming decades.

AcknowledgementsMicroarrays• Weijia Zhang• Erwin Bottinger• Mount Sinai NYSystems biology• Celine Berthier• Matthias Kretzler• University of Michigan and

ERCBRenal Pathology• Mike Madaio• Medical College of Georgia

Gene expression• Ram BethunaickanMouse therapies• Zheng Liu• Weiqing HuangMice• Haiou Tao• Ingrid Solano

Rheuminations