disease causation- the big picture
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Advances in the pathogenesis and management of SLE Anne Davidson MBBS Feinstein Institute for Medical Research, Manhasset NY. Chance/Fate. Environment. Genetic risk. Innate and adaptive immune responses. Disease phenotype. Amplification. Target organ damage. - PowerPoint PPT PresentationTRANSCRIPT
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Advances in the pathogenesis and management of SLE
Anne Davidson MBBSFeinstein Institute for Medical Research,
Manhasset NY
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Disease causation- the big picture
Disease phenotypeAmplification
Target organ damage
Genetic risk Environment
Chance/Fate
Innate and adaptive immune responses
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Systemic autoimmunity
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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
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The source of nucleic acids in SLE
J Exp Med. 1994;179:1317-30
DNA
Ro
DNA LL37
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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
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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
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Immunity. 2010 Mar 26;32(3):305-15
Endosome
Nucleus
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SLE associated genes with definitive statistical evidence on GWAS
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Many lupus associated genes are involved with both the induction, and response to, type 1 IFNs
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Recognition of intracellular nucleic acids by innate receptors is pro-inflammatory
Nat Rev Rheum 6:146 2010
Tissue damage
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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
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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.
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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
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The germinal center is a specialized microenvironment
1
2
EF focus
3
4
(CD4 T cells)
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Effector T cell subset differentiation and plasticity
Science. 2010 Feb 26;327(5969):1098-102.
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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
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Local organ damage
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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
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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
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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
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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)
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CD45
CCL5
Fn1
EGF
C Berthier and M Kretzler
Proteinuric mice vs human SLE nephritis
ITGAM
CD68
CXCL10
IL1
VCAM-1
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Treatment
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Therapeutic targets suggested by an enhanced understanding of biology
Genetics + Trigger
Anti-IL-21/IL-17
Anti-TNF
INNATE
ADAPTIVE
Bas
Neut
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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
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Challenges in developing therapies for SLE
• Stage– New cell types– New pathways– Recruitment of
multiple inflammatory molecules
– Irreversible tissue injury/fibrosis
• Heterogeneity• Homeostatic
mechanisms
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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.
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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.
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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.
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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