Download innate adaptive - El Corte Inglés

Advances in the pathogenesis
and management of SLE
Anne Davidson MBBS
Feinstein Institute for Medical Research,
Manhasset NY
Disease causation- the big picture
Chance/Fate
Environment
Genetic risk
Innate and adaptive immune responses
Disease phenotype
Amplification
Target organ
damage
Systemic autoimmunity
SLE is associated with aberrant clearance of
nucleic acid containing debris
Apoptotic cell debris,
NETs, microparticles
Virus
IgG immune
complexes
FCR
Autoantibodies
BCR
Plasmacytoid DC
TLR
FCR
Neut and Basoph
TLR
Proliferation and Memory
BAFF/APRIL
Type I IFN
Cytokines
Myeloid DC
Antigen presentation
Costimulation
T Cell
TCR
Innate
Adaptive
Cytokines
The source of nucleic acids in SLE
DNA
Ro
DNA
LL37
J Exp Med. 1994;179:1317-30
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
Apoptotic cell debris,
NETs, microparticles
Virus
IgG immune
complexes
FCR
Autoantibodies
BCR
Plasmacytoid DC
TLR
FCR
Neut and Basoph
TLR
Proliferation and Memory
BAFF/APRIL
Type I IFN
Cytokines
Myeloid DC
Antigen presentation
Costimulation
T Cell
TCR
Innate
Adaptive
Cytokines
Endosome
Nucleus
Immunity. 2010 Mar 26;32(3):305-15
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
Tissue damage
Nat Rev Rheum 6:146 2010
Other genetic contributors to SLE
Apoptotic cell debris,
NETs, microparticles
FcγR
C4, C1q
Nucleic acid DNAseI
TREX1
digestion
IgG immune
complexes
FCR
Plasmacytoid DC
TLR
IRF5
IRAK1
ITGAM
TLR7
TNFAIP3
Type I IFN
Cytokines
Autoantibodies
BCR
MHC
BANK
BLK
PTPN22
IL10
PCDCD1
FcRIIB
TLR7
TLR
Proliferation and Memory
BAFF/APRIL
Myeloid DC
Antigen presentation
Costimulation
T Cell
TCR
Cytokines
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
Extrafollicular
Short-lived PC
Blimp1
BAFF/APRIL
Short-lived
PC
Naive
EBI2
Bcl6
GC
BAFF
Long-lived
PC
BAFF/APRIL
Stromal factors
Memory
Tolerance
checkpoints
PC
The germinal center is a specialized
microenvironment
1
(CD4 T cells)
2
4
EF focus
3
Effector T cell subset differentiation and
plasticity
Science. 2010 Feb 26;327(5969):1098-102.
Abnormal T cell signaling in SLE
Preformed
rafts
Replacement
of  with Fc
Use of Syk
instead of
ZAP70
Ca2+
IL-2
IL-17
NEJM 365:
2110. 2012
Local organ damage
SLE is associated with damage to
multiple organs
Soluble inflammatory mediators, autoantibodies
Complement and Fc
receptor mediated
inflammatory cascades
Vascular injury
Damage to blood
brain barrier allows
antibody entry
Thromboses
Inflammatory cell
infiltrates, hypoxia,
fibrosis
Genetic risk for
tissue injury
Atherosclerosis
Traditional risk
factors
Parenchymal toxicity
Stress, other environmental
factors damage BBB
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
Podocyte injury
Mesangial cell
activation
P
Endothelial cell
activation
P
M
Antibody
Complement
Thrombosis
Lymphocytic and DC
infiltration
Intrinsic macrophage
activation
Endothelial cell
activation/death
Tubular
Hypoxiacell activation
Tubular atrophy
Tubular atrophy
Hypoxia
Fibrosis
Soluble
mediators
Heterogeneity among different models
NZB/NZW
NZW/BXSB
NZM2410
pos 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
hemopoietic or lymphoid organ
development
regulation of peptidyl-tyrosine phosphorylation
response to chemical stimulus
lymphocyte proliferation
positive regulation of cell motion
response to bacterium
mononuclear cell proliferation
response to other organism
Cytokine, T-cell, macrophages
Inflammation
Hypoxia,
ER-Stress,
Apoptosis
Top ten Biological processes enriched in the shared network (Z-score >10)
Proteinuric mice vs human SLE nephritis
CD45
CXCL10
VCAM-1
CCL5
CD68
IL1
ITGAM
EGF
Fn1
C Berthier and M Kretzler
Treatment
Therapeutic targets suggested by an
enhanced understanding of biology
Genetics + Trigger
INNATE
Bas
Neut
Anti-TNF
Anti-IL-21/IL-17
ADAPTIVE
Success in SLE has been limited
Innate
DNAse I – failed
Anti-IFN - ongoing
B cell
LJP toleragen – failed
Rituxan - failed
Atacicept – toxicity
Belimumab – modest success
Anti-CD22 - ongoing
Costimulation
Anti-CD40L – failed (toxicity)
Abatacept – failed?
Cytokines
Anti-IL6 – toxicity
Anti-TNF - toxicity
Challenges in developing therapies
for SLE
• Stage
– New cell types
– New pathways
– Recruitment of
multiple
inflammatory
molecules
– Irreversible
tissue
injury/fibrosis
• Heterogeneity
• Homeostatic
mechanisms
Response to remission induction is
strain and context dependent
NZB/W IFNα induced
NZM2410
100
Control
TACI-Ig Day 21
75
50
25
0
Percent survival
Percent Survival
100
75
Ad-LacZ
Ad-BAFF-R-Ig
Ad-TACI-Ig
50
25
0
0
25
50
75
100
125
150
Days after adenovirus
Liu, J. Immunol 187;1506-13. 2011.
0
10
20
30
40
50
Age (weeks)
Ramanujam, M. A&R 62(5):1457-68. 2010.
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.
Acknowledgements
Gene expression
• Ram Bethunaickan
Mouse therapies
• Zheng Liu
• Weiqing Huang
Mice
• Haiou Tao
• Ingrid Solano
Microarrays
• Weijia Zhang
• Erwin Bottinger
• Mount Sinai NY
Systems biology
• Celine Berthier
• Matthias Kretzler
• University of Michigan and
ERCB
Renal Pathology
• Mike Madaio
• Medical College of Georgia
Rheuminations