Psoriasis Immunology and Pathogenesis Christoph Schlapbach...Psoriasis - Immunology and Pathogenesis...
Transcript of Psoriasis Immunology and Pathogenesis Christoph Schlapbach...Psoriasis - Immunology and Pathogenesis...
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Psoriasis -
Immunology and Pathogenesis
Selected topics in Clinical Immunology
Christoph Schlapbach MD, PhD
Department of Dermatology
University of Bern
Switzerland
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Boehncke, Lancet, 2015 / Nestle, NEJM, 2009
Definition of Psoriasis
Genetics
Immune system
Innate IS
Adaptive IS
Environmental factors
Skin manifestations
Joint manifestations
Comorbidity
Quality of life
Metabol. disease
Chronic - relapsing
Common disease
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Goff KL, BJD, 2015 / www.cdc.gov
Prevalence
Prevalence world wide: 2%
North America / Europe: up to 4% Lapps/Africa/Asia: 0.4 – 0.7%
Prevalence Asthma world wide: 4.5% - 14%
Prevalence Rheumatoid Arthritis world wide: 0.4 – 1.3%
Ethnicity? Climate? Sun exposure?
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Schön, NEJM, 2006 / Reich K, JEADV, 2009 / Sugiura K, J Dermatol Sci, 2015 /
Epidemiology: Good and bad news
80% mild psoriasis (topical treatment only)
75% onset before 40 years of age
5 - 20% psoriasis arthritis
nail changes: 50% at diagnosis, 70% life time
80% psoriasis of the scalp (most frequent localisation)
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Clinical face of psoriasis
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Clinical face of psoriasis
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?
Clinical face of psoriasis
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Abnormal differentiation and hyperproliferation of keratinocytes
Infiltration of inflammatory cells Increased dermal blood vessels
Pathological hallmarks of psoriasis
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Normal & psoriatic skin
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The skin immune system
Nestle, Nat Rev Immunol, 2009
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Schlapbach, Semin Immunopathol, 2016
Immuno-pathogenesis of psoriasis
pDC
Self-DNA LL-37
IL-1α/β TNFα IL-6
mDC
IL-8
Danger signals
IFNα
mDC
IL-17
Lymph node
Mph
Th22
iDC
IL-22
IL-12
IL-23
Th1
Th17
IFNγ TNFα
Th17
IL-17
IL-17
Th17 Th1
IL-1 IL-6 IL-23
IL-12
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Boehncke, Lancet, 2015
Trigger factors
Trauma
Drugs
Infections
Occupational factors Behavioural factors
Streptococci
HIV
Koebner phenomenon
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Genetics & Pathogenesis
Genetics
Immune system
Innate IS
Adaptive IS
Environmental factors
Skin manifestations
Joint manifestations
Comorbidity
Quality of life
Metabol. disease
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Boehncke, Lancet, 2015
Genetics of psoriasis
Population studies
1st/2nd degree relatives: Higher incidence of psoriasis
Concordance rate in monocygotic twins =
3-times higher than in discordant twins
Type I: positive family history – more severe course
Type II: negative family history – milder course
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Mahil SK, Dermatol Clin, 2015
Genetics of psoriasis
Genetic studies
>40 susceptibility loci are associated with psoriasis
Candidate genes suggest key role for
• adaptive immunity • innate immunity • skin barrier functions
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Hüffmeier U, Nat Gen, 2010
Genetics of psoriasis
PSORS1
HLA-Cw6
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Barker J & Krueger JG, KOM, 2015
Genetics of psoriasis
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TH17
TH2
TH1
Sallusto, Eur J Immunol, 2009
T helper (TH) cells
IFN-γ TNF-α
IL-17
Intracellular pathogens
parasites
Extracellular pathogens
Function Cytokine profile Target
macrophages
eosinophils
neutrophils
IL-4 IL-5 IL-13
naive
Polarization
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Sallusto, Eur J Immunol, 2009
T helper cell subsets
TH17
IL-23R
TH2
TH1 IFN-γ TNF-α
IL-17
Psoriasis
Allergy
Psoriasis
Pathology Defining properties
IL-4 IL-13
naive
Polarization
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Boyman et al. J Exp Med. 2004;199: 731
Xenotransplantation models
1. Non-lesional human skin from healthy or psoriasis donor
2. Engrafted onto immuno-compromised mice
3. Spontaneous development of psoriatic phenotype (psoriasis donors but not healthy donors)
4. Blocking of T cells lead to inhibition of psoriasis development
Day 0
anti–human CD3 mAb
Role of T cells in psoriasis
Boyman, J Exp Med, 2004
CD3
Day 56
CD3
CD3
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• Infiltrate:
- memory-effector T cells
CD4 DC, macrophages
CD8 keratinocytes
Krueger JG. J Am Acad Dermatol 2002; 46: 1
Nickoloff et al. J Invest Dermatol. 1998; 110, 459-460
CD4 > CD8
CD8 > CD4
• T cells are activated - CD69, CD25, HLA-DR
CD 69
TCR
TCR
TCR
T cell TCR TCR
• clonal T cell expansions
- antigen-specific stimulation
Role of T cells in psoriasis
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What is the antigen ?
The 1 million dollar question in psoriasis
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• -haemolytic streptococci can trigger psoriasis
• T cells cross-react with epitops which are common to streptococcal M protein and keratins
TCR
TCR
TCR
T cell TCR TCR
Putative antigen(s)?
Gudjonsson, Clin Exp Immunol 2004 / Baker, Scand J Immunol, 2003
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DC
Signal 1: Antigen
Signal 2:
- Co-stimulatory molecules
- Adhesion molecules
CD28
CD2
LFA1
CD80
LFA3
ICAM1
Signal 3:
- Cytokines (IL-2, IL-12, IL-23,…)
T cell
Innate immunity is critical for T cell activation
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Psoriatic skin is highly infiltrated by dendritic cells (DC)
- plasmacytoid DC (BDCA-2)
- myeloid DC (CD11c, BDCA-1-)
Innate immunity in psoriasis
Abrams, J Exp Med, 2000 / Lowes, PNAS, 2005 / Zaba, J Invest Dermatol, 2009
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Activation of DC and production of cytokines
Schlapbach, Semin Immunopathol, 2016
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Day 0
Day 35
Anti-BDCA-2
Xenotransplantation models: - Psoriasis is inhibited by anti–BDCA-2 - fully restored by addition of human IFN-
Nestle et al. J Exp Med. 2005; 202: 135
Anti-BDCA-2 + IFN
Key cytokines in psoriasis: IFN-α
Boyman, J Exp Med, 2004
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• Enhanced expression in
- skin
- joints
- serum (correlates with activity)
• Produced by multiple cells
- DC, macrophages
- T cells
- mast cells
- keratinocytes, endothelial cells
Key cytokines in psoriasis: TNF-α
TNF-a
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TNF
Stimulation of
cytokines/ chemokines
Keratinocyte activation
Adhesion molecules
Neovascularisation Recruitment of further
leucocytes
Key cytokines in psoriasis: TNF-α
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TNF
Etanercept
Adalimumab
Infliximab
TNF Antagonists
Modulation of key cytokines
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before Infliximab on Infliximab since 3 years
Infliximab (anti-TNF-α Antibody)
Dept. of Dermatology, Inselspital, Bern University Hospital
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IL-12 IL-23
Key cytokines in psoriasis: IL-12 and IL-23
Lee et al. Exp Med. 2004 / Yawalkar et al., J Dermatol Science, 2009
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Sallusto, Eur J Immunol, 2009
T helper cell subsets
TH17
IL-23R
TH2
TH1 IFN-γ TNF-α
IL-17
Psoriasis
Allergy
Psoriasis
Pathology Defining properties
IL-4 IL-13
naive
Polarization
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1. Blauvelt A. J Invest Dermatol. 2008;128: 1064
• IL-12 and IL-23 bind to specific receptors on T cells and natural
killer cells
• Strongly influence T cell differentiation and activation
p40
p35
p40
p19
IL-12 & IL-23: heterodimers with common p40 subunit
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Th1 IFN
TNF
Adapted from: Lowes MA, et al. Dermatol Clin. 2004; 22:349
iNOS (NO)
IL-8
MIG, IP-10
VEGF
MHC Class II
ICAM-1
VCAM-1 Keratinocyte and
endothelial cell activation
Neovascularisation
T cell influx
Neutrophil influx
Vasodilation
Th1 cytokines: inflammatory processes in psoriasis
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Th17
IL-17
IL-22
TNF
Aggarwal S, Gurney AL. J Leukoc Biol. 2002; 71:1
Monocyte and neutrophil recruitment
Neovascularisation
Vasodilatation
T cell influx
Keratinocyte hyperplasia
MCP-1
Gro-
IL-8
G-CSF
GM-CSF
IL-6
PGE2
ICAM-1
VCAM-1
Th17 cytokines: inflammation and keratinocyte hyperplasia
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Ustekinumab
• Anti-IL-12/Il-23 p40
Modulation of key cytokines
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Images courtesy of the PHOENIX 2 Investigators
week 12 week 52 Before Ustekinumab
Ustekinumab (anti-p40-Ab)
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• Activation of DC and T cells
Th17
Th1
IL-12
IL-23
• Perpetuation of inflammation
• Stimulation of keratinocytes
• Neovascularisation
• Recruitment of further leucocytes
IFN
TNF
Summary: Key steps in the immunopathogenesis
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Schlapbach , Semin Immunopathol, 2016
Immunogenetics of psoriasis
Th1
Th17 pDC
Th17 Th1
Mph
Th22
iDC
Self-DNA LL-37
IL-1α/β TNFα IL-6
mDC
IL-8
mDC IL-1 IL-6 IL-23
IL-12
IFNα
IL-17
IFNγ TNFα
IL-22
IL-12
Th17
IL-17
IL-17
IL-23
Danger signals
Lymph node
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Thank you for your attention