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Het immuunsysteem: het brein achter de huid
H. Bing Thio
Dermatologie, ErasmusMC, Rotterdam
NVPD Symposium Stress die onder je huid gaat zitten
VRIJDAG 26 JANUARI 2018
AMC te Amsterdam
Psychiatriegebouw zaal PA3-102
Disclaimer & Disclosure
The views as expressed in these slides are those of Hok Bing Thio.
The information shown in this slide deck may be outside the current indications of presented drugs. Please refer to the complete SmPCs for valid prescribing information.
Hok Bing Thio has been a consultant and invited speaker for Dr. Reddy, Biogen/Idec, Janssen, AbbVie, Celgene, Biologix, Pfizer, MSD, Galderma, Leopharma, Lilly, Almirall and Novartis. He has received educational and research grants from AbbVie, Celgene, Janssen and Biogen/Idec.
M. Aragona and C. Blanpain/Nature 2017
T. Hirsch et al. Regeneration of the entire human epidermis using transgenic stem cells. Nature. Published online November 8, 2017. doi: 10.1038/nature24487.
A boy with a genetic disease called junctional epidermolysis bullosa lost the upper layer of his skin from most of his back and legs from an infection. Red shows where skin was missing. Green indicates blistered areas. People with this condition are called “butterfly children” because their skin is as fragile as the insect’s wings.
T. Hirsch et al. Regeneration of the entire human epidermis using transgenic stem cells. Nature. Published online November 8, 2017. doi: 10.1038/nature24487.
Ujiie, Hideyuki. Journal of Dermatological Science , 2015, Volume 78 , Issue 1 , 5 - 10
Patient Talk-
CME Medscape: Introducing JAK-inhibitors in Rheumatoid ArthritisRonald van Vollenhoven, MD, PhD; Roy Fleischmann, MD, MACR; Andrea Rubbert-Roth, MD, PhDCME Released: 8/25/2017. Valid for credit through: 8/25/2018
This grandround ( 9 January 2017)was first presented by Aleksandra Filipovic, from the Department of Surgery and Cancer, division of cancer, Imperial College, London, as a live webcast for the European School of Oncology. It is edited by Susan Mayor.
Dermatologic toxicities:
Dermatologic toxicities are the most common irAEs reported with both anti–CLTA-4 therapy (50%) and anti–PD-1 agents (up to 40%).
The rash occurs weeks or even months after initial therapy (not during infusion) and responds well to corticosteroids .
Occasionally, severe rashes can be seen, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or full thickness dermal ulceration.
https://www.inpractice.com/~/media/Global/Partners/ONS.pngAuthor: Gail Wilkes, Section Editor: Marlene SanFilippo, Editors In Chief: Dawn Camp-Sorrell, ;Rebecca Hawkins, Last Reviewed: 6/6/17 (What's New)
Andreas Bergthaler& Jörg MencheNature Immunology 18, 481–482 (2017) doi:10.1038/ni.3727 Published online 18 April
2017
The immune system as a multi-layered social network.
Wendi Kuebler
The influence of skin microorganisms on cutaneous immunityYasmine Belkaid & Samira Tamoutounour. Nature Reviews Immunology 16, 353–366 (2016)
Florence Abdallah, Lily Mijouin, and Chantal PichonMediators Inflamm. 2017; 2017: 5095293. Published online 2017 Oct 18. Skin Immune Landscape: Inside and Outside the Organism
https://childrenallergyclinic.wordpress.com
BioSpectrum-sphweb.bumc.bu.edu-
courses.lumenlearning.com-
Innate cell PRRs/activating receptors Products/molecules Innate function
DC (general) TLRs, CLRs, RLRs, NLRs Various Immune sentinels; proinflammatory or anti-inflammatory effects
LCLangerin/CD207 (CLR) FcγR and FcεR DEC205
Chemokines CCL2, CCL17 and CCL22 Attraction of other leukocytes to sites of inflammation
Surface molecules ICOS-L Inhibition of T-cell responses (immune tolerance)
Enzyme IDO Immunoregulatory activity
dDC (mDC) TLR2, TLR4, CD206, DC-SIGN (CD209) CCL17, CCL22 Attraction of other leukocytes to sites of inflammation
TNF and iNOS Proinflammatory effects
dDC (pDC) TLR7, TLR9 Type 1 IFNs Immunity against viral infections and promote function of T-cells, B-cells, NK cells
KeratinocyteTLR1, TLR2, TLR4, TLR5, TLR6 (cell surface) and TLR3, TLR9 (endosomes)
AMPs: β-defensins and cathelicidin Anti-microbial defence
AMP: LL37 Loss of immune tolerance
IL-1, IL-6, IL-10, TNF, TGFβ Broad range of effects
CXCL1, CXCL8Mediate attraction of neutrophils and other immune cells to inflamed skin via CXCR2 expression
Neutrophil TLRs (excluding TLR3 and TLR7)
IL-1α, IL-1β, TNF, IL-6 Host defence
Chemokine CXCR2Migration towards CXCL1- and CXCL8-expressing keratinocytes in inflamed skin
Adhesion molecules L-selectinand LFA-1 (αLβ2)
Promote neutrophil rolling, adhesion and diapedesis for recruitment to skin
AMPs: cathelicidins, lysozyme, α-defensins Direct microbicidal activity
Proteinases: cathepsin G, neutrphil elastase and proteinase 3/myeloblastin
Contain acid hydrolases to degrade bacterial components
Proteins: lactoferrin, transcobalamin II, NGAL and calpotectin
Sequester essential nutrients to limit bacterial growth
Mann ER, Smith KM, Bernardo D, Al-Hassi HO, Knight SC, et al. (2012) Review: Skin and the Immune System. J Clin Exp Dermatol Res S2:003. doi: 10.4172/2155-9554.S2-003
Classically activated macrophage
TLRs (T-cell/NK cell-derived IFNγ and macrophage-derived TNF needed in combination with TLR ligation for macrophage activation)
IL-12 Induces IFNγ production from T-cells and NK cells
TNF Activates macrophage (second signal)
IL-23 Promotes inflammatory immune responses
Toxic intermediates (NO and ROI) Bactericidal activity
Alternatively activated macrophage
TLRs (CD40/CD44 signalling can occur instead of TLR ligation). FcγR ligation by IC required in combination with TLR ligation for activation
IL-10/no IL-12/no toxic intermediates Potent anti-inflammatory effects
G-CSF Anti-inflammatory effects via DC modulation
Fibronectin, βIG-H3 Fibrogenesispromoting tissue repair and collagen formation
Arginine Polyamine and proline synthesis promoting cell growth and tissue repair
Mast cellTLRs (murine skin MC express TLR3, TLR7, TLR9)
TNFα, IL-1, IL-6, IL-10, lipid mediators (PG and LT)
Contribute to allergic and inflammatory responses
Chemokines Recruitment to skin
NK cellNKG2A, NKG2D (stressed/dying cells) TLR3, TLR9 (exogenous microbes)
IFNγ, TNFα Cytotoxicity and inflammation
IL-22 (in response to IL-23) AMP production, host defence, constraint of inflammation
IL-17 (in response to zymosan) AMP production and host defence
Chemokines CXCR3, CCR5 and CCR6 Migration towards CXCL10, CCL5 and CCL20 on keratinocytes of inflamed skin
NKT cellInvariant TCRα chain combined with limited set of TCRβ chains
IFNγ, IL-4, IL-2, IL-5, IL-10, IL-13, TNFα Inflammatory and allergic responses
Perforin, granzymes, FasL, TRAIL, granulysin Cytotoxicity
γδ T-cell
TLRs(microbial recognition) Vδ1 receptor (stressed/dying cells and tumour cells) NKG2D (stressed/dying cells and tumour cells)
IL-2, IFNγ, TNFα Inflammation
CCL3, CCL4, CCL5, XCL1 Chemotaxis to recruit cells to site of damage
KGF Tissue repair/wound healing
IGF-1, IL-2 Epidermal maintenance and development
IL-17 Host defence
Mann ER, Smith KM, Bernardo D, Al-Hassi HO, Knight SC, et al. (2012) Review: Skin and the Immune System. J Clin Exp Dermatol Res S2:003. doi: 10.4172/2155-9554.S2-003
David Artis& Hergen Spits. Nature 517, 293–301 (15 January 2015)
The biology of innate lymphoid cells
Stephen A. Newland et al.
Nature Communications
8, Article number: 15781
(2017)
doi:10.1038/ncomms1578
1
Received:27 May
2016Accepted:27 April
2017 Published online:07
June 2017
Type-2 innate
lymphoid cells
control the
development of
atherosclerosis in
mice
Figure 6: ILC2
derived IL-5 and
IL-13 are required
to reduce
atherosclerosis.
Florence Abdallah, Lily Mijouin, and Chantal PichonMediators Inflamm. 2017; 2017: 5095293. Published online 2017 Oct 18. Skin Immune Landscape: Inside and Outside the Organism
Yasmine Belkaid& Samira Tamoutounour. Nature Reviews Immunology 16, 353–366 (2016)
IL-12
Crohn's Doesn't Live Here Anymore
https://www.studyblue.com/notes/note/n/medim-1-study-guide-2015-16-shnyra/deck/15146053
Pathogen Strategies to Evade Innate Immune Response: A Signaling Point of ViewChapter · June 2012. In book: Protein Kinases, Chapter: Pathogen Strategies to Evade InnateImmune Response: A Signaling Point of View, Publisher: InTech, Editors: Gabriela Da Silva Xavier, pp.123-164
Tomotaka Mabuchi et al. Journal of Dermatological Science. Volume 65, Issue 1, January 2012, Pages 4–11
Less activeimmune system:Immunodeficiency
Overactive immune system
https://www.studyblue.com/notes/note/n/sm-255/deck/17228387
https://www.expmedndm.ox.ac.uk/principal-investigators-2/project/genetic-defects-and-immune-dysregulation-in-patients-with-early-onset-inflammatory-bowel-disease
ScienceMedia 2017
Southern African Journal of HIV Medicine
Chantal Mathieu. IBMS BoneKEy (2011) 8, 178–186
