intestinal immune system and responses to antigens...intestinal immune system and responses to...
TRANSCRIPT
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Intestinal immune systemand responses to antigens
CEM15 May 2010 Institut [email protected]
Host-environment interfaces
1,75m2
100-200g/j dietary proteins
Microbiota 1014 bacteries
130 m2
Infectious diarrhea1.8 millions deaths/ year
300 m2
Pulmonary infections3 millions deaths/year
Allergens, polluants
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MICROBIOTA AND HOST IMMUNE SYSTEM
Intestine Floranutrients
Commensalism…
Nutrients (colonocytes)Post-natal maturation (digestion)
Fat metabolismBehaviour
(Gordon et coll)
Barrier against pathogens
300 m300 m²²
Si vis pacem, para bellum
« Immune barrier »
1014 bacteria (ileum, colon)symbionts
Flora Intestine/hostMutualism…
Maintain/restore homeostasisNecessary for organ/barrier function
Handle relationships with commensalsAvoid inappropriate responses
against non infectious antigens (allergens)
Fight against local agression by pathogens
Avoid systemic dissemination of pathogens
IMMUNE SYSTEM AND INTESTINE
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THE HOST TOOL BOX
1012 lymphoid cells/m intestine
Epithelial barrier
Adaptive immunity
Macrophages
Innate defenses
Dendritic cellsPhysical / chemical
barrier
Immunological sensorand regulator
Target of effector cells
Polymorphonuclears
Hematopoietic cellspatrolling/migration/recruitment
INTESTINAL EPITHELIAL CELLS
IL13, IL-17,IL-22
Luminal Sensor
NF-kB
TLR
Nod/IPAFATG16L1…
Luminal Sampler
INNATE/ADAPTIVE IMMUNE CELLS
PHYSICAL/CHEMICAL BARRIER
Target of immune cells
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Johansson et al PNAS 2008
THE EPITHELIAL CELLS: A PHYSICAL BARRIER
Bacteria (Eub333) DAPI
WT mice Muc2-/- mice colitis
Swidsinksi et al 2005 J Clin Microb
Crohn’s disease/pathogens
Bacteria
Modulable : bacteria, parasites (IL-13,)
GOBLET CELLS
Bevins Current Op Gastroenterol 2004
Lehrer Nature Immunol 2004
Hooper LV
Pamer E. Deleterious impact of ATB
ββββ-defensinsHB-D1/HB-D2,3Cathelicidins (LL37, Cramp )
α-defensinsLysosyme
PLA2
Angiogenin 4Reg III β,γ,δ
Matrilysin
EPITHELIAL CELLS: A CHEMICAL BARRIERconstitutive/ inducible
TLR/NFkB NOD2TLR
IL22 (stat3)T/NK cells
Pamer E. Nature 2008 Deleterious impact of ATB
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THE EPITHELIAL CELLS : SENSOR/SWITCH
NF-kB
TLR
Nod1/2NALP/ IPAF
ReceptorsFor extrinsic signals
(PAMPs/MAMPs)Activating
signals
Negative signals
Host: Inflammation/homeostasisControl of niches by microbes ?
Commensals
Pathogens
Intracellularactivating cascades
DEFENSINS versusPROINFLAMMATORY CYTOKINES
Recruitment of PMN/MACROPHAGES
ColitisadenoK
Xiao H et al Immunity 2007Nenci et al Nature 2007
with endogenouscheck-points
IkB
SIGIRR
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1012 lymphoid cells/m intestine
Epithelial barrier
Adaptive immunity
Macrophages
Innate defenses
Dendritic cells
dialogue host-microflora HOMEOSTASIS
mucusdigestive secretions
biliary salts , Ezperistaltism
Polymorphonuclears
MM
Peyer’sPatches
ILF
Thoracic duct
Bone
blood
Effector site:
The adaptive intestinal immune system
Inductive siteOrganized lymphoid tissue
MesentericLymph nodes
IgA plasma cellsMature T cells
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MM
Development of the adaptive intestinal IS
Genetic programme
PP, MLN
cryptopatches
Antenatal period D8 (mice)Birth Post natal period
ILF (NOD1)
Flora-driven maturation
IgA
GC
PP
T
Pathogen-driven activation
INTESTINAL ADAPTIVE IMMUNE RESPONSES
MM
Innate
NF-kB
TLR
TLR
Nod/IPAFATG16L1…
Nod/IPAFATG16L1…
Rescigno et al
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INTESTINAL ADAPTIVE IMMUNE RESPONSES
NF-kB
TLR
TLR
MM
Nod/IPAFATG16L1…
Innate
Nod/IPAFATG16L1…
SIgAAdaptive/innate ?
PLASMA CELLS IgA
INTESTINAL ANTIBODY RESPONSES
Ig synthesisLamina propriaPlasma cells
Transepihelial transport of IgA/MBy polymeric Ig receptor
Release of SIgBinding to mucus
Exclusion of antigens
_80%
15%
5%
?? FcRn
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1-Exclusion ++in mucus 2-Neutralisation
Virus, LPS3- Elimination
of immune complexes
Barrier against Bacteria/enteroviruses/ parasites ( Giardia)preventing systemic dissemination
maintaining local homeostasis
PROTECTION BY SECRETORY ANTIBODIES
INTESTINAL ADAPTIVE IMMUNE RESPONSES
NF-kB
TLR
TLR
MM
SIgA
Tproinf
IEL (CD8)
LPL (CD4)
Treg
Nod/IPAFATG16L1…
Innate Adaptive/innate ?
Adaptive
Nod/IPAFATG16L1…
PLASMA CELLS IgA
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Defenses against virusesIntracellular bacteria
( cytotoxicity, IFN γ)
CD4+ T CELL SUBSETS
Th17Th2Th1
NaiveT cell
Treg
IL-17 (IL22) IL-10, TGFβIL-4, IL-5, IL-13IFNγ
Intracellular bacteria Th1
Th2
Th17 DC
TSLP,IL-33IL-4
IL-12
IL-6IL-23
Retrocontrol/brake
FoxP3
Retinoic acidTGFβ
ParasitesExtracellular
Bacteriafungi
?
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Mucosal Macrophages
flora
PMNsT cells
IFN-γPhagocytosis
IL-17
Barrier/defensins
IL-22
CD4
No eliminationof mycobacteria by macrophages
Systemic dissemination
Ziehl
PROTECTIVE ROLE OF CD4+T CELL RESPONSES
TIGHT CONTROL OF GUT IMMUNE RESPONSES
To maintain local homeostasis despite the microbiot aUlcerative colitis, Crohn’s disease
To avoid mucosa destruction in response to pathogen s: shigellosis
Epithelial cells, DC, tissue macrophages/regulatory T cells
TGFβ, IL-10
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Host immune system Microbes (genetics)Pathogens/opportunists/dysbiosis
HygieneAntibioticsVaccines
(local/systemic protection)
Host genetics
Inheritedmonogenic diseases
Poygenic diseases