Intestinal immune system and responses to antigens...peristaltism Polymorphonuclears M M Peyer’s...
12
Intestinal immune system and responses to antigens CEM15 May 2010 Institut Pasteur [email protected] Host-environment interfaces 1,75m2 100-200g/j dietary proteins Microbiota 10 14 bacteries 130 m2 Infectious diarrhea 1.8 millions deaths/ year 300 m2 Pulmonary infections 3 millions deaths/year Allergens, polluants
Transcript of Intestinal immune system and responses to antigens...peristaltism Polymorphonuclears M M Peyer’s...
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
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
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
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
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
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
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
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
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
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 Th
1Th2
Th17 DC
TSLP,IL-33IL-4
IL-12
IL-6IL-23
Retrocontrol/brake
FoxP3
Retinoic acidTGFβ
ParasitesExtracellular
Bacteriafungi
?
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
Host immune system Microbes (genetics)Pathogens/opportunists/dysbiosis
HygieneAntibioticsVaccines
(local/systemic protection)
Host genetics
Inheritedmonogenic diseases
Poygenic diseases
