Introducere in Imunologie UMF Nov 2012
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Transcript of Introducere in Imunologie UMF Nov 2012
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Aurora Salageanu
Laborator Imunitate AntiinfectioasaInstitutul Cantacuzino
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Imunitate innascuta vs. Imunitate dobindita
Recunoasterea agentului patogen
Rolul si functiile imunitatii innascute
Raspunsul imun anti-bacterian
Sistemul imun
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adaptat dupa“Microbiology and Immunology on-line”, University of South California, School of Medicinehttp://pathmicro.med.sc.edu/book/immunol-sta.htm
SISTEM IMUN
Imunitateinnascuta
(prima linie de aparare)
Imunitatedobindita
(a II-a linie de aparare)
Componente celulare
Componente umorale
Componente celulare
Componente umorale
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Celulele sistemului imun
preluat din “Microbiology and Immunology on-line”, University of South California, School of Medicinehttp://pathmicro.med.sc.edu/book/immunol-sta.htm
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preluat din “Microbiology and Immunology on-line”, University of South California, School of Medicinehttp://pathmicro.med.sc.edu/book/immunol-sta.htm
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Tesutul limfoid
preluat din “Microbiology and Immunology on-line”, University of South California, School of Medicine
http://pathmicro.med.sc.edu/book/immunol-sta.htm
Distributia organelorlimfoide
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Circulatia limfocitelor in organele limfoide periferice
preluat din “Microbiology and Immunology on-line”, University of South California, School of Medicinehttp://pathmicro.med.sc.edu/book/immunol-sta.htm
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preluat din “Microbiology and Immunology on-line”, University of South California, School of Medicinehttp://pathmicro.med.sc.edu/book/immunol-sta.htm
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Raspunsul imun fata de patogeni
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Raspunsul imun fata de patogeni
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IMUNITATE INNASCUTA
Disponibila in orice moment
(innascuta)
Intra in actiune imediat (in citeva ore) dupa
expunere la antigen
Raspuns initial pentru: • eliminare microbi • prevenire infectii
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IMUNITATE INNASCUTA
Mecanism universal de aparare fata de infectii
Prima linie de aparare a organismului
Precede raspunsul imun adaptativ
prezent la toate organismele pluricelulare
receptori si efectori ancestrali
raspunde la o mare varietate de patogeni
Distinctie perfecta self-nonself
Defecte foarte rare si in general letale
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IMUNITATE INNASCUTA
preluat din Janeway, CA, Travers, P, Walport M, Shlomchik M “Immunobiology“, New York and London: Garland Science; c20http://www.ncbi.nlm.nih.gov/sites/entrez?db=books
IMUNITATEA INNASCUTA este importanta!
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IMUNITATE
raspuns independent de antigen
receptori pt. patogeni:
codificati in genom
specificitate joasa
raspuns imediat
lipsa memorie
prezenta la toate organismelepluricelulare
raspuns dependent de antigen
receptori pt. patogeni:
generati (rearanjare genica)
specificitate inalta
raspuns lent
memorie imunologica
(expansiune clonala ly)
prezenta doar la vertebrate
SISTEM INTEGRAT
INNASCUTA / nespecifica(innate immunity)
DOBINDITA / specifica(adaptive immunity)
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Fiecare limfocit: un singur receptor (specificitate unica)
Interactia receptor-ligand activarea limfocitului
Celulele efectoare diferentiate dint-un limfocit activat:
acelasi receptor
Limfocitele cu receptori self sunt eliminate (toleranta)
Specificitatea raspunsului imun adaptativTeoria selectiei clonale
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ROL SI FUNCTII
Recunoastere
Functii efectoare
• prevenire intrare
• eliminare
Rol “instructiv” asupra imunitatii specifice
Innate immunity
microorganisme patogene
initierea si tipul raspunsului
originea si contextul atg
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ELEMENTE CONSTITUTIVE
1. Bariere anatomice
2. Componente moleculare
3. Componente celulare
Innate immunity
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Factori fizici / mecanici
1. Bariere anatomice- piele- mucoase
Innate immunity
• Functia de prevenire a intrarii microorganismelor patogene
Factori chimici
Factori biologici
• motilitate: muco-ciliara, peristaltica• mucus• fluxul fluidelor prin organism
• pH • molecule antimicrobiene
• limfocite T intraepiteliale ()• celule B-1
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2. Componente moleculare- receptori- molecule secretate
Innate immunity
Functia de recunoastere
Functii efectorii
Mol. anorganice: HCl, NO, H2O2
Peptide antibacteriene: defensine, cathelicidine, histatineProteine antibacteriene: lizozim, lactoferina, transferinaLectine: colectine, ficoline, receptori manozaComplementCitokine: IFN-/, IL-1, TNF-, CSFChemokine: IL-8, MIP, MCPReceptori TLR
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3. Componente celulare
Innate immunity
• Functia de eliminare a microorganismelor patogene
celule NK
Fagocitoza
Inflamatie
Citotoxicitate
neutrofile monocite/macrofagecelule dendritice
bazofilemastociteeozinofile
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RECEPTORI
Recunoastere imuna
INNASCUTA(innate immunity)
codificati in genom
distributie non-clonala
recunosc structuriconservate
DOBINDITA(adaptive immunity)
generati prin rearanjare genica
distributie clonala(expansiune clonala ly)
recunosc detalii de structura moleculara(epitopi)
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Recunoastere imuna
Ipoteze
selfnon-self
origine antigen / context biologic
Receptori (self vs. nonself microbian)
(Medzhitov & Janeway, 1997)
Semnale de pericol “Danger hypothesis”
(self vs. self alterat)
(Polly Matzinger, 1994)
Recunoastere “prin lipsa”(‘‘missing self”)
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Recunoastere imuna
Ipoteze
Receptori (self vs. nonself microbian)
PRR Pattern Recognition Receptor
PAMP Pathogen Associated Molecular Pattern(Medzhitov & Janeway, 1997)
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PAMP
invariabile inalt conservate specifice microbilor
(patogeni + nonpatogeni) comune pentru o clasa de microbi vitale pentru microorganisme
•lipopolizaharid •peptidoglican•acid lipoteichoic•lipoproteine•manoza•ADN•ARN dc•flagelina•pilina•zimozan
Gram-negative Gram-positive
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Pattern Recognition Receptors - PRR
Endocytic PRRs• glycosylphosphatidylinositol (gpi)-linked receptor• Scavenger receptors (SR)• C-type lectin receptors (CLR)
LPS
oxLDL; microbes Microbes; microbial moieties
Signaling PRRs• Toll-like receptors (TLR)
• NOD-like receptors (NLR)
• RIG1-like helicases (RLH)
Microbial moieties
Bacterial lipoproteins
Nucleic acids
Bridging molecules
• Collectins
• Ficolins
• Pentraxins
Sugars
Glycoproteins
Microbes; microbial moieties
(adaptat dupa Jeannin et al. “Pattern recognition receptors in the immune response againstdying cells”, Current Opinion in Immunology 2008, 20:1–8)
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Pattern Recognition Receptors - PRR
a) ENDOCITOZA Endocytic PRRs
proteina bact.
receptori manoza(lectina C)
FAGOCIT
receptori scavenger(CD36, CD68, SRB-1)
C3bglicoproteina
bact.
receptori opsonine(CR1)
Bacterie
LPS, LTAman
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Pattern Recognition Receptors - PRR
b) TRANSMITERE SEMNAL Signaling PRRs
TLRToll-like receptors
NODnucleotide-binding oligomerization domain
RIG-1retinoic acid-inducible gene-1
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Toll-like receptors (TLR) proteine transmembranare tip I conservate filogenetic (Drosophila om) domeniu extracelular bogat in leucina domeniu intracelular TIR (similar IL-1R) TLR mamifere (11-om, 13-soarece):
recunoastere PAMPs asociere cu alti TLR sau alte proteine (MD2,CD14)
Lipoproteins, lipopeptidesPeptidoglycanZymosanLPS Leptospira interrogans LPS P.gingivalisGPI (T.cruzi)LipoarabinomannanPhosphatidylinositol dimannoside(M. tuberculosis)
TLR2+(TLR1/TLR6)
LPS
Taxol
HSP60
Fibronectin
F Protein (RSV)
Flagellin CpG DNA
TLR4 TLR5 TLR9
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TLR
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Rol “instructiv” asupra imunitatii specifice
Infectie
Insecte MamifereNFkB
• Peptide antimicrobiene• iNOS (soarece)• Molecule costimulatoare• Citokine proinflamatorii
Peptide antimicrobiene
SpatzleToll
PAMP
PAMP
dorsal
TLR
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TLR: semnalizare intracelulara
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Receptori (self vs. nonself microbian)
(Medzhitov & Janeway, 1997)
Semnale de pericol “Danger hypothesis”
(self vs. self alterat)
(Polly Matzinger, 1994)
IPOTEZE
Recunoastere imuna
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Danger hypothesis
Danger signal
Naive
T cells
APC
Normal cell
Damaged cell
Signal 1 Signal 2 (costimulation)
- infection- tissue damage- stress cells- hypoxia- temperature shifts- hsp
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Recunoastere imunaIPOTEZE
- Receptori
(Medzhitov & Janeway, 1997)
- Semnale de pericol (“danger hypothesis”)
(Polly Matzinger, 1994)
- Recunoastere “prin lipsa”(‘‘missing self”)
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CelulaNK
Celulatinta
CelulaNK
Celulatinta
Absenta citotoxicitatii
Citotoxicitate
NKR
NCR Ligand activator
MHC cls I
NKR
NCR Ligand activator
Missing self
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ROL SI FUNCTII
Recunoastere
Functii efectoare
Innate immunity
microorganisme patogene
•prevenire intrare
•eliminare
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Functiile imunitatii innascute
PAMP
Stimulare PRR stimuleaza fagocitoza
induce activitate microbicida
induce citokine inflamatorii:
IL-1, IL-6, TNF- (NF-kB)
activeaza imunitatea dobindita
expresia mol. costim. (MHC cls.II, CD80/CD86)
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Functii efectorii: Fagocitoza
Distrugerea
Ingerarea
Atasarea
microorganisme patogeneChemotaxianeutrofileeosinofilemonocitemacrofagecelule dendriticelimfocite B
celule fagocitare
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Fagocitoza
independent de oxigendependent de oxigen
Mecanism
- defensine- cathepsina B- lizozim- lactoferina- enzime proteolitice
O2–
H2 O2
1O2
OClOH
Rol• eliminare a microorganismelor patogene
• prelucrare atg pt. prezentare
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Inflamatia
permeabilitate capilara
expresia mol. adeziune cel. endoteliale
diapedeza
- citokine pro-inflamatorii (TNF-, IL-1) PAMP / PRR
- vasodilatatoare- complement- bradikinine
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Citokine Macrofag activat
IL-1
- activeaza endoteliul vascular
- activeaza ly- acces cel. efect.
- activeaza endoteliul vascular
- creste permeab. vasculara
- acces cel. efect.
- activeaza ly- producere atc.
- activeaza NK- induce dif. Th1
TNF- IL-6 IL-12
EFECTE LOCALE
EFECTE SISTEMICE- febra- producere de IL-6
- febra- mobilizare metaboliti- soc
- febra- inducere proteine
faza acuta
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Chemokine proteine masa moleculara mica (8-12 kDa) rol: inflamatie, reglare raspuns imun, angiogeneza, hematopoieza,
interactie cu SNC 4 Cys pozitie conservata (punti disulfidice) structura tertiara caracteristica (1- 3, ) redundanta (receptori si celule)
CXC
monocite limfocite limfociteneutrofile
CC C CXXXC
IL-8-mo/m-fibroblaste-cel.endoteliale
NAP-2-plachete
IP-10-fibroblaste-endoteliu
SDF-1-celule stromale
MCP-1
MIP-1,
RANTES
MDC- mo/m- fibroblaste- cel.endoteliale- cel.epiteliale etc
FRAKTALKINALIMFOTAKTINA
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Functii efectorii: Rolul interferon
IFN-/
Celula infectata viral Celula neinfectata
IFN receptor
2-5 (A) Sintetaza PKR
Inhibare sinteza proteica
degradare mRNA translatie mRNA
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ROL SI FUNCTII
Recunoastere
Functii efectoare
• prevenire intrare
• eliminare
Rol “instructiv” asupra imunitatii specifice
Innate immunity
initierea si tipul raspunsului
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APC
TLR
T cell
PAMP
costimulator
CD28
MHC / peptide
TCR
Infectie
Activare
Co-stimulare: initierea raspunsului imun specific
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(adapted after Medzhitov R, Nature Reviews Immunology, 1, 2001, 135-145)
PAMP
TLR
pathogen
Endocytic PRR
Naive
T cells
CD80/86
Th1
IFN-
CD28
MHC-II TCR
IL-12
DC
Th1
IFN-
INNATE IMMUNITY
ADAPTIVE IMMUNITYcellular immune response
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Celule dendritice umane diferentiate din monocite izolate din singele periferic
Laborator Imunitate Antiinfectioasa, INCDMI “Cantacuzino”, 2006
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NIPC = Natural Interferon-Producing Cell
Immature DC Mature DC
INFECTIE VIRALA
IFN-/
Citokine imunoreglatoare: orientarea raspunsului imun specific
(Plasmacytoid precursor dendritic cells)
1/500 – 1/200 din celulelemononucleare din singele priferic Produc de 1000x mai mult IFN decitalte celule si cantitati mari de TNF• Recognition mechanism: probably TLR7, TLR9• Functie? Imunitate innascuta anti-virala; stimulare im adaptativa ?
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Nu este doar un sistem de aparare simplu, menit sa tina in loc infectia pina la interventia imunitatii dobindite
“Instruieste” sistemul imunitatii dobindite pentru a raspunde la infectii
Decizia majora de a raspunde sau nu unui antigen este luata de
imunitatea innascuta, prin receptorii codificati in genom !
Imunitate innascuta
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The Nobel Prize in Physiology or Medicine 2011 was divided, one half jointly to Bruce A. Beutler and Jules A. Hoffmann
"for their discoveries concerning the activation of innate immunity"
and the other half to Ralph M. Steinman
"for his discovery of the dendritic cell and its role in adaptive immunity"
The Nobel Prize in Physiology or Medicine 2011http://www.nobelprize.org/nobel_prizes/medicine/laureates/2011/advanced-medicineprize2011.pdf
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Raspunsul imun fata de patogeni
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CELULE “SANTINELA”: celule dendritice imature, macrofage, mastocite
- recunosc antigenul (infectia)
- induc inflamatie, activare limfocite
CELULE PREZENTATOARE DE ANTIGEN: celule dendritice, macrofage, limfocite B
- specializate in captarea, concentrarea, si prezentarea antigenelor pentrurecunoasterea de catre limfocite
LIMFOCITE
- mediatori ai raspunsului imun adaptativ (receptori specifici pentru antigen)
CELULE EFECTOARE: limfocite, granulocite, macrofage
- functia de eliminare a microbilor
CELULELE SISTEMULUI IMUN
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Bariere anatomice
Factori:- fizici/mecanici- chimici- biologici
Raspuns umoral
IMUNITATE INNASCUTA IMUNITATE DOBINDITA
Raspunsinflamator
Fagocitoza
Activare Complement
Raspuns celular
Raspunsul imun in infectii bacteriene
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Fagocitoza
Activare complement
Raspuns inflamator
Raspuns umoral (predominant)
Raspuns celular (in masura mai mica)
IMUNITATE INNASCUTA IMUNITATE DOBINDITA
Raspunsul imun in infectii cu bacterii extracelulare
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Citotoxicitate celule NK
Secretie IFN gamma
Raspuns celular
– Ly T citotoxice: liza bacterii
– Ly Th1 secretie citokine (activare
macrofage)
IMUNITATE INNASCUTA IMUNITATE DOBINDITA
Raspunsul imun in infectii cu bacterii intracelulare
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Imunitate innascuta Raspuns umoral
RECUNOASTERE IMUNA MECANISME EFECTOARE
Imunitate dobindita Raspuns celular
Cum raspunde sistemul imun la o varietate de agenti patogeni?
adaptate fiecarui tip de agent patogeninitiere & orientare
Protectie la re-infectare
MEMORIA IMUNOLOGICA
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VACCINAREACel mai mare succes al politicilor de sanatatepublica
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preluat din http://hugmeimvaccinated.org/
INFORMATII VACCINARE: http://www.cdc.gov/vaccines/default.htm