c9 ric_ nk_ apar antivir stud (fin 2014)
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Apararea antivirala
Celulele NK
RIC
Apararea antiinfectioasa Organism Reprez Fag
(II) CK (II)
NK (II)
Complement Ac neutral
CTL
VIRUSURI
•Gripă •Oreion •Pojar •Rinovirus
+++ +++ +++ +++
IFN
+++ +++ +++ +++
--- --- --- ---
+++ +++ +++ +++
+++ +++ +++ +++
BACT INTRA CELULARE
•Listeria m •Legionella •Mycobact •Ricketsia
--- --- --- ---
+++ +++ +++ +++
--- --- --- ---
+++ +++ +++ +++
+++ +++ +++ +++
BACT EXTRA CELULARE
•Staph spp •Strep spp •Neisseria •Salmonella
+++ + +
+++
--- --- --- ---
+++ + +
+++
+++ +++ +++ +++
--- --- --- ---
Apararea anti-virala
Raspunsul Imun mediat Celular Scop: 1. Apararea impotriva microbilor cu habitat
intracelular: – Celule fagocitare
– Celule non-fagocitare =>
• Recunoasterea & distrugerea celulor expun : – AgEndogene+MHC I (infectie/ tumorale): cel singenice
(proprii/self)
– Ag + MHCI ≠ : Cel allogenice (non-self) (grefe tisulare /organ)
Mecanismul de distrugere:→ Citotoxicitate
RIC: celule
I. Celule efectoare 1. specifice:T CD8+ (citotoxice, LTC)
2. ne-specifice: Natural killer (NK)
Roluri: • Recunoasterea celulelor-tinta
(mecanisme diferite)
• Distrugerea celulelor-tinta
(mecanisme similare)
II. Celule Auxiliare:
1. APC (→ TCD4⁺)
2. T CD4⁺ (TH) → TCD8⁺ (Mφ)
Rol: activarea completa a LT CD8⁺
APC
1
2
Apararea antivirala innascuta si adaptata
RI antiviral: Innascut si Adaptat
Interferoni • Structura Prot & Gp → familii:
– Tip I (α, β, ω,ξ,κ) -secretati de • celulele infectate viral • CD, • Leucocite (α) • Fibroblaste (β)
– Tip II ( γ) – secretati de
• celulele imune efectoare RIC: TH1, LTC, NK • APC: profesionale
• Stimuli: – Infectia virala (α β, γ) – Status inflamator (γ)
• Receptori: – RTip I (com) → IFN-αR1 & R2 – R Tip II (γ) →IFN-γR1 & R2
• Efecte: Similare • + transcriptiei gene ~IFN • +genei ds-RNA PKR (enzima) => blocarea sintezei proteinelor virale
IFN-regulatory factor 9=
ISRE-IFN-stimulated response elements
STAT,signal transducer & activator of transcription
Principalele functii ale familiei
IFN
1. + celulele sanatoase ― + genele → secretie PKR→ ―blocarea replicarii virale in celulele sanatoase
2. activeaza MФ 3. mobilizeaza NKs
Efectele anti-virale ale IFN α/β
1.fosforilare
2. Auto- Fosforilare
PKR PKR
eIF2α= α subunit of eukaryotic initiation factor 2
PKR=protein kinase (dsRNA-dependent)
Apararea antivirala innascuta si adaptata
RIC: celule I. Celule efectoare 1. specifice:T CD8+ (LTC)
2. ne-specifice: Natural killer (NK)
Roluri: • Recunoasterea celulelor-tinta
(mecanisme diferite)
• Distrugerea celulelor-tinta
(mecanisme similare)
II. Celule Auxiliare:
procesare Ag →MHC I, II
1. APC (→ TCD4⁺) 2. TCD4⁺ (TH) → TCD8⁺
Rol: activarea completa a LT CD8⁺
APC
1
2
remember:
Hematopoiesis
I. Celulele imunitatii innascute remember:
Celule NK
• I linie de aparare impotriva:
1. Celulelor infectate viral
2. Celulelor tumorale
3. Altor patogeni intracelulari
• Implicate in: 4. Respingerea grefei
5. Autoimunitate
6. Avortul Spontan
NK Cell
Tumor Cell
remember:
Celule NK: caracteristici (I)
Denumirea: semnalizeaza functia citotoxica
Localizari: circulante: 5-15% populatia Lf organe: splina, ficat, uter
Identificare: CD3⁻ CD56⁺ CD16⁺
CD3 ⁻ → implicat in transducerea semnalului prin TCR CD56 ⁺ → ? CAM CD16 ⁺ → receptor tip Ig FcγRIIIA (recunoaste Fc IgG→ fctie efectoarea NK (ADCC)
• 3 Subseturi – Majoritatea: CD3- CD56dimCD16+
• Contin perforine si granzyme→ citolitica • Moduleaza secretia CK
– Minoritate: CD3_CD56brightCD16- • Secreta cant ↑CK (IFNγ,TNFα, IL-10) • Activitate citolitica redusa
– Rare: CD3-CD56-CD16+
• Activitate citolitica foarte redusa • Secreta numai cant scazute de CK • ? Precursori CD3- CD56dimCD16+
Celule NK: caracteristici (II)
Receptori* Kill Activator Receptors (KAR) caracteristici Kill Inhibitor Receptors (KIR) Recunosc: celulele proprii infectate celulele proprii modificate Recunoastere: Lig (P/DAMP) → cel proprii modificate (KAR) (Nespecifica) Lig (MHC I) → cel proprii nucleate N (KIR) Activare: echilibru semnalele activatoare ~ inhibitoare Actiuni: liza celulelor-tinta secreta CK implicate in apararea antivirala
Celule NK: caracteristici (III)
Celule NK: importanta
• RIC mediat NK în infecțiile cu: 1. Arenavirus (vs coriomeningitei limfocitare)
2. Virusul herpetic (vs Herpes simplex)
3. Ortomixovirusuri (vs gripal)
4. Picornavirus (vs Coxsackie)
• Timpul de raspuns: – Răspunsurile maxime celule NK: ore / zile
– Răspunsurile maxime celule T & B: > 7zile
Vivier, E. et al. Innate or adaptive immunity? The example of natural killer cells. Science. 331, 44-49 (2011).
Receptori NK
Ce recunosc NK? • Prezenta & absenta Selfului : MHC I: HLA-A, -Bw, -Cw, -G
• Self-ul indus/ modificat: proteine care semnalizeaza stresul celular:
– HSP, – MIC-A, MIC-B, (MHC I chain-related proteins type A, B)
Fam Receptori NK
Natura
Moleculara Liganzi
Coresp.
soarece
KIR (killer Ig-like R) Superfamilia Ig HLA-A, -Bw, -Cw, -G gp49
ILT/LIR Superfamilia Ig HLA Cls Ia (-G) LRC
CD94/NKG2 (KLR) C-type lectin-like HLA Cls Ib (-E) NKC / Ly49
KAR (NKG2D, KLRK1) C-type lectin-like MIC A,B & MHC I-like NKG2D
NCR Superfamilia Ig Hemaglutinine Virale, NCR
I. C-type lectin:
CD94 (→ NKG2A) – Ligand: MHC I
– Semnal → ITIM
II. Ig-like family:
KillerIg-like R*: – Ligand: MHC I I
– Semnal→ITIM
Receptorii Inhibitori ai NK (KIR*)
Caracteristic: ITIM =Immunoreceptor Tyrosine based Inhibitor motif
Dupa Abas at al. 2012 Elsevier/Saunders
Mecanisme de Activare ai KIR
• Celulele nucleate self N (sanatoase) – Legarea ligandului (MHC I) la receptorul
NK → Da semnal inhibitor – NK „recunoaste‟ tinta drept celula self+
sanatoasa→ – NK se detaseaza fara sa lizeze celula
• Celule infectate/transformate malign – Pierderea ligandului inhibitor (MHC I)→ Nu
semnal inhibitor – NK „recunoaste‟ tinta drept celula “self
absent”/„missing self‟ – DA liza celulara: degranulare → – perforinei & granzimelor
Receptorii Activatori ai NK (KAR)
I. C-type lectin:
NKG2D: – Leaga MIC-A,B
– Semnal ≠ITAM
Caracteristic: ITAM
II. Ig-like family: CD16 (Fc γ RIIIa)
Leaga IgG Semnal→ITAM*
Dupa Abas at al. 2012 Elsevier/Saunders
Mecanisme de Activare ai KAR
• Celulele nucleate self N (sanatoase) – LIGAND: molecule stres => – Fara ligand recunoscut de KAR → Fara
semnal activator – NK “recunoaste” tinta ca fiind N,
sanatoasa → – NK se detaseaza fara sa lizeze celula-
tinta
• Celule infectate/transformate malign – Recunoasterea ligandului stres→ Da
semnal activator – NK “recunoaste” tinta ca fiind
• “self indus”: ( MIC-A, B, HSP) • “non-self” (proteine virale + molecule MHC-
like) – DA liza celulara: degranulare→ perforina &
granzime
Recunoasterecelule
infectate (maligne)
1 2
Asocierile cu Boala ale Combinatiilor Alelice KIR & HLA
Disease KIR HLA Disease progression Proposed contribution by KIRs AIDS 3DS1
3DS1 homozygous HLA-Bw4Ile80
No HLA-Bw4Ile80 Decreased Increased
Less inhibition More inhibition
HCV infection
2DL3 homozygous
HLA-C1 homozygous
Decreased
Less inhibition
Cervical neoplasia (HPV-induced)
3DS1
No 3DS1
HLA-C1 homozygous
and no HLA-Bw4 HLA-C2 and/or HLA-Bw4
Increased
Decreased
Less inhibition
More inhibition
Malignant melanoma
2DL2 and/or 2DL3
HLA-C1
Increased
More inhibition
Psoriatic arthritis
2DS1 and/or 2DS2
HLA-C1 homozygous or
HLA-C2 homozygous
Increased
Less inhibition
Type I diabetes
2DS2
HLA-C1 and no HLA-C2,
no HLA-Bw4
Increased
Less inhibition
Preeclampsia
2DL1 with fewer
2DS (mother)
HLA-C2 (fetus)
Increased
More inhibition
Rajagopalan, S., Long, E. Understanding how combinations of HLA and KIR genes influence disease. J. Exp. Med. 201, 1025-1029 (2005).
Mecanismele efectoare ale NK
I. Citotoxicitate A. Directa:
― Liza osmotica a celulei tinta (perforine) ― Apotoza celulei-tinta (granzime B)
B. Indirecta: • Apotoza celulei-tinta (IFN →+FasL; TRAIL=> +
caspaze) C. *Mecanism mediat de Ac (ADCC: Ab dependent cellular
cytotoxicity)*
Stimulata de CK II: ―IL-12 (GF) ―IL-15 (GF) ―IL-18 ―IFN α/β
Mecanismele citotoxice ale NK Citotoxicitate directa:
-Degranularea
1. Adeziunea inter-celulara, 2. polarizarea citoscheletului
1.Adeziunea , 2.Polarizarea
citoschelet 3. Liza eficienta a
celulei-tinta
Etape: 1. Adeziunea intercelulara 2. Polarizarea citoscheletului 3. Degranularea veziculelor litice 4. Liza celulei -tinta
Mecanismele citotoxice ale NK
Smyth, M. J. et al. Activation of NK cell cytotoxicity. Mol. Immunol. 42, 501–510 (2005).
Mecanismele Efectoare ale NK (II)
II. Secretie de citokine: 1. +Activitate antivirala: secretia de IFNs 2. Amplifica activarea Mφ 3. + mobilizarea NK
Dupa Abas at al. 2012 Elsevier/Saunders
Mecanisme virale de “evadare”
1. Variatia antigenica: – Virusul gripal, HIV, rinovirus
2. Productia de modulatori imuni: – Receptori solubili ai CK → actioneaza ca “ momeli”
=> blocrea actiunii CK (poxvirusurile) – CK imunosupresoare (ex EBV prod IL-10)
3. Angajarea unor cai de inhibare: – LCMV (șoareci), HIV (oameni): PD-1
4. Infecția celulor sistemului imunitar – HIV
5. Inhibarea procesarii Ag pe calea MHC I – Diferite mecanisme: CMV, HSV, EBV, adenovirus
2. Inhibarea procesarii Ag pe calea MHC I
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