L’ Immunità innata

ENNIO CARBONEUNIVERSITA' DEGLI STUDI DI CATANZARO

"MAGNA GRÆCIA"KAROLINSKA INSTITUTET

Microbiology and Tumor Biology Center MTCStockholm

STRUTTURA DELLA LEZIONE

• I patogeni e le difese immunitarie• Definizione di Immunità Innata ed Acquisita• Le cellule• I recettori• Le funzioni• La patologia • Letture di approfondimento

BARRIERE ANATOMICHE

Modalità di infezione dei patogeni

Linee di difesa

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FASI DELLA MIGRAZIONE

IMMUNE SYSTEM: HOW IT WORKS

cancer cells

Innate ImmunityMacrophages, Granulocytes, NK

Adaptive ImmunityT and B lymphocytes

Property Innate immune system Adaptive immune system

Receptors Fixed in genome Encoded in gene segmentsRearrangement is not necessary Rearrangement necessary

Distribution Non-clonal ClonalAll cells of a class identical All cells of a class distinct

Recognition Conserved molecular patterns Details of molecular structure(LPS, LTA, mannans, glycans) (proteins, peptides, carbohydrates)

Self-Nonself Perfect: selected over Imperfect: selected in individualdiscrimination evolutionary time somatic cells

Action time Immediate activation of effectors Delayed activation of effectors

Response Co-stimulatory molecules Clonal expansion or anergyCytokines (IL-1, IL-6) IL-2Chemokines (IL-8) Effector cytokines: (IL-4, IFN)

Janeway CA Jr, Medzhitov R.Innate immune recognition.Annu Rev Immunol. 2002;20:197-216.

Innate and adaptive immunity

THE IMMUNE SYSTEM ORGANIZATION

Innate immunity(0-4 hr)

Pathogen

Risposta adattativa precoce

4-96 hr Risposta adattativa tardiva >96 hr

Espansione clonale cellule della memo

Contributi alla risposta immune dell’ Immunità innata

e quella acquisita

C. Janeway 2000 Immunobiology

Meningococcal septicaemia – haemorrhagic rash

Le cellule del sistema immune

FAGOCITOSI

ANTIBODY-COATED ERYTHROCYTES (EIgG

ZIPPERING BY FcR

FAGOCITOSI

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FAGOCITOSI ED ATTIVAZIONE PMN

FcR

Clearance of apoptotic vs necrotic cells

Nature Reviews Immunology 2; 787-795 (2002)

UN SISTEMA FILOGENETICAMENTE ANTICO PER LA DISCRIMINAZIONE

TRA SELF E PATOGENI

Innate Immune Recognition• All multi-cellular organisms are able to

recognize and eliminate pathogens• Despite their extreme heterogeneity, pathogens

share highly conserved molecules, called “pathogen-associated molecular patterns” (PAMPs)

• Host cells do not share PAMPs with pathogens• PAMPs are recognized by innate immune

recognition receptors called pattern-recognition molecules/receptors (PRMs/PRRs)

I RECETTORI DELL IMMUNITA’ INNATA

TLR STRUCTURE

TLR SIGNALLING

Yeast Cell Wall Yeast Cell Wall ((Candida Candida albicansalbicans))

Fibrillar layer (mannoprotein)

Mannoprotein (30-40%)

ß-Glucan 50-60%

ß-Glucan-Chitin (0.5 -3%)

Plasma membrane

Calderone (1993) TIM

PAMPsPAMPs

opsonisation

TLR E LORO LIGANDI 2001

Nature Immunology Rev. 2001 R. Medzhikov

Toll-like Receptors and Agonists 2005

*Endogenous agonists

LipoarabinomannanTriacylated bacterial

Lipopeptides(OspA, Pam3Cys)

19 kDa Mtb lipoproteinAraLAM*HMGB1

TLR2/1 TLR2/6 TLR3 TLR4 TLR7 TLR8 TLR10TLR9 TLR5

ZymosanPeptidoglycanMALP2 (& other diacylatedlipopeptides)

Enterobacterial LPS Taxol (murine)RSV F proteinchlamydial HSP60pneumolysin*HSP60/70?*fibrinogen*fibronectin*Surfactant Protein A*mDF2β

??

Flagellin(not H. pylori FlaA)

CpG DNA malaria hemazoin

dsRNApolyI:C imiquimod

resiquimod

Measles HP.gingivalis LPSL.interrogans LPS(?2/1 or 2/6?)

LRR

TIR

ssRNA (viral/non-viral)

TLR11(murine)

UPEC(mu)

(mu) (hu)

HOW LPS ACTIVATE INNATE IMMUNITY

RUOLO REGOLATORIO DEI TLR

FUNZIONI DEI TLR

• Non-opsonic APC receptors bind, take up and kill target

• TLR riconoscono I patogeni

• Inducono la produzione di citochine pro infiammatorie

•Cattura degli antigeni maturazione della cellula come APCimmunomodulazione

Ex vivo NK detection by FACS analysis

NK physiology

NK

TUMOR

NK effector function I: natural cytotoxicity

NK effector functions II:ADCC

Mycobacterium killing

Science, Vol 282, Issue 5386, 121-125 , 2 October 1998

NK effector functions III:Differences between NK and

LAK killing

• IFNγ −> Th1, MHC-I induction and anti viral effect

• TNFα−> Maturation of DC and direct citotoxic effect

• GM-CSF-> DC maturation• IL-4-> DC maturation , Th2 induction• MIP1-α−> Macrophage recruitment at the

inflammation site

NK effector function IV: Cytokines and Chemokines

Cytotoxicity molecular mechanism

HOW NK ACTIVATING RECEPTORS WORK

Two receptors model

Stress induced NK activating ligands

DIFETTI GENETICI DELL’IMMUNITA’ INNATA

1) Adesione e Fagocitosi (LAD , Malattiagranulomatosi cronica)

2) Sindrome Chediak-Higashi (difetto nella fusionefagosoma / lisosoma)

3) Malattia Granulomatosa Cronica

4) Sindrome Wegner like

Malattia da difetto di adesione leucocitariaAutosomica recessiva chr 21

CHEDIAK HIGASHI SINDROME

Autosomica recessiva chr 1

Tipiche inclusioni nei PMN

Paziente di 4 anni con albinismoInfezioni batteriche ricorrentiDeceduto in seguito ad insorgenza di neuropatie e linfomi

MALATTIA GRANULOMATOSA CRONICAMalattia ereditaria per deficit di una delle 4 subunitàX linked o in alcune forme autosomica recessiva.Che compongono l enzima NAPDH.I batteri vengono fagocitati ma non uccisi.

Candidosi Granulomatosa

Stafilocco in paziente MGC

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GRANULOMATOSI WEGNER LIKE, MANCANZA DI ESPRESSIONE DELLE

MOLECOLE MHC DI CLASSE IThe Lancet, 2000; 354:1598:1603

A

B

The fall of Troy

Strategie di escape dei patogeni

VIRAL GENES INTERFERING WITH MHC-I

Attack and counterattackwithin the immune system

Letture consigliate

R. Medzhikov The TLR and Innate Immunity Nature Rev Immunol2001; 1:135Janeway C. The virtues of a non clonal system of recognitionCell 1997; 91:295Gordon S. Monocytes and macrophages heterogenicity. Nat RevImmunol. 2005; 5:953Lodoen M and Lanier L Viral modulation of NK cell ImmunityNat Rev Microbiol 2005; 3:59