L’ Immunità innata ENNIO CARBONE UNIVERSITA' DEGLI STUDI DI CATANZARO "MAGNA GRÆCIA" KAROLINSKA INSTITUTET Microbiology and Tumor Biology Center MTC Stockholm
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
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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
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FAGOCITOSI ED ATTIVAZIONE PMN
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)
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
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)
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
• 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
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
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
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