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