STRUTTURA DELLA LEZIONE

Transcript

1 L Immunità innata ENNIO CARBONE UNIVERSITA' DEGLI STUDI DI CATANZARO "MAGNA GRÆCIA" KAROLINSKA INSTITUTET Microbiology and Tumor Biology Center MTC Stockholm

2 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

3 BARRIERE ANATOMICHE

4 Modalità di infezione dei patogeni

5 Linee di difesa

6 FASI DELLA MIGRAZIONE QuickTime e un decompressore TIFF (LZW) sono necessari per visualizzare quest'immagine.

7 Innate Immunity Macrophages, Granulocytes, NK IMMUNE SYSTEM: HOW IT WORKS Adaptive Immunity T and B lymphocytes cancer cells

8 Innate and adaptive immunity Property Innate immune system Adaptive immune system Receptors Fixed in genome Encoded in gene segments Rearrangement is not necessary Rearrangement necessary Distribution Non-clonal Clonal All cells of a class identical All cells of a class distinct Recognition Conserved molecular patterns (LPS, LTA, mannans, glycans) Details of molecular structure (proteins, peptides, carbohydrates) Self-Nonself Perfect: selected over Imperfect: selected in individual discrimination evolutionary time somatic cells Action time Immediate activation of effectors Delayed activation of effectors Response Co-stimulatory molecules Clonal expansion or anergy Cytokines (IL-1, IL-6) IL-2 Chemokines (IL-8) Effector cytokines: (IL-4, IFN) Janeway CA Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20:

9 THE IMMUNE SYSTEM ORGANIZATION Pathogen Innate immunity (0-4 hr) Risposta adattativa precoce 4-96 hr Risposta adattativa tardiva >96 hr Espansione clonale cellule della memo

10 Contributi alla risposta immune dell Immunità innata e quella acquisita C. Janeway 2000 Immunobiology

11 Meningococcal septicaemia haemorrhagic rash

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13 Le cellule del sistema immune

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15 FAGOCITOSI

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17 ANTIBODY-COATED ERYTHROCYTES (EIgG

18 ZIPPERING BY FcR

19 FAGOCITOSI

20 FAGOCITOSI ED ATTIVAZIONE PMN QuickTime e un decompressore TIFF (LZW) sono necessari per visualizzare quest'immagine.

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22 FcR

23 Clearance of apoptotic vs necrotic cells Nature Reviews Immunology 2; (2002)

24 UN SISTEMA FILOGENETICAMENTE ANTICO PER LA DISCRIMINAZIONE TRA SELF E PATOGENI

25 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 patternrecognition molecules/receptors (PRMs/PRRs)

26 I RECETTORI DELL IMMUNITA INNATA

27 TLR STRUCTURE

28 TLR SIGNALLING

29 Yeast Cell Wall (Candida albicans) PAMPs opsonisation Fibrillar layer (mannoprotein) Mannoprotein (30-40%) ß-Glucan 50-60% ß-Glucan-Chitin (0.5-3%) Plasma membrane Calderone (1993) TIM

30 TLR E LORO LIGANDI 2001 Nature Immunology Rev R. Medzhikov

31 Toll-like Receptors and Agonists 2005 Lipoarabinomannan Triacylated bacterial Lipopeptides (OspA, Pam3Cys) 19 kda Mtb lipoprotein AraLAM *HMGB1 Measles H P.gingivalis LPS L.interrogans LPS (?2/1 or 2/6?) Zymosan Peptidoglycan MALP2 (& other diacylated lipopeptides) dsrna polyi:c Enterobacterial LPS Taxol (murine) RSV F protein chlamydial HSP60 pneumolysin *HSP60/70? *fibrinogen *fibronectin *Surfactant Protein A *mdf2β Flagellin (not H. pylori FlaA) ssrna (viral/non-viral) imiquimod resiquimod (mu) (hu) CpG DNA malaria hemazoin UPEC (mu)? LRR TIR TLR2/1 TLR2/6 TLR3 TLR4 TLR5 TLR7 TLR8 TLR9 TLR10 TLR11 (murine) *Endogenous agonists

32 HOW LPS ACTIVATE INNATE IMMUNITY

33 RUOLO REGOLATORIO DEI TLR

34 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 APC immunomodulazione

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36 Ex vivo NK detection by FACS analysis

37 NK physiology TUMOR NK

38 NK effector function I: natural cytotoxicity

39 NK effector functions II: ADCC

40 Mycobacterium killing Science, Vol 282, Issue 5386, , 2 October 1998

41 NK effector functions III: Differences between NK and LAK killing

42 NK effector function IV: Cytokines and Chemokines 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

43 Cytotoxicity molecular mechanism

44 HOW NK ACTIVATING RECEPTORS WORK

45 Two receptors model

46 Stress induced NK activating ligands

47 DIFETTI GENETICI DELL IMMUNITA INNATA 1) Adesione e Fagocitosi (LAD, Malattia granulomatosi cronica) 2) Sindrome Chediak-Higashi (difetto nella fusione fagosoma / lisosoma) 3) Malattia Granulomatosa Cronica 4) Sindrome Wegner like

48 Malattia da difetto di adesione leucocitaria Autosomica recessiva chr 21

49 CHEDIAK HIGASHI SINDROME Autosomica recessiva chr 1 Tipiche inclusioni nei PMN Paziente di 4 anni con albinismo Infezioni batteriche ricorrenti Deceduto in seguito ad insorgenza di neuropatie e linfomi

50 MALATTIA GRANULOMATOSA CRONICA Malattia ereditaria per deficit di una delle 4 subunità X 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

51 A The Lancet, 2000; 354:1598:1603 QuickTime e un decompressore TIFF (Non compre sono necessari per visualizzare quest B GRANULOMATOSI WEGNER LIKE, MANCANZA DI ESPRESSIONE DELLE MOLECOLE MHC DI CLASSE I

52 The fall of Troy Strategie di escape dei patogeni

53 VIRAL GENES INTERFERING WITH MHC-I

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55 Attack and counterattack within the immune system

56 Letture consigliate R. Medzhikov The TLR and Innate Immunity Nature Rev Immunol 2001; 1:135 Janeway C. The virtues of a non clonal system of recognition Cell 1997; 91:295 Gordon S. Monocytes and macrophages heterogenicity. Nat Rev Immunol. 2005; 5:953 Lodoen M and Lanier L Viral modulation of NK cell Immunity Nat Rev Microbiol 2005; 3:59