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3RD SEMINAR

3RD SEMINAR. INNATE IMMUNITY : ANTIVIRAL STATE, KILLER CELLS, THE COMPLEMENT SYSTEM. DANGER SIGNALS ARE TRANSLATED TO CYTOKINE SECRETION THROUGH VARIOUS MOLECULAR SENSORS IN DC SUBTYPES. 4. 6. 6. 2. 1. 1. NLR. RLR. RLR. IL-1 β IL-12/23 IL-10. IFN α IFN β. 5. 10. 7. 3. 9. 7.

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3RD SEMINAR

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  1. 3RD SEMINAR INNATE IMMUNITY:ANTIVIRAL STATE,KILLER CELLS, THE COMPLEMENT SYSTEM

  2. DANGER SIGNALS ARE TRANSLATED TO CYTOKINE SECRETION THROUGH VARIOUS MOLECULAR SENSORS IN DC SUBTYPES 4 6 6 2 1 1 NLR RLR RLR IL-1β IL-12/23 IL-10 IFNαIFNβ 5 10 7 3 9 7 8 Plasmacytoid DC Conventional DC TLR1 – bacteriallipoprotein (togetherwith TLR2) TLR2 –bacteriallipoprotein, peptidoglycane, lipoteicholicacid (heteromerwith TLR1 and TLR6) TLR3 –viraldsRNA TLR4 – bacterial LPS TLR5 – bacterialflagellin TLR6 –bacteriallipoprotein(togetherwithTLR2) TLR7 – viralssRNA TLR8 – viralssRNA TLR9 – unmethylatedCpG DNA TLR10 – modifiedviralnucleotides NLRs – microbialproducts, DAMPs RLRs – viraldsRNA

  3. THE TYPE I INTERFERON RESPONSE: ANTIVIRAL STATE Plasmacytoid dendritic cells (pDCs) produce 1000x more type I interferon than other cells (Natural Interferon Producing Cells – NIPC) After viral infection they are accumulated at the T cell zone of the lymph nodes plasmacytoid dendritic cells

  4. VIRUS-INDUCED TYPE I INTERFERON PRODUCTION Type I IFN receptor IFN response Virus IFN- IRF-3 NFB AP-1 IRF-3 IFN- paracrine IFN- IRF-7 autocrine Infected cell IFN response IFN- subtypes IRF: interferon regulatory factor

  5. INTERFERON EFFECTOR PATHWAYSinduction of the „antiviral state” • 1.MxGTPase pathway • block viral transcription • 2. 2',5'-oligoadenylate-synthetase (OAS)-directed Ribonuclease L pathway • degrade viral RNA • 3. Protein kinase R (PKR) pathway (Ser/Thr kinase, dsRNA-dependent) • inhibit translation • 4. ISG15 ubiquitin-like pathway • modify protein function CONTROL ALL STEPS OF VIRAL REPLICATION

  6. MULTIPLE EFFECTS OF TYPE I INTERFERONS Increasedcitotoxicity and proliferationof NK-cells TLR4 TRAM TRIF TLR7 TLR8 TLR9 TLR3 TRIF MyD88 TANK IRAK-1 Activation of - and γδT-cells TRAF-6 RIG-1 IKKε TBK1 IRF-7 Increasedantigenpresentation inmyeloiddendriticcells IRF-3 IRF-5 IFN-β, IFN-α IRF-7 Stimulation of Ig-production inB-cells Type I interferon receptor

  7. EFFECTOR MECHANISMS OF INNATE IMMUNITY KILLER CELLS COMPLEMENT SYSTEM PHAGOCYTIC CELLS

  8. NK CELLS • Similarfunctionstocytotoxic T cellsbut: • larger than lymphocytes • no rearranged antigen-specific receptors • contain large cytoplasmic granules • respond fast, circulate in a partly activated state

  9. RECOGNITION AND KILLING BY NK CELLS KIR KAR KIR KAR • Contents of lytic granules: • Perforin: forming pores in the target cell membrane  lysis • Granzyme: inducing apoptosis in the target cell

  10. NK-CELLS PRR Virus-infected cell RECOGNITION ACTIVATION Lysis of infected cell IFN IL-12 RECOGNITION OF ALTERED HOST CELLS NK-cells Relative level/activity Kinetics of the activity of the complement system and NK cells in virus infection Complement system days NATURAL KILLER CELL ACTIVATION

  11. EFFECTOR MECHANISMS OF INNATE IMMUNITY KILLER CELLS COMPLEMENT SYSTEM PHAGOCYTIC CELLS

  12. THE COMPLEMENT SYSTEM • The complement system is a set of plasma proteins that act in a cascade to attack and kill extracellular pathogens. • Approximately 30 components: • activating molecules • regulator factors • complement receptors • membrane proteins which inhibit the lysis of host cells • Most of the complement proteins and glycoproteins are produced in the liver in an inactive form (zymogen). Activation is induced by proteolytic cleavage.

  13. AMPLIFICATION OF THE COMPLEMENT CASCADE limited proteolysis inactive precursors enzyme activating surface Activating surface needed!

  14. ACTIVATION OF THE COMPLEMENT SYSTEM

  15. THE CLASSICAL PATHWAY

  16. THE C1 COMPLEX Collagen „legs” Gobular „heads” C1 is alwayspresentinserumbutitrequires an activatingsurfaceforactivation LowaffinitybindingtotheFcregion of antibody conformationalchange  activation

  17. ACTIVATION OF THE C1 COMPLEX

  18. THE CLASSICAL PATHWAY: FIXATION OF COMPLEMENT, GENERATION OF C3b BY THE CLASSICAL C3 CONVERTASE

  19. THE MANNAN-BINDING LECTIN PATHWAY

  20. Eukariotic cells GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES Prokariotic cells galactose glucoseamine neuraminicacid (sialicacid) mannose (polymer = mannan)

  21. MANNOSE-BINDING LECTIN (MBL) PATHWAY MBL: part of the collectin family • similar structure to C1 complex, MASP-1,2 ~ C1r,s • binds mannose and similar sugar molecules on the surface of bacteria, fungi, protozoa and viruses  conformational change  cleavage of C2 and C4 molecules MASP = MBL-associatedserin protease

  22. ACTIVATION OF THE MBL COMPLEX

  23. THE ALTERNATIVE PATHWAY

  24. C3b can derive from classical or the lectin pathway too Alternative pathway is instantly inactivated on eukaryotic cell surfaces (in the presence of sialic acid molecules)

  25. THE CENTRAL COMPONENT OF THE COMPLEMENT SYSTEM Strong covalentbindingComplementfixation (3900000000000000 molecules/ml)

  26. C5-CONVERTASE C3 convertase + C3b = C5 convertase (C4bC2bC3b) The classical and alternative C3convertase is different in structure but common in function

  27. MEMBRANE ATTACK COMPLEX (MAC = C5b-C9n) MACsinthecellmembrane

  28. COMPLEMENT ACTIVATION SUMMARY

  29. COMPLEMENT SYSTEM CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY Antigen-antibody complex Mannose Pathogen surface MBL MASP-1/MASP-2 Serin protease C4, C2 C3 B, D C1q, C1r, C1s Serin protease C4, C2 C4a* C3a, C5a C3 CONVERTASE Terminal C5b – C9 C3b Inflammatory peptide mediators Phagocyte recruitment Opsonization Binding to phagocyte CR Immune complex removal MAC Pathogen/cell lysis

  30. THE ANAPHYLATOXINS: C3a, C4a, C5a

  31. OPSONIZATION COMPLEMENT-MEDIATED PHAGOCYTOSIS

  32. MOVIES: ACTIVATION VIA THE CLASSICAL PATHWAY

  33. REGULATION OF THE COMPLEMENT SYSTEM

  34. DEFICIENCIES OF COMPLEMENT COMPONENTS AND REGULATORS

  35. HEREDITARY ANGIONEUROTIC EDEMA (HANE)(HEREDITARY C1INH DEFECT) Inhibition by C1INH in many steps • bradykinin and C2-kinin: enhance the permeability of postcapillarvenules edema • C1 is always active without activating surface because plasmin is always active Main symptoms: • swellings of skin, guts, respiratory tracts • serious acute abdominal pain, vomiting • larynx swelling – suffocation, may cause death Treatment: • iv C1INH, FFP, steroid • kallikrein and bradykinin receptor antagonists Children with symptoms of HANE

  36. PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) • Acquired clonal mutation of PIG-A gene in myeloid progenitors – no GPI-enchored proteins in the cell membrane of affected cells (rbc, plt, wbc) • CD59 and CD55 complement regulatory proteins are GPI-enchored proteins • No CD59 and/or CD55  PNH patients are highly susceptible to complement-mediated lysis • The lysis of red blood cells leads to high levels of hemoglobins in the blood that appears in the urine (hemoglobinuria) • Elevated levels of TF derived from complement-damaged leukocytes cause thromboses

  37. Change in the colour of urine samples taken from PNH patient during the day

  38. PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) SYMPTOMS THERAPY Specific th.: eculizumab (Soliris) = anti-C5 monoclonalantibody Curative th.: bonemarrowtransplantation Alternative th.: steroids (generalimmunosuppression) Anticoagulants: s.c. heparin p.o. kumarin Ironreplacement Transfusion (filtered-irradiatedblood) • Haemolyticanaemia and associatedsymptoms • Haemoglobin and itsproductsintheurine • Thrombosis: • brainveins, • mesenthericveins, • hepaticveins (Budd-Chiari-syndrome) • May transformtoleukemiaorotherbonemarrowdiseases

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