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

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Presentation on theme: "3RD SEMINAR INNATE IMMUNITY: ANTIVIRAL STATE, KILLER CELLS, THE COMPLEMENT SYSTEM."— Presentation transcript:

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

2 Conventional DC Plasmacytoid DC NLR IL-1β IL-12/23 IL-10 IFNα IFNβ RLR DANGER SIGNALS ARE TRANSLATED TO CYTOKINE SECRETION THROUGH VARIOUS MOLECULAR SENSORS IN DC SUBTYPES TLR1 – bacterial lipoprotein (together with TLR2) TLR2 –bacterial lipoprotein, peptidoglycane, lipoteicholic acid (heteromer with TLR1 and TLR6) TLR3 –viral dsRNA TLR4 – bacterial LPS TLR5 – bacterial flagellin TLR6 –bacterial lipoprotein (together with TLR2) TLR7 – viral ssRNA TLR8 – viral ssRNA TLR9 – unmethylated CpG DNA TLR10 – modified viral nucleotides NLRs – microbial products, DAMPs RLRs – viral dsRNA RLR

3 THE TYPE I INTERFERON RESPONSE: ANTIVIRAL STATE plasmacytoid dendritic cells 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

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

5 INTERFERON EFFECTOR PATHWAYS induction of the „antiviral state” 1. Mx GTPase 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 TRIF TANK IKKεTBK1 IRF-3 TRIF TRAM TLR3 TLR4 MyD88 IRF-5 TLR7 TLR8 TLR9 IFN-β, IFN-α RIG-1 Stimulation of Ig-production in B-cells Type I interferon receptor IRF-7 Increased citotoxicity and proliferation of NK-cells Activation of  - and γδ T-cells Increased antigen presentation in myeloid dendritic cells IRAK-1 TRAF-6 IRF-7 MULTIPLE EFFECTS OF TYPE I INTERFERONS

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

8 NK CELLS Similar functions to cytotoxic T cells but: larger than lymphocytes no rearranged antigen-specific receptors contain large cytoplasmic granules respond fast, circulate in a partly activated state

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

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

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

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 inactive precursors limited proteolysis activating surface enzyme Activating surface needed!

14 ACTIVATION OF THE COMPLEMENT SYSTEM

15 THE CLASSICAL PATHWAY

16 C1 is always present in serum but it requires an activating surface for activation Low affinity binding to the Fc region of antibody  conformational change  activation Collagen „legs” Gobular „heads” THE C1 COMPLEX

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 glucoseamine mannose (polymer = mannan) galactose neuraminic acid (sialic acid) GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES Prokariotic cells

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-associated serin 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 ( molecules/ml) Strong covalent binding Complement fixation

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

27 MACs in the cell membrane MEMBRANE ATTACK COMPLEX (MAC = C5b-C9 n )

28 COMPLEMENT ACTIVATION SUMMARY

29 Antigen-antibody complex MannosePathogen surface C1q, C1r, C1s Serin protease C4, C2 MBL MASP-1/MASP-2 Serin protease C4, C2 C3 B, D COMPLEMENT SYSTEM CLASSICAL PATHWAYMB-LECTIN PATHWAYALTERNATIVE PATHWAY C3 CONVERTASE C4a* C3a, C5a Inflammatory peptide mediators Phagocyte recruitment C3b Opsonization Binding to phagocyte CR Immune complex removal Terminal C5b – C9 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 Deficient complement protein Effects of deficiency C1, C2, C4 C3 Immune-complex diseases (similar to SLE), susceptibility to pyogenic infections MAC, alternative pathway components Susceptibility to Neisserial infections C1INHHereditary angioneurotic edema (HANE) DAF (CD55), MIRL (CD59)Paroxysmal nocturnal hemoglobinuria (PNH)

35 HEREDITARY ANGIONEUROTIC EDEMA (HANE) (HEREDITARY C1INH DEFECT) 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 bradykinin and C2-kinin: enhance the permeability of postcapillar venules  edema C1 is always active without activating surface because plasmin is always active Inhibition by C1INH in many steps

36 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 PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)

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

38 PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) SYMPTOMS Haemolytic anaemia and associated symptoms Haemoglobin and its products in the urine Thrombosis: –brain veins, –mesentheric veins, –hepatic veins (Budd-Chiari-syndrome) May transform to leukemia or other bone marrow diseases THERAPY Specific th.: eculizumab (Soliris) = anti-C5 monoclonal antibody Curative th.: bone marrow transplantation Alternative th.: steroids (general immunosuppression) Anticoagulants: s.c. heparin  p.o. kumarin Iron replacement Transfusion (filtered-irradiated blood)


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