Innate immunity

1. Innate immunity • PartⅠ overview of innate immunity • PartⅡ innate immune cells • PartⅢ functions of innate immunity

2. 1. definition of innate immunity protection against infections that relies on the mechanisms that exist before infection and are capable of rapid response to pathogens . .Innate immunity is the first line of defence against infection

4. Innate immunity 2.Characteristics • set up at birth • non –specific •    hereditable • no immune memory • Little individual difference

5. 3.Composition Barriers Humoral factors Cells ----Phagocytes (neutrophils, macrophages) natural killer cells(NK)

6. 1)  Barriers • mechanical defense: skin & mucous membrane • Anatomic barrier .blood-brain barrier, .blood-placental barrier . Blood – thymus barrier • Biological barrier: normal flora

7. 2)  humoral factors complement lysozyme Cytokine

8. 3)Cells of the innate immunity NK cells Phagocytes: neutrophils monocytes, macrophages Others: DC, basophils, mast cells eosinophils, γδT cells, B1 cells,NKT cells

9. Hematopoietic Stem Cell

11. PartⅡ innate immune cells -----Immunocytes participating in innate immunity Phagocytes (Macrophage) NK cells Other cells

12. 2. Natural killer(NK )cells in innate immunity Concept : large lymphocytes which can directly kill tumor cells and virus-infected cells without induction of antigens

13. Natural killer cells (NK) • Source: Bone marrow, exist mainly in peripheral blood, spleen and liver. • Characteristics : contain cytotoxic substances • functions: 1) Fighting infection and cancer killing virus infected cells and tumor cells 2) Immunoregulation secreting INF-γ

14. 1). Recognition (1). Direct recognition receptors Recognizing tumor cell and virus- infected cell(2). FcRRecognizing Ab-bound target cell

15. (1).Direct recognition receptors • HLA I molecules recognizing receptors • Non-HLA I molecules recognizing receptors

16. (1). Direct recognition receptors • HLA I molecules recognizing receptors 1） killer immunoglobulin-like receptor KIR2DL, KIR2DS; KIR3DL, KIR3DS 2） killer lectin-like receptor CD94/NKG2A, CD94/NKG2C recognize the MHC-I molecules on normal cells in normal condition, transduce inhibitory signals to inhibit the killing effect of NK cell.

17. (1).Direct recognition receptors 1）natural cytotoxicity receptors,NCR） NKp30,NKp44,NKp46 2）NKG2D recognize the ligands on virus-infected cells and some tumor cells ----transduce active signals to kill target cells

18. Normal condition: HLA I molecules recognizing receptors (KIR,KLR) inhibition effect > activation effect ----- killing effect of NK cell is inhibited Abnormal condition: Non-HLA I molecules recognizing receptors (NCR NKG2D) Activation effect > inhibition effect -----NK cells kill target cells

19. (2). FcRRecognizing Ab-bound target cellADCC

20. 2. The mechanisms of killingperforin and granuzyme Perforin: creates pores in target cell membranesgranzymes : enzymes which enter through perforin pores and induce apoptosis of target cells. Fas-FasL pathway

21. NK cell Target cell

24. Natural killer cells (NK) • Source: Bone marrow, exist mainly in peripheral blood, spleen and liver. • Characteristics : contain cytotoxic substances • functions: 1) Fighting infection and cancer killing virus infected cells and tumor cells 2) Immunoregulation secreting INF-γto enhance immune response

25. Monocyte/ macrophage

26. Mononuclear phagocytes Macrophages are 5- to 10-fold larger than monocytes and contain more organelles, especially lysosomes

28. Process of phagocytosis Recognization Endocytosis Killing and digestion

29. Mononuclear phagocytes Macrophages are 5- to 10-fold larger than monocytes and contain more organelles, especially lysosomes

30. 1) Recognition (1) pattern recognition receptors (2) Opsonic receptor

31. Recognition(1) pattern recognition receptors----- pathogen associated molecular pattern, PAMPPAMP:distinct structures or components that are common for many pathogens e.g. LPS, proteoglycan, N-formylated peptides, double RNA of viruses et al.

32. Pattern recognition receptors, PRRthe receptors that can recognize pathogen associated molecular patterns, locating on the surface of macrophages e.g. mannose receptor, scavenger receptor, CD14, Toll like receptors et al.

35. (2) Opsonic receptorFcRthe receptor for Fc region of AbCRthe receptor for complement component,C3b/4b

38. 2) Endocytosis

39. 3) killing and digestion Activated macrophages kill phagocytosed microbes by producing microbicidal molecules in phagolysosome • Oxygen-dependent system. • Oxygen-independent system: ---Low pH(3.5-4) , Lysozyme

40. oxygen-dependent system: reactive oxygen intermediates, ROIs NADPH+ O2 O2- ,OH- , H2O2 , 1O2 reactive nitrogen intermediates, RNIs: inducible nitric oxide synthase, NO oxygen-independent system Low PH (3.5-4.0), lysozyme Digestion by various types of enzymes in phagocytes

43. Functions of monocyte/macrophage • Phagocytosis • Induction of inflammation • Presentation of antigen

44. Part III functions of innate immunity 1. Fighting infection 2. Taking part in adaptive immunity 1)Innate immunity initiates adaptive immunity Presenting antigens Expressing B7 2)Innate immunity regulats adaptive immunity C3d Releasing cytokines