Chapter 10 Innate Immunity

1. Chapter 10Innate Immunity

2. Introduction of innate immunity • Innate immunity is the first line of defense against infections. • Innate immunity exist before encountering with microbes and are rapidly activated by microbes before the development of adaptive immune responses. • Innate immunity is present in all multicellular organisms, including plants and insects.

5. Characteristics: • Set up at birth • Non–specific and early • Heredity • Racial or species difference • No immune memory

6. No Immunologic memory Characteristicsof Innate and Adaptive Immunity Innate Immunity Adaptive Immunity Antigen independent Antigen dependent No time lag A lag period No antigen specific Antigen specific • Development of memory

7. Componentsof Innate and Adaptive Immunity Innate Immunity Adaptive Immunity physical barriers skin, gut Villi, lung cilia,etc none soluble factors many protein and non-protein secretions Immunoglobulins (antibody) cells phagocytes, NK cell, B1, γδT, APC T , B lymphocytes APC

8. Contents • PartⅠ Components of innate immune system • PartⅡ Cells participating in innate immunity • PartⅢ Recognition features of the innate immune system • PartⅣ Functions of innate immunity

9. PartⅠ Components of innate immune system Ⅰ.Barriers Ⅱ.Humoral factors Ⅲ. Cells

10. PartⅠ Components of innate immune system Ⅰ.Barriers: • Mechanical defense: skin & mucous membrane • Anatomic barrier: blood–brain barrier blood–placenta barrier blood – thymus barrier • Biotic barrier:normal flora • Chemical defense (lysozyme, acid)

12. PartⅠ Components of innate immune system Ⅱ.Humoral factors: Complement Cytokine---macrophage, neutrophil, NK cell Lysozyme Ⅲ. Cells: Mononuclear phagocyte, NK cell, Neutrophils, Dendritic cells，Eosinophil, Basophil, Mast cell， γδT cell, B1 cell, Microfold cell

14. ICC

16. PartⅡ Cells participating in innate immunity • Natural killer cells (NK) • Mononulear phagocytes • Neutrophils • Dendritic cells • Other cells participating in innate immunity

17. PartⅡ Cells participating in innate immunity Ⅰ. Natural killer(NK)cells 1. Source: Bone marrow,exist mainly in peripheral blood(5-7%) and spleen.

18. Also called large granular lymphocytes (LGL) Kill various infected and malignant cells spontaneously, without stimulation of antigen and MHC restriction Identified by the presence of CD56,CD16 (FcRⅢ) Activated by IL-12 and produce IFN -γ 2. Characteristics of NK cells

19. 3. Recognition mechanism of NK cells • FcγRⅢ: recognize antibody covered cell ------ADCC • Killer activating receptor and killer inhibitory receptor

21. ADCC

23. NK receptors bind with class Ⅰ MHC molecules NK receptors bind with non class Ⅰ MHC molecules Receptors associated with killer activation and killer inhibition on NK cells

24. (1) NK Receptors bind with class Ⅰ molecules: -KIR(killer immunoglobin-like receptors): • Number of immunoglobin-like domain:KIR2D/KIR3D • Cytoplastic region: longer---KIR2DL/KIR3DL(ITIM), inhibitory receptor shorter---KIR2DS/KIR3DS, non-covalent combination with DAP-12(ITAM), activating receptor -KLR(killer lectin-like receptor): • Heterodimer of CD94 & NKG2 (C type lectin) CD94: short cytoplastic region, no signal transmission NKG2A: ITIM in cytoplastic region --------CD94/NKG2A, inhibitory receptor NKG2C: no signal transmission, bind with DAP-12(ITAM) --------CD94/NKG2C, activating receptor ITIM：immunoreceptor tyrosine-based Inhibitory motif ITAM：immunoreceptor tyrosine-based activation motif

25. (2) NK receptors bind with non class Ⅰ MHC molecules --NKG2D:Express mainly on the surface of NK and γδT No signal transmission Non-covalent binding with DAP-10(ITAM) MHC class Ⅰ chain-related molecules A/B(MIC A/B) --Natural cytotoxic receptor(NCR): NKp46,NKp30,NKp44 IgSF Express on the surface of NK cells Bind with other molecules(ITAM) Kill target cells when KIR/KLR lose their function

26. Receptors associated with killer activation and killer inhibition on NK cells Killer activatory receptor Killer inhibitory receptor Function KIR: KIR2DS,KIR3DS KLR: CD94/NKG2C NKG2D NKp46 NKp30 NKp44 KIR2DL,KIR3DL CD94/NKG2A Bind class I HLA molecules Bind non-class I HLA molecules NCR

27. Figure 3-23 These are important NK inhibitory ligands（ CD94/NKG2A/B/C） These are important molecules for presentation of peptides to CD8 T cells

29. Normal condition(Class Ⅰ HLA molecules are expressed normally): Effect of Inhibitory recepter > Activatory recepter------Killing effect of NK cell is inhibited • Abnormal condition(Class Ⅰ HLA molecules are expressed abnormally) : NK cells lose ability of distinguishing self from non-self------NK cells kill target cells（NKG2D and NCR)

30. NK cells is tolerant to self-antigen: • Only virus infected cells and tumor cells could be killed by NK cells, not the normal tissue cells. • Virus infected cells or tumor cells  MHC-I inhibitory signal Killed by NK cells。

31. 4. Effector of NK cells • Secretion of cytokines,e.g. IFN-γ, to a activates macrophages • Cytotoxicity: -ADCC-mediated by FcγRⅢ(CD16) -Granules like CTLs: Perforin: creates pores in target cell membranes Granzymes : enzymes which enter through perforin pores and induce apoptosis of target cells. -FasL/Fas pathway -TNF-α/TNFR-Ⅰ pathway

32. TNFR-I TNF- α Target cell Contact tightly NK cell ADCC

33. 5. Functions of NK cells • Participate in anti-tumor and anti-virus immunity • Participate in immunological regulation

34. PartⅡ Cells participating in innate immunity Ⅱ. Mononuclear phagocytes

35. monocytes and macrophages

36. George Bernard Shaw wrote: “There is at bottom only one genuine treatment for all diseases,…to stimulate the phagocytes. Drugs are a delusion. …(when) the phagocytes are stimulated; they devour the disease…” Phagocytes are the Most Important Cells

37. Tissues macrophage Blood

38. Macrophages • Phagocytose & kill intracellularly • Characteristic nucleus and identified by CD14 • Act as APC • Activated by cytokines • Kill malignant and altered self targets • Adherent of plastic and glass surfaces

39. Macrophages phagocytose and degrade foreign particles, bacteria and dead (and dying) host cells. Receptors on Macrophages: Fcγ receptors Complement receptors IFN-g receptor Chemokine receptors Mannose receptor Toll-like receptors(TLRs) Scavenger receptors(SRs) LPS receptor(CD14)

41. 1. Recognizing and excluding pathogens Recognizing Ingestion Digestion Exclusion recognizing ingestion exclusion digestion

42. (1) Recognition Mechanism Pattern recognition receptor(PRR): The receptor on macrophage which can recognize and bind specific molecular structure on some pathogens , injured or apoptotic cells.

43. The receptor associated with antigen-recognition of macrophage • Pattern recognition receptor (PRR) or non-opsonic receptor ------Mannose receptor(MR) Scavenger receptor(SR) Toll like receptor(TLR) • Opsonic receptor ------FcγR and C3bR/C4bR

44. ScavengerR IgG FcR CR Initiation of Phagocytosis

46. Pathways of Intracellular Killing

47. (2) Ingesting and digesting the pathogen • Oxygen-dependent system: ---Reactive oxygen intermediates, ROIs: O2-, OH-, H2O2, 1O2 ---Reactive nitrogen intermediates, RNIs: NO • Oxygen-independent system: ---Low pH(3.5-4) , Lysozyme,Defensin

49. (3) Excluding the pathogen

50. 2. Functions of macrophage • Recognizing and excluding pathogens and died cells; Killing target cells(tumor cells and virus-infected cells) • Participating in and stimulating inflammation • Participating in immunological regulation • Processing and presenting antigen, initiating adaptive immune response