Qingqing Wang （王青青） Institute of immunology, ZJU wqq@zju

1. 固有免疫 Innate immunity Qingqing Wang （王青青） Institute of immunology, ZJU wqq@zju.edu.cn

2. Contents • Innate immunity • Components of the innate immune system • PAMPs and PRRs • Innate immune response

3. Characteristics: • rapid • does not generate immunologic memory • dependent upon germline encoded receptors recognizing structures common to many pathogens Innate ImmunityFirst Line of Defense

5. Characteristics of Innate and Adaptive Immunity Innate Immunity Adaptive Immunity • Antigen dependent • TCR/BCR • A lag period • Antigen specific • Memory • Antigen independent • pattern recognition • No time lag • Not antigen specific • No memory

6. Functions • Innate immunity is the initial response to microbes that prevents, controls, or eliminates infection of the host by many microbes. • Innate immune mechanisms recognize the products of damaged and dead host cells and serve to eliminate these cells and to initiate the process of tissue repair. • Innate immunity to microbes stimulates adaptive immune responses and can influence the nature of the adaptive responses to make them optimally effective against different types of microbes.

7. Innate Immune System 1. Physical, chemical，microbial barriers • physical barriers include skin and mucus membranes (epithelial) • chemical barriers include stomach acidity, secreted anti-microbial peptides, defensins (防御素), cathelicidins (抗菌肽) • Normal bacterial flora 2. Cells • macrophages, neutrophils, DC, NK, B1, T, NKT… 3. Blood proteins • Complement and mediators of inflammation 4. Cytokines

9. Barrier • Skin-mucosal barrier • Physical barrier • Chemical barrier • Biological barrier • Blood brain barrier • Blood placental barrier

10. Epithelial defense mechanisms

13. 防水脂质层 板层小体：防御素和抗菌肽 Gut epithelium 表皮 Epidermis of skin

14. What happens when the physical and chemical barriers are breached?

15. Leukocyte Players of Innate Immune Responses

16. Innate-like lymphocytes（ILLs） • Unique, minor subsets of T and B lymphocytes that undergo receptor gene rearrangements to generate receptor diversity (unlike NK cells) • These subsets express limited receptor diversity, utilizing only a small number of receptor gene segments - Tend to found in specific locations in the body, usually sites that encounter exogenous antigens or pathogens

17. NK T cells Distribution bone marrow, liver, thymus, spleen, peripheral blood, lymph node NK T ＜1% in blood T cells； NK T in liver (mouse 30%，human 4%）

18. NK T cells 1, cytokine: IL-4, IFN-, IL-12 2, cytotoxity perforin and FasL/Fas 3, MCP-1, MIP-1

19. T细胞 Surface marker：TCR、CD4-CD8-、CD8+ distribution：mucosa of skin、intestine、lung and genitals restriction：non-classical MHCⅠmolecule restriction classification：epidermis T cell systemic T cell

20. T cells：function Anti-infection Immune surveilence Immune regulation Immune tolerance Anti-tumor

21. B1 cells • B1 cell mainly located in abdomen cavity, thorax and intestines • B1 cell recognize LPS and capsular polysaccharide • IgM antibody • No class switch and immune memory

22. Two types of phagocytes(1) Neutrophil granulocytes phagocytosis, intracellular killing, inflammation and tissue damage characteristic nucleus, cytoplasm granules and CD67 membrane marker.

24. (2) Monocytes and macrophages phagocytosis, intracellular and extra-cellular killing, tissue repair, antigen presentation for specific immune response characteristic nucleus and CD14 membrane marker.

25. （2）monocyte/macrophage

26. macrophages

29. Dendritic cells, DC • cDC myeloid DC, conventional DC • pDC (plasmacytoid DC) TLR7,9 type I interferon

30. Complement system

32. Cytokines of innate immunity

33. TNF

34. IL-1

35. Innate Immune Receptors • Innate immune receptors are not clonally distributed • Binding of receptors results in rapid response • Innate immune receptors mediate three functions: - phagocytic receptors to stimulate pathogen uptake - chemotactic receptors that guide phagocytes to site of infection - stimulate production of effector molecules and cytokines that induce innate responses and also influence downstream adaptive immune responses

36. Pathogen Recognition • Most microorganisms express repeating patterns of molecular structures termed Pathogen Associated Molecular Patterns (PAMPs) • Endogenous molecules that are produced by or released from damaged and dying cells are called Damage-Associated Molecular Patterns (DAMPs) • Innate immune system has evolved mechanisms capable of recognizing these repeating patterns termed Pattern Recognition Receptors (PRRs)

39. 免疫识别的危险模式理论Danger signalDanger Theory Polly Matzinger 理论免疫学家

40. PAMPs DAMPs

41. Structure of bacteria DNA pilin for adhesion flagellum for motion shape and rigidity

42. teichoic acid proteins OM peptidoglycan peptidoglycan IM Shared features of bacteria: cell walls lipopolysaccharide proteins 胞壁酸

43. Peptidoglycan 肽聚糖 teichoic acid proteins peptidoglycan N-乙酰氨基葡糖和N-乙酰胞壁酸交替的杂多糖

44. OM peptidoglycan IM Lipopolysaccharide 脂多糖 lipid A类脂质A

45. Flagellin 鞭毛 钩状体 丝状体

46. Bacteria Frequent CG sequences Cytosine not methylated Mammals Rare CG sequences Cytosine in CG is methylated Bacterial DNA

47. Viruses and double-stranded RNA • Some viruses have dsRNA genomes (rare) • Many more viruses have single-stranded RNA genomes but produce dsRNA during replication and mRNA synthesis

48. Engagement of innate immunity • Recognition of organisms based on conserved patterns • Lipopolysaccharide (gm-) • Peptidoglycan (most bacteria) • Flagella (many bacteria) • Unmethylated CpG in DNA • Single-stranded RNA (viral)

49. Pathogen Recognition • Examples of Pattern Recognition Receptors (PRRs) : - Mannose-Binding Lectin (MBL) - Macrophage Mannose Receptor - Scavenger Receptors - Toll-like Receptors (TLRs) - RIG-I like Receptors (RLRs) - Nod-like Receptors (NLRs)

50. Toll-like receptors single stranded RNA TLR8