1. Innate Immunity 미생물학교실 권 형 주

2. Routes of antigen entry Physical, Chemical, Cellular barriers

3. Innate Immunity/Adaptive Immunity

4. Anatomic Barriers

5. Psoriasin prevents colonization of skin by E. coli EM of E. coli bacteria adhering to surface of epithelial cells of the urinary tract

6. IMMUNE SYSTEM How does the immune system distinguish self from non-self? Innate Immunity Antimicrobial peptides, Phagocytes, Alternative Complement Pathway Activated immediately after infection Rapidly control the replication of the infecting pathogen PRR recognize PAMPs Adaptive Immunity B, T cells Size, Diversity -Repertoire of Antigen Receptors is very large and extremely diverse Clonal Selection -Each lymphocyte displays a single kind of structurally unique receptor

7. Strategy of the innate immune response Focus on a few, highly conserved structures present in large groups of Microorganism Structures (Pathogen-Associated Molecular Patterns, PAMPs) Receptors (Pattern-Recognition Receptors, PRRs) Examples of pathogen-associated molecular patterns (Bacteria) Lipopolysaccharide Peptidoglycan Lipoteichoic acids Mannans Bacterial DNA Double-stranded RNA Glucan Complement systems Phagocytosis Toll-like receptors (TLRs)

8. Families of Pattern-Recognition Receptors - Structurally Leucine-rich domains Calcium-dependent lectin domains Scavenger-receptor protein domains - Functionally Secreted Endocytic Signaling

9. Mannan-Binding Lectin Calcium-dependent lectin family Synthesized in the liver and secreted into the serum as a component of the acute-phase response Can bind to carbohydrates on gram-positive and gram-negative bacteria and yeast, as well as some viruses and parasites Associated with the serine proteases of the classic complement pathway

10. Endocytic pattern-recognition receptors Macrophage mannose receptor Calcium-dependent lectin Recognizes the carbohydrates with large numbers of mannose Mediates their phagocytosis by macrophage Macrophage scavenger receptor Binds to bacterial cell wall Clearance of bacteria from the circulation

11. Signaling receptors Recognize pathogen-associated molecular patterns Activate signal-transduction pathways that induce the expression of a variety of immune-response genes, including inflammatory cytokines Toll-like receptors

12. Recognition of pathogens by pattern recognition receptors

13. Effectors of innate immune responses to infection Opsonin : Microorganism 에 결합하고, macrophages, neutrophils 의 surface receptor 에 결합되어 Microorganism 의 phagocytosis 를 증가 시킬 수 있는 molecules - IgG – phagocytes 의 Fc  receptor 에 결합 - Fragments of complement proteins (C1q) – CR1 (CD35), Mac-1 Opsonization : Opsonin 이 microbial surface 에 결합하여 Microorganism 을 phagocytosis 시키는 과정

14. Connections between innate and adaptive immunity Medzhitov R, & Janeway C Jr.,N. Engl. J. Med., 2000. 343, 338-344

15. Inflammation

16. The second line of defence is mediated via recognition of common bacterial components

19. Steps in the phagocytosis of a bacterium

20. Soluble molecules and membrane-associated receptors Soluble molecules - Antimicrobial peptides - Acute phase response protein Receptors - MBL : Mannan binding lectin - CRP : C-reactive protein - LBP : Lipopolysaccharide-binding protein - NOD : Nucleotide-binding oligomerization domain - TLR : Toll-like receptors - SRs : Scavenger receptors

21. Antimicrobial peptides - 800 여개가 알려져 있음 - Positively charged - 6 – 59 amino acids - disulfide bonds (2-3 개, six cysteines)

22. Human α-defensins HNP1 A C Y C RIPA C IAGERRYGT C IYQGRLWAF CC HNP2 C Y C RIPA C IAGERRYGT C IYQGRLWAF CC HNP3 D C Y C RIPA C IAGERRYGT C IYQGRLWAF CC HNP4 V C S C RLVF C RRTELRVGN C LIGGVSFTY CC TRVD HD5 ARAT C Y C RTGR C ATRESLSGV C EISGRLYRL CC R HD6 RAFT C H C RRS C YSTEYSYGT C TVMGN HRF CC L 1 6 2 4 35 Human β-defensins hBD1 DHYN C VSSGGQ C LYSA C PIFTKIQGT C YRGKAK CC K hBD2 DPVT C LKSGAI C HPVF C PRRYKQIGT C GLPGTK CC KKP hBD3 QKYY C RVRGGR C AVLS C LPKEEQIGK C STRGRK CC RRKK hBD4 LDRI C GYGTAR C RKK C RSQEYRIGR C PNTYA CC LRKPWDE 1 6 2 4 3 5

24. Receptors

25. Mannan-Binding Lectin Calcium-dependent lectin family Synthesized in the liver and secreted into the serum as a component of the acute-phase response Can bind to carbohydrates on gram- positive and gram-negative bacteria and yeast, as well as some viruses and parasites Associated with the serine proteases of the complement pathway

26. Macrophages contain intracellular receptors for pathogens - Intracellular proteins : microbial wall degradation products 인식 : Leucine-rich repeats, pyrin, caspase-associated recruitment domains (CARD), nucleotide oligomerization domains (NOD) NOD-1 :  NOD-2 : expression - monocytes and macrophages recognition – cytosolic muramyl dipeptides originated from bacteria degradation NOD-2 mutation : Crohn’s disease, a chronic granulomatous inflammatory bowel disease 유발

27. Toll-like Receptors (TLRs) Pathogen-associated molecular patterns (PAMPs)

29. Therapeutic applications for TLRs agonists Krieg, A. M. (2006) Nat. Rev. Drug Discov. 5, 471-484

30. Cell types of innate immunity The major leukocytes of innate immunity

31. Neutrophils and macrophages

33. Recently recruited cells are particularly effective in microbial killing Macrophages : effector mechanisms activation -  release of potentially injurious macrophage molecules secretory products -  released into the extracellular environment -  tissue damage ; autoimmune disease, chronic inflammatory disease in joints, lung, nervous system

34. NK cells

37. Signal transduction pathways

38. Ubiquity of innate immunity TRAF6 dTRAF Immune response genes MyD88 IL-1R Toll Toll Xa-21 Vertebrates Insects Plants Pelle IBIB NF-  B Cactus Dorsal, Dif, Relish Pto,Pit, fen TLR TLR TLR Jun/Fos Tube IRAK

39. 사람과 초파리의 Toll pathway 의 유사성

40. 사람과 초파리의 LPS 신호전달 체계의 유사성