Chapter 3 Innate Immunity

1. Chapter 3 Innate Immunity Macrophage interacting with Bacteria Oct 3, 5 & 12, 2006

2. 你需要學習的問題: • 有哪些分子及細胞參與先天性免疫反應 (innate immunity)？ 它們的特性是什麼？ • 什麼叫做「模式辨認受體」 (pattern recognition receptor，PRR)？ • 什麼叫做「發炎反應」 (inflammatory response)？ • 什麼叫做 Toll-like receptors ? 有何功能？ • 先天性免疫反應在演化上的意義。

3. Innate immunity is themost ancient • defense against microbes. • Some forms of innate immunity has • been found in all multicellularplants • andanimals. • Adaptive immunity evolved injawed • vertebratesand is a much more recent • evolutionary invention than innate • immunity.

5. Anatomical Barriers

6. Skin and Epithelial Barriers to Infection

8. How does the innate immune response initiate? • The host has “sensors” to detect the invader. • Soluble or membrane-bound molecules of • the host can precisely discriminate between • self (host) and nonself (pathogen). • These molecular sensors recognize broad • structural motifs(主結構) that are present in • microbes but are absent from the host.

9. Pattern Recognition Receptors (PRR) • Because the molecular sensors recognize • particular patterns, such receptors of the host are • called pattern recognition receptors (PRR) • The patterns found on pathogens are called • pathogen-associated molecular patterns (PAMP) • PRRs : soluble: e.g., complement system • membrane-bound: Toll-like receptors (TLR) • - PAMPs : combinations of sugars, certain proteins, • particular lipid-bearing molecules, and • some nucleic acid motifs

10. Inflammation

11. Localized Inflammatory Response described by the Romans almost 2000 years ago: Swelling Redness Heat Pain Loss of function (2nd century by a Greek physician, Galen 蓋倫, 129 -200 A.D.)

12. Vasodilation increase in vascular diameter rise of blood volume in the area → heats the tissue and causes it to redden Edema increase of vascular permeability leakage of fluid from the blood vessels → accumulation of fluid that swells the tissue Extravasation adherence of leukocytes to endothelium → pass through capillaries and into the tissues Phagocytosis leukocytes phagocytose invading pathogens release molecular mediators recruit and activate effector cells

13. Inflammation vasoactive chemotactic exudate chemotaxis extravasation

14. Soluble mediators released by inflammatory cells: 1. Cytokines : hormone- or growth-factor-like proteins that communicate via cell receptors to induce specific cell activities, e.g., interleukin-1 (IL-1), IL-6 & tumor necrosis factor α(TNF-α) 2. Chemokines : a subgroup of cytokines whose activity is their capacity to act as chemoattractants (agents that cause cells to move toward higher concentrations of the agent)

15. A major role of the cells attracted to the inflamed site is phagocytosis of invading organisms :

16. Leukocyte extravasation is essential for inflammation : rolling → activation → arrest/adhesion → migration

17. Interaction between Neutrophils and Endothelium • Cellular Adhesion Molecules (CAMs): • Mucin-like CAMs • Selectins • Integrins • Ig-superfamily CAMs

18. Soluble Molecules

19. Antimicrobial peptides are produced at the site of infection or injury and act locally *

20. Paneth cells provide host defense against microbes in the small intestines. They are functionally similar to neutrophils (also phagocytic and containing lysozymes). When exposed to bacterial antigens, Paneth cells secrete a number of antimicrobial molecules into the lumen of the crypt, thereby contributing to maintenance of the gastrointestinal barrier. *

21. Crypt 腺窩 Secretion of defensins by paneth cells within intestinal crypts serves as a primary barrier to bacterial infection

22. Paneth cells

23. Soluble Pattern Recognition Receptors Acute phase response (APR) proteins: - Complement - C-reactive protein (CRP) - Mannose-binding lectin (MBL) Lipopolysaccharide-binding protein (LBP) Nucleotide-binding oligomerization domain (NOD)

24. Acute phase response (APR) proteins: Complement system (Chapt 7) C-reactive protein (CRP): A pentameric protein, which binds phosphorylcholine, which is present on the surface of many microbes. CRP bound to a microbe promotes uptake by phagocytes and activates a complement-mediated attack on the microbe. Mannose-binding lectin (MBL): Recognizes mannose-containing molecular patterns found on microbes but not on vertebrate cells. MBL directs a complement attack on the microbes to which it binds.

25. Lipopolysaccharide-binding protein (LBP) recognizes lipopolysaccharide (LPS), a component of the outer cell wall of Gram negative (G -) bacteria. of G (−) bacteria (LPS)

26. Nucleotide-binding oligomerization domain (NOD) proteins are cytosolic proteins which recognize degraded products of peptidoglycans of Gram positive (G +) bacteria. Relative structure of gram negative (top) and gram positive (bottom) cell walls. The major differences lie in the thickness of the rigid peptidoglycan layer and in the presence of an outer membrane. In gram negative cells, the peptidoglycan layer is very thin, being only a few molecules thick, whereas in gram positive cells this layer is very thick. outer membrane peptidoglycan

27. gram-positive anthrax bacilli Gram’s stain (with crystal violet) of cerebrospinal fluid

28. Effectors of Innate Immune Responses to Infection

29. Membrane-associated Pattern Recognition Receptors

30. Structure of a Toll-like Receptor (TLR) (XLXXLXLXX) highly conserved among all members of the TIR family Toll/IL-1R

33. (Myeloid differentiation factor 88) (IL-1R-associated kinase) (TNFR-associated factor) (TGF-activated kinase)

35. Cell Types of Innate Immunity (ROS) (RNS) Interferon  TNF Interleukin 1 (IL-1) Interleukin 6 (IL-6) Tumor necrosis Factor  (TNF)

36. (phox) activated by phagocytosis The O2 consumed by phagocytes to support ROS production by the phox enzyme is provided by a metabolic process known as the respiratory burst, during which O2 uptake by the cell increases severalfold.

37. Generation of Nitric Oxide (NO) in Phagocytes L-arginine + O2 + NADPH → NO + L-citrulline + NADP inducible nitric oxide synthetase (iNOS) NO : accounts for much of the antimicrobial activity of macrophages against bacteria, fungi, parasitic worms and protozoa.

38. Adaptive Immunity Has to be Initiated by Innate Immunity

39. Ubiquity of Innate Immunity Well-developed system of innate immunity in non-vertebrate phyla Sea squirt : complement-like lectins (海鞘) Toll-like receptors Fruit fly : NFκB family pathway antibacterial peptide diptericin prophenoloxidase cascades – deposition of melanin around invading organisms

40. Tomato & other plants : - generation of oxidative bursts - raising of internal pH - localized death of infected regions - induction of chitinase – digest fungal wall - induction of α-1,3 glucanase – digest bacterial walls - antimicrobial peptides - nonpeptide organic molecules, such as phytoalexins, that have antibiotic activity - isolate cells in the infected area by strengthening the walls of surrounding cells

42. Questions: • What are the differences between innate • immunity and adaptive immunity? • 2. Describe an inflammatory response. • 3. Examples of pattern recognition and the receptors for pattern recognition. • 4. How does a phagocyte kill pathogens? • 5. How does a dendritic cell bridge innate immunity to adaptive immunity?