Chapter 14: Innate Immune System

1. Chapter 14:Innate Immune System

2. Overview of Immune Defenses • First-line defenses: • Intact, healthy skin and mucous membranes • Normal microbiota

3. Overview of Immune Defenses • Sensory systems: • Pattern recognition receptors • Toll-like receptors • NOD-like receptors • RIG-like receptors • Complement system • Alternative pathway • Classic pathway • Lectin pathway

4. Overview of Immune Defenses • Innate effector actions: • Inflammatory response • Interferon response • Opsonization • Membrane attack complex

5. First-line defenses: SKIN High turnover Immune surveillance: dendritic cells, macrophages Salt Normal skin biota SALT

6. First-line defenses: MUCOUS MEMBRANES High turnover Immune surveillance: dendritic cells, macrophages Secretions Normal biota MALT

7. Mucosal epithelium: intestinal mucosa

8. Mucosal surfaces: respiratory mucosa

9. Antimicrobial substances • Produced by animals: • Lysozyme • Peroxidase enzymes • Lactoferrin • Transferrin • Defensins • Produced by your microbiota: • Fatty acids • Colicins • Lactic acid

10. Cells of the Immune System • Granulocytes: • Neutrophils • Eosinophils • Basophils • Mast cells • Mononuclear phagocytes: • Monocytes • Macrophages • Dendritic cells • Lymphocytes: • T cells • B cells • NK cells

12. Neutrophils • Phagocytic • Granules: • Lysozyme, Phospholipase A2, myeloperoxidase, elastase, acid hydrolases, lactoferrin . . . • Most numerous leukocyte in circulation • Migration to tissue = major component of inflammatory response • Short life span • NETs

13. Macrophages • Phagocytic • Lysosomes: • Lysozyme, peroxidase. . . • Mature, tissue form of monocyte • Increased migration and maturation of monocytes to tissue in inflammatory response • Long life span • TLRs: on cell surface & in lysosomes • Cytokines: • Activation → enhanced killing power

15. Dendritic Cells • Phagocyticsentinel cells • Antigen presenting cells • Most = monocyte/ macrophage cell line • Long life span • Important bridge between innate & adaptive immunity

16. Natural Killer Cells • Non-specific lymphocytes • Do not require antigenic stimulation

17. Cell Communication: SURFACE RECEPTORS

18. Cell Communication: CYTOKINES • Chemokines • Colony stimulating factors • Interferons • Interleukins • Tumor necrosis factor (TNF)

19. Interferonsα and β

20. Cell Communication: ADHESION MOLECULES • Integrins: large family, widely expressed, involved in interaction with ECM • Selectins: small family, differentially expressed by leukocytes & endothelial cells, involved in leukocyte extravasation • Cadherins: large family, widely expressed, involved in adhesion between cells • ICAMs & VCAMs: part of immunoglobulin superfamily; many roles in immune response/inflammation

21. Pattern Recognition Receptors • Recognition of PATHOGEN-ASSOCIATED MOLECULAR PATTERNS / MICROBE-ASSOCIATED MOLECULAR PATTERNS (PAMPs / MAMPs): • Peptidoglycan • Lipopolysaccharide • Techoic acid • Flagellin subunits • Viral RNA • Recognition of DANGER-ASSOCIATED MOLECULAR PATTERNS (DAMPs): • Molecules that indicate cellular damage

22. Pattern Recognition Receptors • Toll-like receptors (TLRs): • Membrane-bound receptors • Macrophages, dendritic cells, cells lining sterile sites (i.e., mesothelial cells) • Detection of PAMPs → signal to nucleus → upregulation of gene expression → response

23. Pattern Recognition Receptors • NOD-like receptors (NLRs): • Located in the cytoplasm – most (all?) cells • Detect PAMPs or DAMPs

24. Pattern Recognition Receptors • RIG-like receptors (RLRs): • Located in the cytoplasm – most (all?) cells • Recognize viral RNA • Allow cells to detect a viral invader • Recognition of viral RNA by RLR → synthesis and secretion of interferons → expression of inactive viral proteins → activation of IVPs by dsRNA → apoptosis of infected cells

25. The Complement System • Consists of interacting proteins produced in the liver and found in blood and tissues • These proteins promote • Opsonization • Inflammation • Cell lysis

26. The Complement System • Central feature = splitting of C3 → C3a & C3b • Enzyme that splits C3 = C3 convertase • C3 also spontaneously degenerates to form C3a & C3b at a constant rate • Alternative pathway: C3b binds to foreign cell surface receptors → formation of C3 convertase • Lectin pathway: pattern recognition receptors = mannose binding lectins (MBLs): bind to mannose molecules on microbial surface → formation of C3 convertase • Classical pathway: antibody binds antigen = antigen-antibody complex → formation of C3 convertase (adaptive immune response)

28. Phagocytosis • Chemotaxis • Recognition and attachment • Engulfment • Phagosome maturation and formation of phagolysosome • Destruction and digestion • Exocytosis

29. Phagocytosis

30. The inflammatory response • Acute inflammation – example of activation: • TLR on sentinel MØ recognizes PAMP → MØ produces TNF → induces liver to synthesize acute phase proteins → activation of phagocytes, activation of complement • Tissue damage: “Danger Model” of immune system – ex. = activation of coagulation cascade in response to blood vessel damage

31. The Acute Inflammatory Response • Calor = heat: increased blood flow to site • Rumor = redness: increased blood flow • Tumor = swelling: fluid and cells accumulate • Dolor = pain: pressure + chemical mediators • Functiolaesa: many possible causes

32. The acute inflammatory response

33. Recruitment of leukocytes from the blood to a site of acute inflammation:

35. Chronic inflammation • Acute response is unsuccessful in resolving the problem • Can last years, often associated with significant tissue damage • May be due to chronic infection, repetitive injury, chronic implantation of foreign material or self-perpetuating because of damage induced by the immune system itself in the absence of ongoing infection/other external cause

36. Fever • Protective mechanism = resetting of the thermostat • Make the body less hospitable to pathogens • Slowed microbial growth = time to raise a defense • Increases rate of enzymatic reactions → enhanced inflammation, phagocytosis, lymphocyte proliferation, hematopoiesis, production/release of cytokines and antibodies • Pyrogens: • Endogenous: interferons • Exogenous: LPS

37. Fever

38. Fever ≠ acute inflammation! Fever = a systemic change in the body temperature Heat associated with acute inflammation = localized increase in temperature