1. Section 11: Extracellular Macromolecules 3. Innate immunity & inflammation 2/14/06

2. The immune system  main function:  distinguish foreign/abnormal molecules & cells from one's own molecules & cells  destroy/neutralize the foreign/abnormal ones  two major divisions: innate & adaptive  innate immune response overview  relatively rapid & nonspecific  microorganisms encounter macrophages  interaction activates macrophages  macrophages secrete signal factors which trigger inflammation inflammation leukocyte activation leukocyte activation phagocytosis phagocytosis activation of lymphocytes (adaptive immune response) activation of lymphocytes (adaptive immune response) 1

3. Definitions  cytokines: proteins that are intercell signal factors; if the cells are leukocytes, the term interleukins (IL) is sometimes used, especially in naming cytokines, e.g., IL1, IL2, etc.  chemokines: small chemoattractant cytokines that stimulate the migration and activation of cells, especially phagocytic cells and lymphocytes  chemotaxins: substances that attract leukocytes  The early phases of the host response to infection depend on innate immunity in which a variety of innate resistance mechanisms recognize and respond to the presence of a pathogen. Innate immunity is present in all individuals at all times, does not increase with repeated exposure to a given pathogen, and discriminates between a group of related pathogens. (from Immunobiology 5 ed. Janeway et al. 2002) 2

4. Definitions (cont’d)  Inflammation is a general term for the local accumulation of fluid, plasma proteins, and white blood cells that is initiated by physical injury, infection, or a local immune response. This is also known as an inflammatory response. Acute inflammation is the term used to describe early and often transient episodes, whereas chronic inflammation occurs when the infection persists or during autoimmune diseases. Many different forms of inflammation are seen in different diseases. The cells that invade tissues undergoing inflammatory responses are often called inflammatory cells or an inflammatory infiltrate. (from Immunobiology 5 ed. Janeway et al. 2002) 3

5. Macrophage activation  macrophages have numerous receptors for molecules on bacterial surface  important example: LPS  binding to LPS receptor  activates intracellular messengers  transcription of several target genes  result:  release of lipid mediators*  secretion of cytokines,* including chemokines 4 *macrophage effectors

6. Bacterial components: endotoxins  lipopolysaccharides (LPS) aka endotoxins (structure at right)  part of the outer membrane of gram–negative bacteria  lipid part called lipid A: 6 hydrocarbon chains  effects activate phagocytes activate phagocytes leukocyte–toxic leukocyte–toxic antigenic antigenic cause release of lytic enzymes from leukocytes cause release of lytic enzymes from leukocytes core O-antigen – – – – l i p i d A core: 8-10 glycosidic units O-antigen: 0-40 glycosidic units 5

7. Surface structures of gram negative bacteria 6

8. Macrophage effectors draw plasma proteins, leukocytes: inflammation  lipid mediators released by macrophages (prostaglandins, leukotrienes, PAF, etc.) produce the inflammatory response  vasodilation (redness, heat)  increased spacing between capillary endothelial cells  this causes plasma proteins* to diffuse into interstitium, changing osmotic balance  result: net fluid flow into interstitium (swelling) 7 prostaglandins, etc. cytokines chemokines protein fluid * including complement proteins (slide 11)

9. Osmotic balance capillaryinterstitial lumenspace  P  hydrostaticoncotic pressurepressure (blood pressure) (plasma-colloid osmotic pressure) source: plasma proteins 60-80 g/L ~ 1-1.3mM for further details, see Sherwood, p. 365 8

10. Macrophage effectors draw leukocytes: inflammation  cytokines activate capillary endothelial cells via TNF-   effects of activation: proteins expressed on luminal surface of endothelial cells  Selectins bind to specific surface glyco moieties on leukocytes  ICAMs bind to integrins on leukocytes  result: neutrophils,monocytes extra- vasate (enter interstitium) (slide 13) 9 cytokines: TNF-  leukocyte extravasation

11. Macrophage cytokines’ systemic inflammatory effects  cytokines (TNF- , IL-1, IL6)  mobilize neutrophils (bone marrow)  endogenous pyrogens (hypothalamus)  activate acute-phase response (liver)  acute-phase proteins  secreted into blood by hepatocytes e.g., mannose-binding (MB) lectin C-reactive protein (CRP)*  main effects: opsonize (bind to & mark for phagocytosis) bacteria for leukocytes opsonize (bind to & mark for phagocytosis) bacteria for leukocytes activate complement cascade activate complement cascade 10 CRP *clinically useful marker for disorders, e.g., CVD

12. Complement activation & effects  the complement system is a set of plasma proteins that act together to attack extracellular forms of pathogens  they get to infection site via permeable endothelium  activation: via a series of proteolytic steps (a cascade like blood clotting) MB= mannose-binding 11 C3b MB lectin

13. Complement effects  complement activation leads to activation of mast cells (by C3a, C5a)  mast cells secrete histamine, a vasodilator  C5b-C9 form pore in bacterial membrane, causing leakage & lysis (see S11L4sl23)  opsonization: marking microorgan- ism’s surface for phagocytes (C3b, C4b)  opsonins bind to bacteria & then bind to a surface receptor on a phagocyte  recruitment of leukocytes  some components are chemokines 12 CR1 C3b

14. Leukocyte adhesion & extravasation Lodich et al., 5 ed. Fig. 6-30 13

15. Phagocytosis & pathogen destruction  bacteriocidal reactions in phagolysosomes 2 O 2 + NADPH → NADPH + + O 2 – NADPH oxidase 2 O 2 – + 2 H + → O 2 + H 2 O 2 superoxide dismutase 2 Cl – + 2 H 2 O 2 → 2 ClO – + 2 H 2 Omyeloperoxidase  other lysosomal bacteriocides lysozymelyses glycopeptide coat proteaseshydrolyze proteins defensinscationic peptides disrupt cell membrane  if/when any of the above lytic molecules escape phagocytes, damage to local tissues results  part of chronic inflammation 14

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