1. Innate Immunity Review on your own: Clathrin-mediated endocytosis Endomembrane transport system Also review slides on innate immunity in previous ppt Note about the alternative pathway of Complement: You are not responsible for knowing the specific steps that are unique to this pathway. Self-Test Questions: A: both B1: all B2-3: 1 - 6, 9 B4: 1 - 4 B5: 1 - 5 B6: 1 Innate Immunity

2. What is inflammation? An Innate response involves cellular & physiological elements Localized Redness (erythrema) -- Capillary vasodilation Swelling (edema) -- Capillary vasopermeation Pain –Nerve pressure (swelling) , damage Heat Loss of function Systemic -- infection only Fever Increase in WBC Changes in serum proteins -- e.g., Acute phase proteins Diagnostic for infection Innate Immunity

3. “Danger signals” activate innate cells “Danger signals” = PAMPs “Pathogen-associated molecular patterns” -- molecules of pathogens or wounding -- general structure/widespread occurrence PAMPS bind to Receptors called PRRs “Pattern Recognition Receptor” -- e.g., “Toll-like receptors” (TLR) -- other types also Very important to DC activation -- upregulates MHC expression -- allows T-cell activation Some Danger Signals (See Table 3-1 & Table 7-3) Viral dsRNA Viral ssRNA Bacterial LPS, flagellin, pilin Bacteral and fungal cell wall components Microbial polysaccharides Reactive oxygen molecules H202, OH-, O2- Certain cellular molecules Innate Immunity

4. Danger signals trigger an “anti-viral” state Which can be disabled by many viruses Cell destruction also releases new warning signals Innate Immunity

5. Clinical presentation of the innate response Acute Phase Response immune cells  appetite fever lethargy etc. ΔAcute Phase Proteins C-reactive protein  -- removal of dead cells Ferritin, Hepcidin  -- bind iron Complement proteins  -- attack pathogens Coagulation proteins  -- enhance blood clotting Etc. Innate Immunity

6. Sedimentation rate, Black bile & Medieval blood letting Fibrinogen & Rouleaux = “Black bile” Rouleaux Innate Immunity

7. Chronic inflammation causes tissue damage, disorders and cancer Liver, colon, and stomach cancer arteriosclerosis Tuberculosis Consequence of “collateral” damage by secreted enzymes and oxidative chemicals Innate Immunity

8. Helicobacter pylori and peptic ulcers causes 60-80% of stomach ulcers 90% doudenal ulcers Stomach cancers Innate Immunity

9. What is complement? What are the 4 principal functions of complement? Innate Immunity

10. Complement involves a “proteolytic activation cascade” C1 activates C4, which activates C2 … to C9 What are the 3 pathways of initiation? Classical (acquired) -- initiated by Ab bound to AG Alternative (innate) -- does not involve Ab binding Lectin (innate) -- activated by mannose-binding lectin C3 Innate Immunity

11. The Classical Pathway involves 3 stages Initiation begins with C1 binding to Ab bound to Ag Bind to Fc part of Ab Innate Immunity

12. Activated C1 triggers activationof C4 and then C2 -- to form C3 Convertase C3 convertase activates C3 -- which acts as an opsonin and becomes part of C5 convertase Activation of C3 is an important ‘amplification’ step Innate Immunity

13. C5b triggers formation of the Membrane Attack Complex MAC is most effective against Gram-negative bacteria Nucleated cells Enveloped viruses Innate Immunity

14. The Alternative Pathway C3 spontaneously fragments into C3a and C3b -- which can bind to AGs -- pathogens and Immune complexes Binding to other protein “factors” creates alternative C3 & C5 Convertases -- leading to MAC formation Lectin pathway is initiated by Mannose-Binding Lectin -- binds to bacterial glycoproteins Creates C1-like activator -- activates C4, C2, etc McGraw-Hill Complement Activation Innate Immunity

15. How is Complement regulated? 1) Lability of protein fragments -- rapid, spontaneous inactivation 2) Sialic acid in glycoproteins -- inactivates C3b on body cells 3) Regulatory proteins -- e.g., C1 inhibitor (see table 3-3) Hereditary Angioedema Complement receptors mediate other functions -- immune complex clearing -- chemotaxis -- opsonization Innate Immunity

16. How does C3b cause opsonization by phagocytic cells? Roles for both Fc and Complement receptors C3b is primary opsonin binds to CR1 receptor Coating of viruses blocks receptors and enhances opsonization Innate Immunity

17. RBCs and CR1 play major role in immune complex clearance Immune complexes generate C3b -- via classical or alternative pathways Transport to spleen & liver Phagocytosis Deficiencies in complement-mediated IM-complex clearing are major cause of Systemic Lupus Erythromatosus (SLE) Innate Immunity