Innate Immunity Notes

NOTES NOTES INNATE IMMUNITY INNATE IMMUNE SYSTEM osms.it/innate-immune-system ▪ Comprises immune system along with adaptive immunity ▪ Includes barriers to repel pathogens ▫ Chemical barriers: lysozyme (tears), low stomach pH ▫ Physical barriers: epithelium (skin/gut), cilia lining airways Key features ▪ Nonspecific cells do not distinguish invaders ▪ Response occurs within minutes–hours ▪ No memory ▫ Always responds to pathogen in same manner Human microbiome ▪ Included in innate immunity ▪ Bacteria, fungi, viruses in/on humans ▪ May affect host response in own way RESPONSE TO PATHOGENS Phagocyte response to pathogens ▪ Phagocytes eat, kill pathogens ▪ Phagocyte consumes pathogen ▫ Phagocytic pattern recognition receptors (PRRs) on phagocyte identify pathogen-associated molecular patterns (PAMPs) on pathogens (e.g. bacterialwall components) ▫ Phagocyte swallows pathogen, traps it in phagosome 400 OSMOSIS.ORG ▪ Phagocyte kills pathogen (postidentification) ▫ Phagosome binds with lysosome, forms phagolysosome ▫ Specific phagolysosome granules (proteases, hydrolases) kill internal microorganisms while decreasing pH ▫ Azurophilic granules (hydrolases, oxidative enzymes) activate in acidic environment → more microorganisms killed ▫ Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases oxidize oxygen molecules → superoxide ion creation ▫ Superoxide dismutase converts superoxide into hydrogen peroxide, killing remaining microorganisms Signalling PRRs response to pathogens ▪ Large amount of pathogens enter → signalling pattern recognition receptors also activated ▪ Signalling PRRs → phagocytes to release cytokines ▪ Toll-like receptors (TLRs) especially important in signalling PRRs ▫ PAMP activation → TLRs activate transcription factor NF-κB → proinflammatory cytokines (e.g. TNFα, IL-1β, IL-6) secreted → vasodilation, fever, recruiting leukocytes ▫ Intracellular pathogens: interferon alpha, beta may be secreted (prevents pathogen multiplication)

Chapter 47 Immunology: Innate Immunity Figure 47.1 Overview of the phagocyte response to pathogens. 1. The phagocyte’s pattern recognition receptors (PRRs) identify pathogen-associated molecular patterns (PAMPs) on the pathogen. 2. The pathogen is phagocytosed and trapped in a phagosome, which then 3. binds with lysosomes, forming a phagolysosome. 3a. Specific granules from the lysosomes act first to kill pathogens and decrease pH. 3b. After the pH is sufficiently lowered, azurophilic granules are activated and kill more pathogens. 4. NADPH oxidases oxidize oxygen molecules to create superoxide ions. The ions are then converted by superoxide dismutase into hydrogen peroxide, which kill the remaining pathogens. OSMOSIS.ORG 401

COMPLEMENT SYSTEM osms.it/complement-system ▪ Collection of plasma proteins called complement proteins ▪ Produced in liver, collectively destroy pathogens COMPLEMENT SYSTEM PATHWAYS ▪ Acts follow one of three pathways ▫ Classical, alternative, lectin Classical pathway ▪ Features C1–C9 proteins ▪ C1 ▫ Component proteins C1q, C1r, C1s (latter two—serine proteases) Figure 47.2 Structure of a C1 protein. Each of the six C1q proteins can bind to an antibody-antigen complex. Calcium ties the protein together. ▪ Proteins inactive until “cleaved” (portion of protein breaks off) ▪ Pathway steps ▫ C1q proteins bind to Fc portion of antibody when bound to antigen ▫ Two C1q proteins bind → C1 changes shapes (conformational change) exposing C1r, C1s 402 OSMOSIS.ORG ▫ C1r cleaves C1s (activating C1 molecule) → C1 cleaves C4 into C4a, C4b → C4b binds to pathogen ▫ C1 also cleaves C2 into C2a, C2b → C2a joins C4b on pathogen → C4b2a (C3 convertase) formed ▫ C3 convertase cleaves C3 into C3a, C3b ▫ C3b binds to pathogen near C4b2a/ C3 convertase, creates C5 convertase (C4b2a3b) ▫ C5 convertase cleaves C5 into C5a, C5b ▫ C5b binds to C6, C7, C8, many C9s → forms membrane attack complex (MAC) → penetrates pathogen cell membrane ▪ C1 consists of six C1q proteins ▫ Binds to six antibody-antigen complexes ▪ Calcium ties together C1 ▫ Lack of calcium → lack of C1 Alternative pathway ▪ Factor B, factor D proteins ▪ C3 cleaved spontaneously (small amounts) ▪ Pathway steps ▫ C3b binds to pathogen → factor B binds to pathogen ▫ Factor D cleaves factor B → forms Ba, Bb → C3bBb formed (C3 convertase) ▫ Follows classical pathway ▪ Constant activation prevention ▫ C1-inhibitor protein dissociates C3bBb Lectin pathway ▪ Features mannose-binding lectin protein (binds to bacterial mannose) ▪ Pathway steps ▫ Mannose-binding lectin protein acts similar to C1 → cleaves C4, C2 to eventually establish C4b2a (C3 convertase) ▫ Follows classical pathway

Chapter 47 Immunology: Innate Immunity Figure 47.3 Overview of the classical complement pathway. 1. C1q binds to an antibody-antigen complex. 2. When two C1q proteins are bound, C1 undergoes a conformational change, exposing C1r and C1s. C1r then cleaves C1s to activate C1. 3. C1 cleaves C4 and C2. 4. C4 and C2 bind to the surface of the pathogen, forming C3 convertase. 5. C3 convertase cleaves C3. 6. C3b binds to the pathogen near the C3 convertase, forming C5 convertase. 7. C5 convertase cleaves C5. 8. C5b joins C6, C7, C8, and then multiple C9s to form the membrane attack complex, penetrating the pathogen cell membrane. OSMOSIS.ORG 403

Figure 47.5 Overview of the lectin pathway. Mannose-binding lectin protein binds to mannose on the pathogen, then cleaves C4 and C2. The rest follows the classical pathway (from step 4 in earlier figure). OTHER COMPLEMENT PROTEIN ROLES Figure 47.4 Overview of the alternative complement pathway. 1. Small amounts of C3 are cleaved spontaneously. 2. C3b and factor B bind to the pathogen. 3. Factor D cleaves factor B. 4. C3b and Bb form a C3 convertase and cleave more C3 proteins. The rest follows the classical pathway (from step 6 in previous figure). 5. C1-inhibitor constantly prevents activation of this pathway by dissociating C3bBb. ▪ In addition to MAC-formation ▫ C3b: opsonin → opsonizes pathogens, coats them with molecules, encourages phagocytosis ▫ C5a, C3a: chemotaxins → recruit neutrophils, eosinophils, monocytes, macrophages ▫ C5a, C3a: anaphylatoxins → cause basophil, mast cell degranulation, releases proinflammatory molecules Figure 47.6 Other roles of complement proteins. C3b acts as an opsonin; it coats pathogens to facilitate phagocytosis. C5a and C3a act as chemotaxins; they recruit neutrophils, eosinophils, monocytes, and macrophages. C5a and C3a also act as anaphylatoxins; they cause basophils and mast cells to degranulate. 404 OSMOSIS.ORG