Key Concepts Innate Immunity PDF

PHMD205A Immunology Course KEY CONCEPTS: Innate Immunology (Dr. Jusiak) I. Major Concepts The body has three lines of defense against pathogens: barriers, the innate immune system, and the adaptive immune system. First line of defense: barriers - skin, gut, lungs, nose, eyes, or...

PHMD205A Immunology Course KEY CONCEPTS: Innate Immunology (Dr. Jusiak) I. Major Concepts The body has three lines of defense against pathogens: barriers, the innate immune system, and the adaptive immune system. First line of defense: barriers - skin, gut, lungs, nose, eyes, oral cavity Mechanical barrier: cell junctions, beating cilia, flow of air or fluid Chemical defenses: peptides, proteins, low pH in the stomach Microbiological: local microbiota outcompetes pathogens but may give rise to opportunistic infections when host is weakened Innate immune response acts following breach in a barrier: Quick, non-specific recognition of pathogen Purpose: limit growth of pathogen, generate inflammation, send signals to activate adaptive immune system If innate immune system insufficient to clear pathogen, adaptive immune system takes action Compare and contrast activity of innate vs. adaptive immune system Many ways for pathogens to enter the body: through air, contaminated food or water, sexual contact, exposure to contaminated blood, wounds/abrasions, insect bites Cells of the innate immune system Use adhesion molecules to gain access to pathogen - interaction between innate immune cells and endothelial cells lining blood vessels Respond to chemokine signals signaling molecules that attract WBC to site of infection May be tissue resident (e.g., macrophages) or circulate in the blood and enter tissues in response to proinflammatory signals (e.g., neutrophils) Recognize pathogens using Pattern Recognition Receptors (PRRs) Multiple methods to kill pathogen Phagocytosis engulfs and destroys pathogens Antimicrobial peptides and enzymes (e.g., lysozyme) Degranulation releases large amounts of antimicrobial molecules, peptides, proteins NETs (only neutrophils) Complement cascade (see below) Antigen-presenting cells alert the adaptive immune system Know the types of innate immune cells and what they do Complement system  Protein-based signaling cascade, uses inactive precursor proteins present constantly in the blood Complements the phagocytic activity of innate immune cells Three pathways Must tightly control activation of the complement cascade Alternative, Classical, Mannose Binding Lectin All converge on formation of C3 convertase Cleaves C3 into C3a and C3b Functional outcomes of complement activation: Signal to recruit more immune cells Opsonize pathogens to target them for phagocytosis Punch holes in bacterial cell membranes (MAC attack) II. Conditions Leukocyte Adhesion Deficiency (LAD) - susceptibility to infections Chronic granulomatous disease/NADPH oxidase deficiency - cannot clear infections Terminal complement pathway deficiency - susceptibility to Neisseria infections Hereditary angioedema (HAE) - recurrent severe swelling III. Know the language/definition of immunological terms: 1. Myeloid cells: the blood cell lineage that includes red blood cells, platelets, and innate immune cells 2. Leukocytes: general term for white blood cells 3. Neutrophils: most common immune cell type, phagocytes & granulocytes, die quickly after eating pathogens, form pus; can form NETs 4. Eosinophils: innate immune cells, defend against parasitic worms & bacteria, phagocytes and granulocytes 5. Basophils: rare innate immune cells, large granulocytes and phagocytes, fight parasites 6. Mast cells: innate immune cells, granulocytes, fight parasites, release pro-allergy molecules 7. Monocytes: short-lived immune cells that circulate in blood, phagocytes, can exit bloodstream and differentiate into macrophages in response to infection 8. Macrophages: innate immune cells, can arise from circulating monocytes or can be long-lived tissue-resident cells; phagocytes and antigen-presenting cells; behavioral plasticity (can be pro- or anti-inflammatory) 9. Dendritic cells (DCs): innate immune cells, phagocytes; conventional (cDCs) eat pathogens and travel to lymph nodes, where they present antigens to T cells; plasmacytoid (pDCs) detect & fight viruses 10. Chemokines (homeostatic and inflammatory): secreted protein ligands that attract immune cells; signal via chemokine receptors; large protein family 11. Cytokines: general name for secreted proteins that signal between immune cells;  have a large variety of functions, including proinflammatory (turn immune system functions on to fight pathogens) and anti-inflammatory (turn immune system functions down/off to prevent excessive inflammation and autoimmunity); chemokines are a subtype of cytokine 12. Adhesion molecules: proteins that cells use to adhere to each other; important for immune cells to exit bloodstream & enter infected tissues 13. Addressins: adhesion molecules expressed by innate immune cells, bind selectins 14. Integrins: adhesion molecules expressed by innate immune cells, bind ICAMs 15. Selectins: adhesion molecules expressed by activated endothelium, bind addressins 16. ICAMs: adhesion molecules expressed by activated endothelium, bind integrins 17. LFA-1/CD18: integrin subunit, its loss causes LAD 18. Pattern Recognition Receptors (PRRs): expressed on innate immune cells, recognize molecular patterns associated with pathogens 19. PAMP (Pathogen Associated Molecular Patterns): molecules associated with pathogens, recognized by innate immune cells 20. DAMP (Damage Associated Molecular Patterns): molecules associated with tissue damage/dying cells, recognized by innate immune cells 21. Toll-like receptors (TLRs): found on cell membrane or in endosomes; recognize broad classes on molecules found on pathogens but not host cells (LPS, flagellin, dsRNA) 22. NOD-like receptors (NLRs): intracellular receptors that recognize intracellular bacteria 23. C-type lectin receptors (CLRs): a type of PRR that recognizes fungal infections 24. NFkB: transcription factor, master regulator of inflammation, active in response to TLR/NLR signaling 25. Phagocytosis: the engulfment and destruction of a pathogen by an immune cell; many innate immune cell types are specialized phagocytes 26. NADPH oxidase: enzyme that catalyzes production of reactive oxygen species, required for efficient destruction of phagocytosed pathogens 27. Neutrophil extracellular traps (NETs): chromatin-based “nets” that trap pathogens 28. Granulocytes: innate immune cells that contain granules packed with antimicrobial substances that are released in response to infection 29. Lipid mediators of inflammation: lipid-based molecules, incl. Prostaglandins, that trigger inflammation; synthesized from cell membrane lipids 30. NSAID (non-steroidal antiinflammatory drugs): inhibit the synthesis of proinflammatory lipid molecules 31. Complement system: proteins that exist as inactive precursors in blood, become activated by pathogens, help innate immune cells fight infection; inappropriate activation causes HAE 32. Classical pathway: complement activation by C1 binding to pathogen (directly or via antibody binding) 33. Alternative pathway: complement activation by spontaneous hydrolysis of C3 to C3(H2O) 34. Mannose binding lectin pathway(MBL): complement activation by MBL binding  to exposed mannose residues on pathogen surface 35. C3 Convertase: enzyme complex that cleaves C3 inactive precursor protein into the active components C3a and C3b 36. C3a: small cleavage product of C3; diffuses away and signals to recruit innate immune cells 37. C3b: large cleavage product of C3; sticks to pathogens and opsonizes them; can also initiate cleavage cascade culminating in MAC formation 38. Opsonization: coating pathogens with C3b, making them easier for phagocytes to eat 39. Membrane Attack Complex (MAC): complement-based protein complex that punches holes in bacterial membranes; attacks Neisseria (Big MACs are Neis) 40. Decay Activating Factor (DAF) and Membrane Cofactor Protein (MCP): proteins that inactivate complement cascade to prevent it from inappropriately targeting host cells