Immunology Lecture 2 2024 PDF

Innate Immunity 13th November 2024 T.S. Wilkinson Introduction to the immune system  Learning objectives Introduce innate immunity Understand the important cells associated with innate immunity Understand the important mediators associated with innate imm...

Innate Immunity 13th November 2024 T.S. Wilkinson Introduction to the immune system  Learning objectives Introduce innate immunity Understand the important cells associated with innate immunity Understand the important mediators associated with innate immunity Differentiate between innate and adaptive immunity  Immune system-anatomy and organisation Immune System 1st line 2nd line 3rd line Intact skin and Innate Immunity Acquired Immunity mucous membranes (Natural) (Adaptive) Barrier Non-Specific Specific B-lymphocytes Complement T-lymphocytes Neutrophils Epithelial cells Memory T cells Monocytes / macrophages Cytotoxic T cells Natural Killer Cells Antibodies Innate vs Adaptive immunity  Neutrophil Staphylococcus aureus Red Blood cell This video is taken from a 16-mm movie made in the 1950s by the late David Rogers at Vanderbilt University. This movie is in QuickTime format and was digitized from the analog footage and made available on the Internet by Philip G. Allen (Boston University) and Gabriel Fenteany (University of Connecticut).  Innate Immunity Complement Toll-like receptors Cytokines Chemokines Phagocytes-neutrophils and macrophages Phagocytosis Inflammation  Complement ‘Sensitizer’ or ‘helpers’ ~20 serum proteins Many are pro-enzymes / zymogens 3 major effects: – Lysis-MAC – Chemoattraction-C5a – Opsonisation-C3b 3 major pathways  Classic Lectin Alternative Microbial Surfaces Antigen-antibody Microbial Saccharides (Diverse activators e.g LPS) complexes (Specific activator) MBL C1 C3(H2O) +B D C1 C3a +C3b C4 C2 C4,2b C3 C3 C3b,Bb (C3 convertase) + C2a,C4a (C3 convertase) C4b,2b,3b C3b,Bb,C3b C5 (C5 convertase) + C3a (C5 convertase) + C3a C5a + C5b Complement C6 C7 C5b,6,7 C8 C9 pathways C5b,6,7,8,9  Toll-like receptors Sentinels- Sense, respond to pathogens Present on leukocytes and mucosal lining cells Recognise PAMPs-pathogen associated molecular patterns-conserved sequences 12 members and each has a specificity Homo- or hetero-dimers Combinations determine response Extracellular 1,2,4,5,6,11 / Intracellular 3,7,8,9, Downstream effects produce cell activation and cytokine secretion Toll-like receptors  Cytokines Cyto-cell, Kinos-movement Diverse group of small proteins (25kDa) Act at low concentration (pg-ng-µg range) They are redundant! Growth, differentiation and activation Synergise with one another  Important cytokines Interleukin-1(IL-1) Tumor Necrosis Factor (TNF) – Early induction, Pro-inflammatory, Up-regulate chemokines Interleukin-10 (IL-10) – Anti-inflammatory Interferon-gamma (IFN-γ) – Anti-viral, increases macrophage bacteriocidal activity  Chemokines Chemotactic cytokines Four subfamilies, overall more than 100 members. Classification based on two first cysteines Two large families:  or CXC and  or CC. Two additional types:  or C and  or CX3C. Receptors – 7 TMD, G-protein coupled (GPCR). Two major receptor families: CXCR1-N and CCR1-N Most of chemokines interact with multiple receptors, and most of receptors respond to multiple chemokines. Subset specificity – IL-8 and neutrophils Chemokines  Macrophages Sentinels and Scavengers Resident phagocyte Eat and clear bacteria and dead cells Monocytes recruit to tissues and become macrophages Killing is Nitrogen related (RNS), iNOS Last for weeks Express TLR and produce cytokines  Neutrophils Blood phagocyte Short half-life / high turnover Multi-lobed nucleus Granules (1°, 2°, 3°) Phagocytosis Killing mechanisms are Oxygen related (ROS), NADPH oxidase Express TLRs NETs Apoptosis  Neutrophil Apoptosis Programmed cell death NOT Necrosis Stimulates clearance by macrophages Membrane remains intact Prevents tissue injury See apoptosis lecture  Phagocytosis ‘Cell eating’ Binding of pathogen to a phagocytic receptor Internalised Sealing Scission from the membrane-phagosome Maturation-sequential fusion – Early endosomes – Late endosomes – Lysosomes Phagolysosome  Phagocytic receptors FcγRII/CD32 FcγRIII/CD16 Y FcγRI/CD64 Y Y Fc γ RECEPTORS CR-1/CD35 Mannose LECTIN RECEPTORS Dectin-1 CR-3 COMPLEMENT RECEPTORS CR-4 SCAVENGER RECEPTORS CD14 SR-A CD36  Phagosome maturation Early endosome Late endosome Early phagosome Lysosome pH=6.1-6.5 NADPH Low hydrolytic activity oxidase Low V-ATPase proton pump Late phagosome pH=5.5-6.0 Proteases Low hydrolytic activity Phagolysosome Low V-ATPase proton pump pH=4.5-5.5 Proteases Phagolysosome High V-ATPase proton pump Lactoferrin Host defence peptides Hydrolytic enzymes NADPH oxidase  Inflammation rubor et tumor cum calore et dolore (redness and swelling with heat and pain), Celsus 1AD Bacteria TISSUE-infection Neutrophil Exudate Resident tissue macrophage Localised vasodilation (↑Ø) Increased capillary permeability Resident macrophage Localised oedema Wall off the inflamed area Emigration of leukocytes Location and destruction of bacteria Return to homeostasis Monocyte BLOOD MATRIX  Inflammation Rolling BLOOD Activation Adhesion PSGL-1 Chemokines Selectins Integrins GPCRs Transmigration ICAM/VCAM Integrins JAMs TISSUE-infection Bacteria  Acute inflammation Neutrophils Bacteria Resident Macrophages Monocyte / Macrophages 0-4hrs 4-96hrs >96hrs Time line  Summary You’ve seen innate immunity in 30s You’ve heard about the parts you could see: Phagocytes, phagocytosis and inflammation We’ve filled in the parts you couldn’t see: Complement, TLRs, Cytokines and chemokines  Summary: Innate immunity Built in mechanisms Aimed at preventing injury Aimed at pathogen removal Physical / chemical barriers to infection DNA encoded proteins that recognise common structures on pathogens Rapid recognition, phagocytosis and destruction Pathogen clearance  Next time… Adaptive Immunity-tomorrow