Immunology - Innate Immune Response Flashcards
Two methods of communication in the immune system
Direct contact
Indirect
Direct contact communication
Receptor (e.g. immune cell)
Ligand (e.g. pathogen, immune cell, tissue cell)
Indirect communication
Injured tissue cells and activated immune cells can produce and secrete cytokines
Autocrine signal acts on immune cells or injured tissue
Paracrine signal acts on nearby cells
Phases of Innate Immune Cell Response
Recognition
Activation
Effector
Recognition Phase
Pathogens express PAMPs (pathogen associated molecular patterns)
Innate immune cells express PRRs (pattern recognition receptors) specific to PAMPs
Activation and Effector Phase
Acute inflammation and pathogen killing
Role of Macrophages
Induction of apoptosis
Recognition and removal of dying cells by phagocytes
Clearance of apoptotic cells
Apoptotic cells release signals to attract and activate macrophages
Macrophages recognise the signals
Macrophages rearrange their cytoskeleton and internalise apoptotic cells
Digestion of apoptotic cells
Secretion of anti-inflammatory mediators
Phagocytosis
Receptor binds to signals of apoptotic cell - forms a phagocytic cup
Cup extends round and pinches off the target, forming a phagosome
Fuse with lysosomes to form a phagolysosome
Contents are degraded
Debris released into extracellular fluid
Innate Immune Response of Macrophages
Kill pathogens
Produce inflammatory mediators
Cannot kill infected tissues
Innate Immune Response of Mast Cells
Produce inflammatory mediators by degranulation (released of preformed) and gene expression (production of new)
Cannot kill infected tissues or pathogens
Innate Immune Response of NK Cells
Kill infected tissue
Produce inflammatory markers
Cannot kill pathogens
Systemic Effects of Cytokine Release
Fever
Acute Phase Response
Increased neutrophil production
Acute Phase Response
Alters pasma concentrations of specific proteins in response to inflammation
Driven by cytokines
Due to altered protein synthesis in the liver
C Reactive Proteins
Acute phase protein
Marker of inflammation
Enhance phagocytosis
Activate complement system
Innate Immune System - Cells of Early Response
Macrophages
Mast Cells
NK Cells
Innate Immune System - Cells of Late Response
Neutrophils
Complement
Inflammation Steps
Increased vascular permeability (Macrophages - TNFa, IL-1 & Mast Cells - TNFa)
Vasodilation and increased blood flow (Macrophages - TNFa & Mast Cells - Histamine)
Endothelial cell activation and expression of selections and ICAM-1/VCAM-1 (Macrophages - TNFa, IL-1 & Mast Cells - Histamine)
Transendothelial migration and chemotaxis of neutrophils (Macrophages & Mast Cells - chemokine gradient)
Transendothelial Migration
Neutrophils bind weakly to selectins
Selectin mediated rolling of neutrophils
Neutrophils bind strongly to ICAM-1/VCAM-1 ligands
Neutrophils squeeze between the endothelial cells
Neutrophils migrate to site of inflammation within affected tissues (chemotaxis)
Neutrophils - Characteristic Features
Intracellular granules + multi-lobed nucleus
Innate Immune Response of Neutrophils
Kill extracellular pathogens
Produce pro-inflammatory cytokines (e.g. TNFa)
Neutrophils Killing Mechanisms
Phagocytosis
Degranulation
NETs
Neutrophils - Phagocytosis
Chemokine like signals and PRRs
Neutrophils encapsulate pathogen in phagosome
Kill pathogens by Antimicrobial proteins (granules filled with these)
OR
NADPH oxidase-dependent mechanisms (respiratory burst = production of toxic reactive oxygen species)
Neutrophils - Degranulation
Release of anti-bacterial proteins form neutrophil granules directly into extracellular milieu
Direct killing of extracellular pathogens
Tissue damage and potentially systemic inflammation
Neutrophils - NETs
Activated neutrophils release intracellular structures into the extracellular environment
NETs immobilise pathogens, preventing them from spreading and facilitating their phagocytosis
Complement System
Should only triggered by pathogens
When triggered, specific complement proteins can enzymatically activate other complement proteins in cascade reaction
Complement Activation - Mannose Binding Lectin Pathway
Mannose on invading battery acts as a ligand for MBL
Activates C4b/C2a, which cleaves C3 to C3a + C3b and activates downstream events
Complement Activation
C3 is cleaved to C3b + C3a
This activates downstream complement proteins and leads to the response
Innate Immune Response of Complement
Pathogen killing
Pathogen opsonisation
Leukocyte recruitment and inflammation
Complement Activation - Alternative Pathway
Spontaneous breakdown of unstable C3 to C3a and C3b
C3b rapidly degraded, or binds to the bacterium
When blinded to bacterium, factor B attaches, forming a new complex
This complex further cleaves C3 to C3b + C3a and causes downstream events
ACTS AS AN AMPLIFICATION LOOP
Complement - Downstream Events
C3a causes innate immune response
C3b cleaves C5 to C5a + C5b
C5a causes innate immune response
C5b binds with C6-C9 giving a membrane attack complex, which causes innate immune response
Complement - Pathogen killing
Membrane attack complex binds to pathogens
Inserts into target cell walls and causes osmotic lysis of cells
Complement - Opsonisation
C3b acts as an opsonin, binding to the bacteria and flagging it up for phagocytes to bind
Complement - Leukocyte Recruitment and Inflammation
C3a and C5a promote inflammation
Act directly on blood vessels
Activate mast cells to release pro-inflammatory mediators and chemokines
Role of Dendritic Cells
Bridge between innate and adaptive immune systems
Present in peripheral tissues in an immature state
Phagocytose antigens, cell debris, particles
Mature and migrate into secondary lymphoid tissues where they play a key role in antigen presentation
