4 - Innate Immunity Flashcards
Phases of immune response
- Innate phase
- Early induced innate responses
- Adaptive immune response
Innate phase
Immediate immune responses mediated by preformed, non-specific effectors
Early induced innate response
- Responses initiated by recognition of pathogens
- Leads to inflammatory response
Adaptive immune response
- Mediated by B and T cells specific for the pathogen
- Occurs late because cells must first undergo clonal expansion in lymphoid tissues then migrate to sites of infection
Three functions of innate immunity
- Initial response to microbes that prevents, controls, or eliminates infection
- Eliminate damaged cells and initiate the process of tissue repair
- Stimulates adaptive immune responses and influences their nature to make them optimally effective against different types of microbes
Innate vs adaptive immunity
- Innate responses are immediate and do not require prior exposure to microbe, whereas adaptive IR occurs over several days as clonal expansion must occur
- No change in quality or magnitude of innate IR upon repeated exposure, whereas adaptive IR have enhanced rapidity, magnitude and effectiveness
- Innate IR is activated by recognition of a limited set of molecular structures whereas adaptive IR can recognise millions of different molecular structures
Mechanical barriers
- Epithelial cells joined by tight junctions
- Movement of mucus by cilia
- Flow of air/fluid
Chemical barriers
- Fatty acids
- Low pH
- Lysozyme in tears
Microbiological barriers
Normal flora
Epithelial barriers
Intact epithelial surfaces form physical barriers between microbes in the external environment and host tissue, and epithelial cells produce antimicrobial chemicals that further impede the entry of microbe
Defensins
- Produced by epithelial cells of mucosal surfaces and granule-containing leukocytes,(e.g. neutrophils, NK cells, and cytotoxic
T lymphocytes) - Protective actions include both direct toxicity to microbes and the activation of cells involved in the inflammatory response to microbes
- Amphipathic peptides that disrupt functions of membranes
How do defensins disrupt cell membranes of microbes
- Insert into the hydrophobic region into the membrane bilayer
- The formation of a pore makes the membrane leaky
- Electrostatic attraction and the transmembrane electric field bring the defensin into the lipid bilayer
Lysozyme
- Digests the cell walls of Gram positive (thick peptidoglycan) and Gram-negative bacteria (thin peptidoglycan with LPS)
- Peptodoglycan is a polymer of GlcNAc and MurNAc
- Lysozyme cleaves linkages between GlcNAc and MurNAc creating a defect in the peptidoglycan layer and exposing the underlying cell membrane to other antimicrobial agents
Epidermis of skin
Keratinocytes in layer of skin produce β-defensins which are incorporated into lamellar bodies and secreted into the intercellular space to form a waterproof lipid layer containing antimicrobial activity
Gut epithelium
Contain paneth cells that produce several kinds of antimicrobial proteins (⍺-defensins and the antimicrobial lectin)
Receptors of innate and adaptive immune system
- Pattern recognition receptors of innate IR are non clonally distributed (identical receptors are expressed on all cells of a particular type - e.g. macrophages). Therefore many cells of innate IR respond to same microbe
- Antigen receptors of adaptive IR are encoded by genes formed by rearrangement of gene segments, resulting in clones of same cell expressing unique receptor
Adaptive vs innnate receptor diversity
- 100 types of innate immune receptors that are capable of recognizing 1000 PAMPs and DAMPs
- Adaptive immune system has two kinds of receptors (Immunoglobulin and TCR), but can recognize millions of different antigens due to their diversity
Four stages of response to infection
- Adherence to epithelium (normal flora)
- Local infection, penetration of epithelium (wound healing induced, antimicrobial agents destroy microorganisms)
- Local infection of tissues (activation of macrophages and dendritic cells)
- Adaptive immunity (infection cleared)
Complement (C’) system
- A collection of >30 heat labile proteins present in blood and other body fluids
- Increases opsonisation, killing of bacteria, and induction of inflammatory responses
Complement system in absence of infection
- C’ proteins circulate in an inactive form (zymogens)
- Detection of pathogens activates cascade of proteolysis in which C’ zymogens are activated sequentially, each becoming an active protease in which cleaves and activates many molecules of the next zymogen in pathway
- Final result is formation of effector C’ components that aid removal of pathogen
Proteolysis
Breakdown of proteins
Three pathways of C’ activation
- Lectin pathway
- Classical pathway
- Alternative pathway
Lectin pathway
Initiated by soluble carbohydrate-binding proteins (mannose binding lectin) that bind to carbohydrate structures on microbial surfaces
Classical pathway
Initiated when C’ component C1 (recognition protein C1q associated with proteases C1r and C1s) recognises a microbial surface or binds to antibodies on microbial surfaces
Alternative pathway
Initiated by spontaneous hydrolysis and activation of C’ component C3, which can then bind to microbial surface
End result of any complement system pathway
When any pathway interacts with a pathogen, a C3 convertase is created which cleaves C’ component C3 to C3a (involved in inflammation) and C3b (the main effector molecule of the C’ system)
Outcomes of other smaller molecules released by complement system
- C3a and C5a recruit phagocytic cells to site of infection and promote inflammation
- Phagocytes with receptors for C3b engulf and destroy the pathogen
- Completion of the complement cascade leads to formation of a membrane attack complex (MAC), which disrupts cell membrane and causes lysis
Small fragments of some complement proteins
Cause local inflammatory responses by acting directly on blood vessels to induce increased blood flow, vascular permeability, and phagocytic activity
Protectin
CD59 (protectin) prevents recruitment of C9 by the complex of C5b, C6, C7 and C8 and therefore, prevents formation of membrane attack complex of the microbial surfave
Disease caused by lack of CD59
Paroxysmal nocturnal haemoglobinuria
DAF
The classical or alternative pathway C3 convertase can be dissociated by the replacement of one component with decay accelerating factor (DAF)
Properdin
- Made by neutrophils and released when neutrophils are activated
- The alternative pathway C3 convertase is very short lived and degrades in absence of binding by properdin
- Properdin deficient patients have increased susceptibility to infection
Alternative pathway C3 convertase complex
C3bBb
Classical pathway C3 convertase complex
C4b2a
Ingestion of complement tagged pathogens by phagocytes is mediated by two signals
- Activation of C’ leads to deposition of C3b on microorganism
- C3b can bind the C’ receptor CR1 on the surface of phagocytes, but is insufficient to trigger phagocytosis
- Binding of C5 to the C5a receptor now activates the cell to phagocytose organisms bound to CR1
Major functions of complement system
- Opsonisation and phagocytosis
- Stimulation of inflammatory reactions
- Complement mediated cytolysis
regulatory proteins that protect host cells from complement
Protectin and DAF
