Innate immune defences and inflammation 1 Flashcards
What are the differences between innate and adaptive immune responses?
Innate: Specificity inherited in genome Triggers immediate response Recognises broad classes of pathogens Interacts with range of molecular structures of a given type. Adaptive: Encoded in multiple gene segments Requires gene rearrangement Clonal distribution
What are the types of memory in immunity?
Epigenetic modification of genes encoding immunological + inflammatory products -> re-challenge -> boosted response, protection, antigen independent -> plants, vertebrates, invertebrates.
Gene rearrangement, clonal expansion, memory population -> re-challenge -> memory population protects, antigen dependent -> vertebrates.
What are the innate barriers to infection?
Physical -> skin, respiratory tract, GI tract
Soluble -> complement, defensins, collectins
Induced -> innate immune cells, pattern recognition
receptors, interferon.
Give some examples of anatomical barriers
Mechanical: skin, gut, lungs, eyes/nose/oral cavity -> epithelial cells joined by tight junctions, longitudinal flow of air or fluid, movement of mucus by cilia, tears, nasal cilia.
Chemical: fatty acids, antimicrobial peptides + enzymes, low pH, pulmonary surfactant.
Microbiological: normal microbiota
What are the events that are followed by tissue damage?
Vasoactive + chemotactic factors -> trigger local increase in blood flow + capillary permeability -> influx of fluid (exudate) + cells -> phagocytes migrate to sit of inflammation (chemotaxis) -> phagocytes + antibacterial exudate destroy bacteria.
What are the soluble innate immune molecules and what are their functions?
Lysozyme –> blood, tears -> disrupts bacterial wall
Antimicrobial peptides -> disrupt microbial membranes
Collectins, ficolins, pentraxins –> bind to pathogens
-> phagocytosis + activate complement.
Complement components -> lyse + opsonise bacteria, induce inflammation.
What is lysozyme secreted by and what are its actions?
Phagocytes + paneth cells from small intestine.
Most effective against Gram+ bacteria.
Cleaves bond between alternating sugars that make up peptidoglycan -> phospholipase A2 disrupts phospholipids.
What are the antimicrobial peptides and what are their actions?
Histatins -> produced in oral cavity, active against fungi e.g. Candida albicans.
Defensins
Cathelicidins -> LL-37 broad-spectrum antimicrobial activity against Gram- and Gram+ bacteria.
Cover epithelial surfaces, in saliva.
Constitutively secreted by neutrophils, epithelial + paneth cells in crypts of small intestine.
Disrupts membrane -> kills bacteria quickly.
Attacks fungi, viruses (influenza + herpes).
Inhibit DNA + RNA synthesis
What are the actions and properties of defensins?
α + β defensins. 35-40 aa amphipathic -> hydrophilic + hydrophobic regions. Disulphide bonds stabilise structure -> positively charged region separated from hydrophobic region.
Forms pore -> disrupt microbial membranes, not host’s
What are the properties and actions of collectins?
globular lectin like heads -> bind bacterial cell surface sugars. Sialic acid hides mannose antigens on host cells
What is the function of ficolins?
Recognise acylated compounds e.g. n-acetylglucosamine, in bacterial cell walls
What are pentraxins and what are their functions?
Cyclic multimeric proteins in plasma.
CRP -> clinical measure of inflammation –> binds to phosphocholine on bacterial surfaces
What are the actions of collectins, ficolins and pentraxins?
Soluble PRRs
Act as opsonins -> bind to pathogens + infected cells
-> phagocytosis
Activate complement through classical + lectin pathways
Outline the complement system
> 30 proteins constantly circulate in blood + fluids -> bathe body tissues.
Detect foreign material -> cascade of reactions -> amplifies signal.
When activated -> cooperate with other host defence systems -> inflammation + rapidly remove pathogen.
Most made by liver, also monocytes, macrophages, epithelial cells of intestine + urinary tract.
How do complement components circulate and what are their actions?
Circulate as pro-form (inactive) in blood
Some have proteolytic enzymatic activity
Activation -> split into small + large fragments -> triggers amplification cascade.
Normally ‘a’ is small fragment -> except c2a
What are the effects mediated by complement components?
Membrane attack complex -> lysis
Complement receptor activation -> opsonisation, activation of inflammatory response, clearance of immune complexes.
Outline the classical pathway - initiation and activation
Initiated by C1 activation
C1 -> complex of 3 proteins -> C1q, C1r and C1s
C1 structure dominated by C1q -> large, 18 polypeptides -> 6 collagen like triple helix structures.
Triggered when C1 binds to Fc region of antibody-antigen complex -> must bind min. 2 FC domains -> IgM has 5 Fc domains so most efficient at activating complement.
Which molecule is unable to bind to C1?
Serum IgM -> has planar conformation -> prevents spontaneous inflammation.
Shape changes on binding to antigen -> reveal binding sites for C1q.
Outline the classical pathway - amplification
Binding C1q with Fc domain -> conformational change in C1r.
C1s is cleaved -> activate C2 + C4 splitting into large + small fragments -> C3 convertase (C4b2a) activates >200 C3 molecules -> massive amplification of signal.
C4b, C2a, C3b -> form C5 convertase -> activates C5 -> MAC.
Outline the lectin pathway
Antibody independent, activated by ficolins + MBL.
MBL binds mannose residues on carbohydrates + glycoproteins on bacteria and some viruses -> MBL forms complex with MASP-1 + MASP-2 (serine proteases)
-> active complex cleaves C2 + C4
Outline the alternative pathway
C3 spontaneous hydrolysis -> C3a + C3b -> C3b binds to a cell membrane + factor B -> susceptible to cleavage by factor D to Bb.
C3bBb has 5 min half-life, unless bound to serum protein properdin -> extends half-life to 30 min by protecting it from proteases.
C3b,Bb can hydrolyse more C3 -> creates more C3b -> amplifies signal.
How does the membrane attack complex (MAC) occur?
C5b binds C6 -> MAC formation -> MAC forms pore + inserts into membrane -> diffusion of ions + small molecules -> water moves into cell + kills it.
Human cells have soluble and cell surface associated proteins that prevent MAC formation.
Which conditions arise due to deficiency in complement inhibitors?
Hereditary angioedema -> C1 inhibitor deficiency.
classical complement cascade easily activated, treated with C1 inhibitor injection.
MBL deficiency -> serious pyogenic infections in neonates + children.
C3 deficiency -> most severe -> successive severe infections.
C8 deficiency -> prone to Neisseria meningitis
Outline complement deficiency in systemic lupus erythematosus (SLE)
90% of C4 deficient people develop SLE.
C4 deficiency -> less C3b -> C3b bound to immune complexes binds to CR1 on erythrocytes -> transports to phagocytes in liver + spleen -> phagocytes recognise immune complexes via Fc receptors + engulfs
