Innate immunity 1 Flashcards
What is innate immunity?
1st line of defence against infection
Present at birth and passed down genetically
Occurs within minutes of pathogen recognition
Characteristics of innate immunity
Specificity inherited in the genome
Triggers immediate response
Recognises broad classes of pathogens
Interacts with a range of molecular structures of a given type
Able to discriminate between even closely related molecular structures
Innate barriers to infection
Physical
- skin
- GI tract
- respiratory tract
Soluble
- complement
- defensins
- collectins
Induced
- innate immune cells
- pattern recognition receptors
- interferon
Tissue damage
Causes release of vasoactive and chemoactic factors that trigger local increase in blood flow and capillary permeability
Permeable capillaries allow influx of fluid and cells
Phagocytes migrate to site of inflammation
Phagocytes and antibacterial exudates destroy bacteria
Soluble innate immune molecules
Enzymes such as lysozyme- disrupt bacterial cells walls, found in blood and tears
Antimicrobial peptides- disrupt microbial membranes
Collectins, ficolins and pentraxins- bind to pathogens targeting them for phagocytosis and activate complement
Complement components- lyse bacteria, opsonise bacteria, induce inflammation
Lysozyme
Secreted by phagocytes and paneth cells fro the small intestine
Most effective against gram positive bacteria
Cleaves the bond between the alternating sugars that make up peptidoglycans
Antimicrobial peptides
Cover epithelial surfaces, found in saliva
Constitutively secreted by neutrophils, epithelial cells and paneth cells in the crypts of the small intestine
Kill bacteria in minutes, by disrupting the membrane
Attack fungi, viruses
Inhibit DNA and RNA synthesis
e.g. histatins, defensins, cathelicidins
Histatins
Produced in the oral cavity
Active against pathogenic fungi e.g. candida albicans
Cathelicidins
LL-377 broad spectrum antimicrobial activity
Against both gram negative and gram positive bacteria
Defensins
Two classes- alpha, beta
35-40 aa amphipathic peptides
Disulphide bonds stabilise the structure to have a positively charged region separated from a hydrophobic region
Disrupt microbial membranes but not that of the host
Collectins
Globular lectin like heads that bind to bacterial cell surface sugars
Sialic acid hides mannose antigens on host cells
Ficolins
Recognises acylated compounds such as n acetylglucosamine, a monosaccharide found in bacterial cell walls
Pentraxins
Cyclic multimeric proteins found in the plasma
Actions of collectins, ficolins and pentraxins
Soluble pattern recognition receptors
Act as opsonins that bind to pathogens and infected cells targeting them for phagocytosis
Activate complement through the classical pathway/ lectin pathway
3 complement pathways
Classical pathway
Lectin pathway
Alternative pathway
Complement system
Series of over 30 proteins constantly circulate in blood and fluids that bathe the body tissues
When they detect presence of foreign material, they initiate a cascade of reactions that amplify the signal
When activated, cooperate with other host defence systems to generate inflammation and rapidly remove the pathogen
Most made by the liver, also produced by monocytes, macrophages and epithelial cells of the intestine and urinary tract
Complement components
Circulate as pro-form in the blood
Numbered in the order they were discovered, not in the order they are activated
Some have proteolytic enzymatic activity
On activation they split into a small and large framents triggering an amplification cascade
Effects mediated by complement components
Lysis
Opsonisation
Activation of inflammatory response
Clearance of immune complexes
Classical pathway
Initiated by C1 activation
C1 is a complex of three proteins: C1q, C1r and C1s
The structure of C1 is dominated by C1q
- large molecule of 18 polypeptides
- form 6 collagen like triple helix structures
Classical pathway: activation
Triggered when C1 binds to the Fc region of an antibody- antigen complex
C1 must bind at least 2 Fc domains
Causes conformational change in C1r
C1s cleaved and can activate C2 and C4 splitting
C3 convertase activate over 200 C3 molecules- amplification
C4b, C2a and C3b fragments form C5 convertase that activates C5 leading to membrane attack complex
Serum IgM
Cannot bind C1 as it has a planar conformation
Shape changes on binding antigen to reveal binding sites for C1q
IgM
Most efficient at activating complement
Has 5 Fc domains
Lactin pathway
Antibody independent, activated by ficolins and mannose binding lectin
BML binds mannose residues on carbohydrates and glycoproteins on bacteria and some viruses
Similar downstream mechanism to classical pathways
Upon binding BML forms a complex with MASP-1 and MASP-2 (serine proteases)
Active complex cleaves C2 and C4
Alternative pathway
C3 spontaneous hydrolysis into C3a and C3b
C3b binds to cell membrane and factor B, making it susceptible to cleavage by factor D to Bb
C3bBb has half life of 5 minutes, unless it binds to serum protein properdin, which extends its half life to 30 minutes protecting it from proteases
C3bBb can hydrolyse more C3 creating more C3b which can amplify the signal
Membrane attack complex
MAC forms a pore that inserts into the membrane
Allows diffusion of ions and small molecules
Water moves into the cell killing it
Human cells have soluble and cell surface associated proteins that prevent MAC formation
Complement inhibitors
C1 inhibitor: soluble protein that prevents C1 activating C4 and C2
Series of soluble and membrane bound inhibitors prevent C3 activation, especially in alternative pathway
Membrane bound inhibitors prevent action of the membrane attack complex
Heriditary angioedema
C1 inhibitor deficiency
Classical complement cascade easily activated
Can be easily treated with an injection of C1 inhibitor
Complement deficiency
Deficient of components of complement pathway experience recurrent infections
MBL deficiency causes serious pyogenic infections in neonates and children
C3 deficiency is the most severe leading to successive severe infections
Patients deficient of C8 are prone to infections with Neisseria meningitis
SLE
Systemic lupus erythematosus
COmplement deficiency in SLE
90% people deficient for C4 develop SLE
C4 deficiency means less C3b (C4b2a is C3 convertase)
C3b bound to immune complexes binds to Cr1 on erythrocytes which transports them to phagocytes in the liver and spleen
Phagoyctes recognise the immune complexes via their Fc receptors and engulf them
