2. innate immunity: soluble effectors Flashcards
what is innate immunity?
1st line defence against infection
present at birth, passed form generation
occurs within minutes of pathogen recognition (rapid)
innate immunity memory
present in plants, invertebrates, vertebrates
epigenetic modification
epigenetic modification
innate immunity memory histone modification DNA methylation modification miRNA long-noncoding RNA expression
physical innate barriers to infection
skin
respiratory tract
gastrointestinal tract
soluble innate barriers to infection
complement
defensives
collectins
induced innate barriers to infection
innate immune cells
pattern recognition receptors (PRRs)
interferon
what happens when tissue is damaged?
causes release of vasoactive and chemotactic factors, triggering local increase in blood flow and capillary permeability
permeable capillaries allow an influx of fluid (exudate) and cells
phagocytes migrate to site of inflammation
phagocytes and antibacterial exudate destroy bacteria
soluble innate immune molecules
enzymes (lysozymes)
antimicrobial peptides
collectins, ficolins, pentraxins
complement components
lysozyme actions
secreted by phagocytes and paneth cells from small intestine
most effective against Gram+ bacteria
cleaves bond between alternating sugars making up peptidoglycan wall
leaves bacteria lipid bilayers exposed and vulnerable
antimicrobial peptides
histacins
defensins
cathelicidins
cover epithelial surfaces
kill bacteria in minutes (disrupt membrane)
secreted by neutrophils, epithelial cells, paneth cells
inhibit DNA and RNA synthesis
histatins
antimicrobial peptides
produced in oral cavity
active against pathogenic fungi, eg. candida albicans
cathelicidins
antimicrobial peptides
LL-37
broad spectrum
against gram negative and positive bacteria
defensins
2 classes: alpha and beta
35-40aa amphipathic peptides
stabilised by disulphide bonds
disrupt microbial membranes (not of host)
collectins
globular lectin-like heads
bind bacterial cell surface sugars
sialic acid cleaves mannose antigens on host cells
ficolins
recognises acylated compounds (COCH3)
eg n-acetylglucosamine, monosaccharide in bacterial cell walls
pentraxins
cyclic multimeric proteins found in plasma
c-reactive protein (CRP)
used as clinical measure of inflammation
actions of collectins, ficolins and pentraxins
soluble pattern recognition receptors (PRRs)
act as opsonins that bind pathogens and infected cells
targets cells for phagocytosis
activate complement through classical pathway/lectin pathway
complement system
series over 30 proteins - constantly circulate in blood and fluids and bathe body tissues
detect presence of foreign material - initiate cascade which amplify signal
cooperate with other host defence systems to generate inflammation and rapidly remove pathogen
complement components
circulate as pro-form in blood
some have proteolytic activity
on activation, split into small and large fragments - triggers amplification cascade
normally ‘a’ is small fragment, except c2a
classical pathway
initiated by c1 activation
antibody:antigen complex
c1 = complex of 3 proteins (c1q, c1r, c1s)
classical pathway activation
triggered when c1 binds to Fc region of antibody-antigen complex
c1 must bind at least 2 Fc domains
IgM most effective (IgG1 and IgG3 also, when close together)
why is IgM most efficient at activating complement?
has 5 Fc domains
serum IgM
cannot bind c1
has planar conformation
shape changes on binding to antigen, reveals binding site for c1q
classical pathway amplification
binding c1q with Fc domain causes conformational change in c1r
c1s is cleaved - can active ate c2 and c4 splitting into large/small fragment
c3 convertase can activate over 200 c3 molecules
c4b, c2a and c3b form c5 convertase to activate c5
lectin pathway
antibody independent, activated by ficolins and mannose binding lectin (MBL)
MBL binds mannose residues
similar downstream mechanism to classical pathway
upon binding, MBL forms complex with MASP-1 and MASP-2
activate complex cleaves C2 and C4
alternative pathway
c3 spontaneously hydrolyses
c3b binds to cell and factor B
susceptible to cleavage by factor D to Bb
C3bBb can hydrolyse more C3 to create more C3b
membrane attack complex (MAC)
final product of complement cascade
forms a poor that inserts into membrane
allows diffusion or ions and small molecules
water moves into cell, killing it
human cells have soluble and cell surface associated proteins that prevent MAC formation
