Innate immune response Flashcards
what molecules are involved in the innate immunity
antimicrobial peptides, antimicrobial enzymes, and complement system
2 antimicrobial enzymes
lysozyme and phospholipase A2
what is the function of lysozyme
enzyme which attacks chemical features specific to bacterial cell walls -> it is a glycosidase that breaks the beta(1,4) linkage between two sugars of the polymer of the peptidoglycan layer.
killing which type of bacteria is lysozyme more effective, and why?
more effective killing gram-pos bacteria because they don’t have LPS (outer layer) so the peptidoglycan is more exposed
function of phospholipase A2
enters bacterial cell wall and hydrolizes phospholipids in the membrane = killing bacteria
types of antimicrobial peptides
defensins, cathelicidins, histatins
which cells produce antimicrobial enzymes and where are they secreted
phagocytes and paneth cells (small intestine) and they are secreted in the saliva and tears (for example)
which cells produce antimicrobial peptides
phagocytic immune cells = neutrophils (granules) and epithelial cells = lungs for example (secreted into the mucosal surfaces)
what are defensins and what is their mechanism of action
small, cationic proteins which disrupt the cell membrane of bacteria and fungi (also some enveloped viruses). they are amphipatic and they insert their hydrophobic region into the cell membrane bilayer of bacteria. results into the loss of membrane integrity
what are three subfamilies of defensins and which cell produce them?
alpha - neutrophils, beta - epithelial cells of the respiratory and urinogenital tracts) and theta-(not in humans)
what are cathelicidins and what cells produce them?
similar as defensins (also disrupt microbial membrane) - but they do not have the disulphide bonds. constantly produced by neutrophils, macrophages, epithelial cells (lungs, intestine) and keratinocytes -> in response to an infection.
what are histatins and their function?
small, cationic proteins constantly produced in the oral cavity. they are active against pathogens in the mouth.
what are lectins?
carbohydrate-binding proteins with a bactericidal function
what is a C-type lectin fold?
it’s the structure of the carbohydrate-recognition domain (CRD) -> can bind a variety of different carbohydrate structures
what molecules are included in the C-type lectin family and what is their function?
selectins, collectins, proteoglycans, and endocytic receptors = some are secreted and some are transmembrane proteins
they function as adhesion and signalling molecules in many different immune functions -> for example, inflammation, immunity to tumour, and virally infected cells
what is the complement system composed of
30+ plasma proteins mainly produced by the liver
3 pathways of complement activation
classical -> antibody-triggered pathway
alternative -> amplification pathway
lectin pathway -> activated by lectin-type proteins that recognize and bind carbohydrates on pathogen surfaces
what are the 3 effector functions of the complement cascade?
inflammation, phagocytosis, and membrane attack
zymogen?
inactive pro-enzyme (proteases are synthesized as zymogens which become enzymatically active only after proteolytic cleavage -> usually by another complement protein)
how is the lectin pathway initiated
direct recognition of pathogens -> initiated by soluble carbohydrate-binding proteins = MBL and ficolin
MASPs? function?
MBL-associated serine proteases -> they are associated with the recognition proteins of the lectin pathway and they are the ones who activate the complement cascade
how is the classical pathway initiated?
it is initiated when C1 - which comprises of C1q + 2 serine proteases = C1r and C1s -> either recognizes a microbial surface directly or binds to antibodies already bound to a pathogen
how is the alternative pathway initiated?
can be initiated by a spontaneous hydrolysis and activation of C3, which can then directly bind to microbial surfaces. or more commonly -> is activated once lectin/classical pathway is activated
what is the purpose of the alternative pathway?
amplification of the complement cascade -> it drives the production of more C3a and C5a to activate mast cells (inflammation), more complement to opsonize the pathogen, and more production of the membrane attack complex
what factors are involved in the alternative pathway (exclusively)
factor B and D and properdin (factor P)
what is the central step of the complement cascade
the initiation of the enzymatic activity of the C3 convertase
what is the main effector molecule of the complement system and what is the function?
C3b - molecule that opsonizes pathogens –> phagocytic cells have receptors for C3b
what are the complement molecules which mediate inflammation?
C3a and C5a
what are the 2 functions of C3a and C5a?
recruitment of phagocytic cells (they act as chemokines) and the promotion of inflammation
what is the mechnism of action of C3b opsonization of microbes?
C3b can form a covalent bond with the microbial surface -> due to a highly reactive thioester bond which is hidden inside the folded C3 protein –> cannot react until C3 is cleaved by C3 convertase
what happens after the release of C3a fragment?
C3b undergoes conformational changes -> this allows the thioester bind to react with a hydroxyl or amino group on the nearby microbial surface
what bacterial features are detected by the recognition proteins of the lectin pathway?
gram-pos bacteria -> lipoteichoic acid (cell wall)
gram-neg bacteria -> LPS (outer membrane)
what is an MBL monomer and what is it comprised of?
mannose binding lectin.
a collagen region, an alpha-helix neck region, and a carbohydrate recognition domain -> C-type lectin like domain
MBL structure
3 MBL monomers form a trimer. then between 2 - 6 trimers assemble into oligomers => mature MBL molecule
MBL activation mechanism
Once MBL binds to a carbohydrate on a pathogen’s surface -> causes a conformational change in the MBL which activates the serum proteases . Then the active serine proteases activate C4 and C2 -> production of C3 convertase
why is the MBL molecule an oligomer?
Because MBL has low affinity, but an MBL oligomer has a high avidity for carbohydrates
what is an additional function of MBL?
MBL serves as an opsonin for monocytes which lack the macrophage mannose receptor but have receptors that can bind mannose-binding lectin coating a bacterial surface
difference between MBL and ficolins
overall similar shape and function but instead of the lectin domain -> they have a fibrinogen-like domain
the regulation of the lectin and classical pathways (2 ways)
- the removal of the pathogen
- C4-binding protein and factor I can dissociate the C3 converatse (C4b2a molecule)
how is the membrane attack complex regulated?
by CD59 = protein expressed on human cells -> prevents the recruitment of C9 to form pores
