Innate immunity: Complement Flashcards
What does complement system refer to
Group of soluble proteins that cooperate with both innate and adaptive immune systems =
Eliminate pathogens, during cells and immune complexes from body
What is a protease
Most make up complement system
>30 in blood and other fluids
Enzyme that performs proteolysis = can break down proteins
Naming proteases
Called C followed by number
Some called factor followed by cap letter
Most numbered based on when discovered
What are complement proteins produced by
Mostly produced by liver
What do complement proteins do
Set off A chain reaction that helps clear pathogens = cascade/chain reaction of events
Describe 3 key mechanisms of action of complement system
Increasing vascular permeability and chemo taxis = promote inflammation, vasodilate= more cells to site of infection
Destroy pathogen cells membranes = Poke holes
Increasing reognxiiotn of pathogens and facilitating phagocytosis = opsonization
Define opsonizaton
Coating of surface of Pathogen by antibody and/or complement that makes it more easily ingested by phagocytes, make tasty, enhance phagocytosis
Define phagocytosis
Receptor of opsonins on Phagocytes
Internalization of a particular matter by cells by a process of engulfment, cell membrane surrounds material, eventually forming intracellular vesicle = phagosome = contains ingested material
How does complement get activated
Classical, alternative or lectin pathway
Initially pro proteases then act as cascade = proteolytic cleavage generating 2 fragments
Describe products of proteolytic cleavage of complement
One small = a, with specific function
One large = b, with proteolytic activities on new substrate
Name the 2 c3 convertases
C4b2a
C3bBb
Both cleave c3 into c3a and c3b
Describe functional categories of complement proteins - gen
Group of pro proteases = inactive, circulate in blood until activated= cleaved
Proteins are inactive untill cleaved by proteases
Need initiators first
Describe functional categories of complement proteins - whole cascade generally
Initiators = initiate respective complement reactions
Convertase activators and some enzymatic mediators = cleave and activate next member of a complement reaction sequence = cleave other complement proteins, immune cells have receptors for these complement proteins
= 3 outcomes = opsonins, anaphylatoxins and membrane attack complex
Regulators = inhibit formation of Mac on host cells —> always regulated
What’s essential to know about complement activation
3 pathways can activate compel T
All 3 generate c3 convertase = cleaves c3–> c3a + c3b
3 main outcomes = downstream effects
What is lectin pathway triggered by
Triggered by soluble proteins known as lectins
= prrs that circulate in blood, not membrane bound
Binds polysaccharide antigen
Name lectins
Mannose binding lectin
Ficolins
What increases during infection
Expression of lectins
Describe lectin pathway prrs
Bind surface of pathogens
Triggers signalling cascade on pathogen surface = c3 convertase generated (c4b2a) = cleaves c3
Describe lectin pathway - generally whole process
Once binds pamp = change conformation of MASPs (proteases)= starts cleaving complement proteins = triggers cascade = c4b2a
Describe how classical pathway activated
C1q binds pathogen surface
Can bind pathogen directly
Can bind antibodies that are bound to pathogen surface
What does classical pathway do
Connect adaptive to innate
Antibodies produced by B cells - can bind antibodies
Innate immune component helps mediate humoral response
What happens when c1q binds
Triggers signalling cascade on pathogen surface
Proteases = c1r2r2 switches on and cleaves and makes c4b2a
What do all pathways converge on
C3
Classical and lectin = make c4b2a
Alternative = makes c3bBb
What does c3 convertase do
Cleaves c3–> c3a and c3b
What c3a involved In
Enhancing inflammation
What c3 b involved in
Oposonization
And is c5 convertase = c5 —> c5a and c5b
Name the 2 ways alternative pathway activated
C3b given from lectin or classical pathway
When high conc c3
Describe process of alternative pathway - c3b gen
Once c3b produced by lectin or classical pathway = amplification loop for c3b formation (depositing more c3b molecules on the pathogen) = requires factor b and protease factor d
C3bBb on surface of pathogen = c3 convertase
Describe process of alternative pathway - c3b specifics
C3b deposited by lectin or classical on surface pathogen
C3b binds factor b then factor d comes in and cleaves factor b into bb or ba
Bb =gives c3bBb
Pos feedback loop =more c3b s and c3a s
Describe when high conc c3 - alt pathway
High conc c3= c3 can undergo spontaneous hydrolysis = also involves factors b and d
Binds factor b —> can be cleaved by factor b and ultimately forms c3 convertase
Describe c3 convertase of alt pathway
C3bBb = v unstable
On surface
What stabilizes c3bBb
Properdin = factor p, secreted by neutrophils
Stabilize c3 convertases since it can bind to some microbial surfaces
Describe which type of proteins complement mainly acts on
Extracellular = on surface, phagocytosis not inside cell, Mac =outside on surface =
ALL EXTRACELLULAR
What does cleavage of c3 do
CASUES MANY DOWNSTREAM EFFECTs
Name 3 downstream effects
Inflammation
Increased phagocytosis
Pathogen lysis
Describe inflammation
Additional signalling results in cleavage of other complement molecules
What causes inflammation
C3a and c5a recruit phagocytes and promote inflammation
What happens if too much c3a and c5a
Anaphylactic shock
What do complement receptors do - downstream effects inflammation
Complement receptors connect complement tagged pathogens to effector cells
describe receptors on granulocytes for downstream effect of ifnalmmtion
C3a R/C5a R
= Stimulates release of pro inflammatory cytokines and granule components from basophils, eosinophils, neutrophils, mast cells
Helps recuiremtn and leads to secreting pro inflammatory cytokines
Describe increased phagocytosis downstream effect
Phagocytes have receptors for c3b
Opsonization of pathogen = more readily taken up by phagocytosis
Describe how opsonization can occur - downstream effects
Via complement deposition and/or antibodies (phagocytes Also ahev receptors for antibodies, many initiators lead to opsonization)
Describe downstream effect = pathogen lysis
Additional complement factors create membrane attack complex (mac)—> cell lysis
Describe downstream effect = pathogen lysis = WHAT COMPLEMENT proteins involved
C5 and c3 are involved = c5b directly forms Mac and c3b indirectly since converts c5–> c5a and c5b
Describe downstream effect = pathogen lysis = WHAT IS THE IMPORTANT PART
Cascade leading to formation of MAC = pore in surface of pathogen that lyses pathogen
DESCRIBE negative regulation of c activation
Do not want Mac on host cells or anaphylactic shock
Complement regulatory proteins in plasma or cell surfaces prevent complement activation from proceeding under normal/basal conditions = downreg
What does neg reg of c activation do
Prevent appearance of c3 convertase
Promote disappearance of c3 convertase
Does only the complement system have regulatory component
NAWWWW
Each pathway/process in immune system has a regulatory component
Describe ex of negative regulation of c activation
CD59 = protectin = inhibits mac formation, prevents c9 binding and polymerization
