Lecture 3 – complement

where is complement within the immune system?

 innate
 non-cellular component

→ 50 proteins : soluble in plasma (mainly produced in liver) or membrane bound

activator

MASPs

C1-9

Factor B + D

receptors

CR1-4

regulators

soluble (factor H) and membrane bound (CD46, CD55)

recognition -see what's damaged and what is not

activation - only activated when there's a foreign body

effector - the actual killing, depends on the pathogen

pathways

1. classical

molecular structures (usually proteins) recognised by antibodies - very specific

when antibody is recognised

C1q - in charge of recognition - that are dangerous or related to danger

C1r and C1s - linked to activation

complement doesn't act in isolation, the whole immune system works together

1. Mannan-binding lectin (MBL)

the part the recognised is not an antigen, it's a pattern

recognises different sugars

first — green component - recognises

then — purple - linked to activation

this works similarly to PRRs - they recognise PAMPs

1. alternative

C3 (that's just in the cytoplasm) spontaneously hydrolyse

ALL have a recognition part and then an activation one

activation - molecular cascade

classical and MBL follow a very similar pathway

break down 2 molecules that are floating in plasma - C4 and C2

C2 is smaller and will diffuse away

then C4 lysis

C2a and C4b with join together to make C3 convertase

the red line- which is the bond - covalent bonding - these two molecules lack specificity so
the only way the complement only gets activated when needed is the covalent bond
C3b stays, C3a diffuses away

C3 works effectively and fast - this is important so that it doesn't divide exponentially

the outcomes
alternative pathway

happens because C3 has the capacity to hydrolyse itself spontaneously

factor D can strengthen the reaction

fluid phase C3 convertase - not stable - the activation is closed - it hydrolyses molecules of
C3

neutrophils release factor b which causes secretion of C3

there's an amplification step - because pathogens divide quickly

after activation - effector

complement activation
→ soluble anaphylatoxins (C3a, C5a)

→ membrane bound (B3b, C5b (C4b))

 inflammation
 recruitment
 opsonisation
 direct lysis

anaphylatoxins generates a gradient - creates a signal, to tell other cells of the immune system
that there is something to do

→ the cells with move towards an increased concentration of anaphylatoxins

endothelial cells - allows lymphocytes to flow quickly

opsonisation

a tagging system

for cells that have the complement receptor for C3b

only occurs in the presence of C5a (C5a is always circulating)

lysis

some elements are very small so the macrophages wont have a problem to wat it, but
sometimes it's easier for the membrane to open and engulf it

summary

regulation

 C3b and C5v are highly reactive and non-specific - they bind host tissue

this regulation is protection of self tissue from complement attack

 short half-life of the activated thioester (rapid degradation of C3b/C4b)

 tight regulation of activation pathways (DAMPs/TLR co-signal required)

every step will be regulated

factor H prevents covalent bonding

complement - disease

some people lack the proteins in complement or they malfunction

without complement - infection

diagnosis

1. test overall complement activity : Ch50 or Ch100 test

2. quantification of specific complement protein levels

treatment

1. overreactive : immunosuppressants
2. deficiency : supplementation, antibiotics (prophylactic)

 complement malfunction also cause autoimmune disease (adaptive immunity)

circulating vs immune cell derived complement ("complosome")

but

 complement links innate and adaptive immunity

 is activated intracellularly (autocrine) in T cells
 is not only pro-inflammatory — resolution in T cells
 interacts with T cell metabolism