L3 The complement system

Question 1

what is complement?

Answer 1

an innate, non cellular component of the is. 750 proteins soluble in plasma, produced in the liver or membrane bound.

Question 2

activators

Answer 2

masps, c1,2,3,4,5,6,7,8,9 (complement cascade proteins), factor b and factor D,

Question 3

receptors

Answer 3

CR1,CR2,CR3,CR4

Question 4

soluble

Answer 4

Factor H
membrane bound: DC46,CD55

Question 5

Recognition, activation and effector pathways of the complement cascade?

Answer 5

recognition: of pathogens, apoptotic cells and immune complexes
activation: complement cascade and amplification
effector: inflammation, recruitment, opsonization, direct lysis

Question 6

how is the classical pathway activated?

Answer 6

antigen-antibody complex. c1s and cr1s are crucial for the activation of the classical pathway. c1q binds to the fc region of antibodies (usually igG or igM - A clear link to adaptive immunity- that have attached to pathogens, apoptotic cells or immune complex. c1s and c1r (key enzymes) help proppogate the activation signal
1. c1q and antibodies= c1q conf change. activates c1r
2. c1r cleaves and activates c1s
3. c1s cleaves c4 + c2 to c4bc2a
even tho complement is innate it is activated by antibodies via the classical pathway.

Question 7

how else is the classical pathway activated?

Answer 7

DNA: AB against DNA form immune complexes with DNA. c1q binds to their fc region.
CRP: (c - reactive protein)
prions: can form immune complexes with antibodies against prions which bind to c1q
(info from chatgpt must fact-check)

Question 8

what is mannan binding lectin?

Answer 8

MBL (Pattern recognition receptor): binds to mannose +other sugars on pathogen surface called PAMPS which are absent on healthy cells but may be found in bacteria, fungi and viruses.
MBL in the collecti-ns family. MBL and collections 10, 11 and 12 bind to oligosaccharides and lipids on the pathogen surface.

Question 9

what are ficolins?

Answer 9

a prr that bind to N-acetylglucosamine (a sugar in bacterial cell walls) ficolins and mbl are both involved in the lectin pathway.

Question 10

describe the lectin/ mb-lectin pathway

Answer 10

masp 1 +2 (mbl-associated serine proteins) are activated when mbl or ficolins bind to pathogen surfaces. masp-2 cleaves c4 +v2 complement proteins to c4bc2a- c3 convertase.

Question 11

what is the alternate pathway?

Answer 11

initiated by spontaneous hydrolysis of c3 to c3(h20) (fluid-phase c3 convertase) that binds to factor B, allowing factor D to cleabe factor B to Bb and Ba.
note: c3(h20)Bb is fluid phase c3 convertase.

Question 12

describe the activation of the classical and mb-lectin pathways in detail

Answer 12

c1 cleaves c4 and c2 into c4a, c4b, c2a, c2b. c4bc2a is c3 convertase where c4b has a convalent binding thioester bond in its structure allowing it to bind to the pathogen surface. c3 convertase splits c3 into c3a and c3b. c4bc2ac3b form c5 convertase which splits c5 into c5a and c5b.
AMPLIFICATION STEP: c3b binds to the pathogen surface for oponisation. amplifies by promoting c5 convertase formation. c5b recruits more immune cells and leads to the formation of the membrane attack complex to form pores in the pathogen membrane. c5a acts as an anaphylatoxin.

Question 13

describe the amplification loop of the alternative pathway

Answer 13

c3b binds to the pathogen surface for oponisation. c3b interacts with factor B, so factor D cleaves factor b into alternative c3 convertase (c3bBb). factor P stabilises this complex on pathogen surface enhancing the cleavage of more c3 into c3a and c3b. c3bBbC3b is alternative c5 convertase which then cleaves more c5.

Question 14

what do anaphylatoxins do

Answer 14

c5a anc 3a: enhance inflammation and attract immune cells to the site of infection e.g: for phagocytosis by macrophages and neutrophils. bind to receptors on mast cells and basophils for the release of histamine and other proinflammatory factors (fact check).

Question 15

complement effectors for recruitment and inflammation?

Answer 15

c3a«c5a (c5a greater potency and activity). they act on c5a and c3a receptors on:
endothelial cells- cause muscle contraction, increased vascular permeability and promoting adhesion molecule expression.
mast cells- cause histamine release (fever and allergic reaction), pathogen recognition and cytokine
macrophages, monocytes and granulocytes such as neutrophils: chemotaxis to attact these cells, cause phagocytosis and degranulation of mast and basophils.
T cell- promote their activation (by promoting antigen presenting cell activation (macrophages) and promote their resolution.

Question 16

complement effectors for opsonisation?

Answer 16

c3b and (c4b) bind to complement receptors (CR).
MACROPHAGES- CR1, LIGAND- C3b
MONOCYTE: CR2, LIGAND: iC3b
B CELLS- CR3, LIGAND: C3dg
PMN (neutrophils), LIGAND (c4b)
EFFECT- PHAGOCYTOSIS IN THE PRESENCE OF C5a

Question 17

complement effectors for lysis?

Answer 17

membrane attack complex forms upon the completion of the complement cascade. C5-C9. c5b binds to c6 and this complex binds to c7. c5bc6c7 complex inserts into the pathogen lipid bilayer and binds to c8. several c9 molecules bind to this complex to form pores in the membrane.

Question 18

why is there regulation of the complement cascade?

Answer 18

c3b and c5b are highly reactive and non specific so can bind to host tissue. regulation protects self tissue from a complement attack.
- there is short-half life of the activated thioester so rapid degranulation of c3b/c4b so activation of proteins only on pathogen surface
- tight reg of activation pathways (DAMPS -damage associated molecular patterns and TLR co signal needed
- there is complement regulation on host tissue

Question 19

how does regulation of the complement cascade occur?

Answer 19

(SOLUBLE IN PLASMA) C1 inibitor: inhibits the classical and mbl preventing c1r and c1s and masps from activating the complement cascade.
(SOLUBLE) C4bp: regulate the classical and mbl pathway by binding to c4b so preventing c3 convertase formation
(SOLUBLE) factor H: REG alt by binding to c3b preventing c3bBb formation and promoting its degradation
( MEMBRANE BOUND) DAF (dissosication accelerating factor) : accelerates dissaosication of c3/c5 convertase in all pathways so stops cascade early. binds to c3b in alt and c4b in classical and mbl (factcheck)
(MEMBRANE BOUND) CR1: helps break down c3b and c4b to prevent further activation of complement.
(SOLUBLE) Factor I: chops the complement proteins and changes its shape to make it more susceptible to truncation. a protease.
(MEMBRANE BOUND): properdin (factor p) : an activator that stabilises the complement by binding and enhances the survival of the complement on membrane. in the alternative pathway.
(MEMBRANE BOUND): CD46: membrane co factor protein. acts as a co factor to factor i to cleave c3b and c4b. releases c3f so c3b becomes ic3b.
(MEMBRANE BOUND): CD59: prevents mac formation by inhibiting c9 insertion in the membrane so stops lysis.
(SOLUBLE) PROTEIN S: co factor. inhibits mac assembly. stabilises c5b complexes in the fluid phase preventing binding to host membranes.

Question 20

complement in disease?

Answer 20

aquired or inherited. complement malfunction=
C1, C2, C3, C4: removal of Ag/Ab complexes:
Lupus-like illness
Chronic renal disease
Repeated infections
* C5, C6, C7, C8:
Repeated Neisseria infection (gonorrhoea, meningitis)
* C9: normal (as it is only in the final step of mac)AUTOIMMUNE DISEASE (adaptive immunity)
- Systemic Lupus Erythematosus (SLE): C1, C4, C2
- Rheumatoid Arthritis: C1q, C2
- Systemic Sclerosis: C3
- Inflammatory bowel disease: CD55/DAF

Question 21

complosomes?

Answer 21

not circulating complement. is immune cell derived (can be produced by immune cells like T cells) so function inside cells.
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

Question 22

disease testing and treatment?

Answer 22

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)