Complement Flashcards
What is the commonest reason for abnormal complement study result?
Delayed transport to laboratory for processing
Complement is heat labile and degrades quickly
What are the major function so fthe complement pathway?
- cytolysis: creates pores in cell walls
- opsonisation: coating or target cell with complement enhances phagocytosis
- intiate inflammatory response: release of anaphylotoxins
- immue compex clearing: coating with complement results in solubisation, increased circulatory clearance (autoimmune disease often unable to clear–> deposition)
Which are the componenets of the classical complement pathway?
C1q, C1r, C1s, C2, C4, C3
Which are the componenets of the alternate complement pathway?
C3, B, D, Properdin (factor P)
Which are the componenets of the common complement pathway?
C5, C6, C7, C8, C9
What is the C3 tickover component of the alternate pathway?
“Innate” part of the complement system
Aim is to generate C3b which can bind to foreign surfaces
Low level constant conversion of C3–> C3b int he body, if comes into contact with water (eg no surface), is degraded
if comes into contact with a surface not expressing a complement control protein–> labels as foreign, and activates pathway
What is the remainder of the alternate pathway after foreign surface is identified through tickover?
C3b binds to foreign surface
binds factor B and D, C3bBb (alternate pathway C3 convertase) is stabilised by Properidin
converts C3 to C3b further, coats target surface with multiple molecules
C3bBb can bind another C3b and become C3bBbC3b, which is C5 convertase
How is the classical complement pathway triggeredd?
principle effector mechanism of IgG and IgM
acitvation results in classical pathway C3 convertase which generates C3b on the surface targeted by the antibody
once C3b is generated, amplificaiton by alternate pathway occurs
What is the action of C1 in the complement system?
5 proteins (C1q, 2xC1r, 2xC1s)
C1q binds to Fc portion of antibody 9must be bound, not free/circulating)
C1s able to cleave C4 and C2
activating C1q also binds directly to some bacteria and to CRP
Which immuoglobulins are able to bind complement?
IgG and IgM IgG3>1>2>>>4 cia CH2 domain IgM via CH3 domain not IgA, E, D needs >/= 2 IgGs or IgM
How is C4 activated in the classical pathway?
C1s cleaves C4 (C4a and C4b)
C2b (cleaved by C1s) binds to C4b
C4b2b is classical pathway C3 convertase
What is the action of classical pathway C3 convertase?
C4b binds to C3
C2b cleaves it to C3b–> opsonisation and amplification
C3b binds to C4b2a to be C5 convertase
What is the interaction between the classical and alternate pathways?
classical pathway utilises alternate to amplify response
C3b can also bind to Factor B
Converted by D to Bb
stabilised by properdin which generates more C3b
What are the components of the Lectin complement pathway
activation of the pathway by Mannose-Binding Lectin and Ficollins1-3
MBL: structurally and functionally similar to C1q, associates with MASPs1&2 which on activation cleave C4 and C2
Ficollins: bind to various surface structures or microorganisms and altered self proteins, assembles into large mulimeric structures that interact with MASPs1&2
Which componens of the complement cascade are anaphylatoxins? What are their physiological effects?
C5a>C3a»C4a
designed to act locally and mediate inflammation
excessive release can cause anaphlylactic shock
- induce smooth muscle contraction
- increased vascular permeability
- increase expression of adhesion molecules
- activate mast cells
C5a is also a potent chemotactic factor
What is the function of the membrane attack complex?
forms a pore in a target cell
C5 cleaved into C5a and C5b, C5b activates C5-C9
membrane damage and lysis of target cell
What are complement control proteins?
Aim to maximise complement function on foreign cells and minimise it’s action on self
Which complement control proteins are involved in controlling the alternate pathway?
Expressed by self cells:
- MCP (membrane cofactor protein)
- CR1 (complement receptor 1)
- DAF (decay accelerating factor)
In serum:
- Factor I
- Factor H
All either block interaction between B and C3b or break down C3b
Which complement control proteins are involved in controlling the classical pathway?
Membrane Control Factors - MCP (membrane cofactor protein) - CR1 (complement receptor 1) - DAF (decay accelerating factor) - Factor I Block interaction between C4b and C2, break down C4b Expressed on surface of "Self" cells
Fluid phase Control Factors
- C4 binding protein (C4BP)
promotes dissociation between C4b and C2b
- C1 inhibitor
binds to C1r, C1s and dissociates them from C1q
Which complement control proteins are involved in control of MAC?
S protein, LDLs, CD59 (protectin, MIRL- membrane inhibitor of reactive lysis), HRF (homologous restriction factor)
all prevent binding of C5b to C7 or C8
What are the features of Hereditary Angioedema?
- Aetiology
- Clinical Manifestations
- Types
- Investigation findings
- Treatment
- Aetiology
deficiency of C1 inhibitor, results in complement activation and release of vasoactive mediators (mostly kinins) - Clinical Manifestations
typically school age, frequency of attacks variable
extravasation of plasma into deep layers of dermis or submucosa
recurrent attacks of non-pruritic, nonwhealing, painless oedema, resolves within 24 hours
laryngeal oedeam in approx 50% at one time–>asphyxia
recurrent abdominal pain (bowel oedema), vomiting, diarrhoea, hypovolaemia
precipitated by: trauma, surgery, illness, stress, drugs (oestrogens, ACEi) - Types
Hereditary Angioedema, 3 types, low or dysfunctional C1 inhibitor, type III related to oestrogen
Acquired: assocaited with B cell proliferative disorders, autoimmune disease
- Investigation findings C4 low, C3 normal C1 inh low functional C1 inh assay abnormal C1q normal in hereditary, low in acquired forms
- Treatment purified C1inh protein Bradykinin 2 receptor antagonist Kallikrein inhibitor ecallantine steroids, tranexamic acid (to prevent)
What conditions are associated with deficiency of C1q, C1r, C1s?
SLE, pyogenic infections
What conditions are associated with deficiency of C4?
SLE, GN
What conditions are associated with deficiency of C2?
SLE (50%), vasculitis, GN, recurrent pyogenic infections
What conditions are associated with deficiency of C3?
recurrent pyogenic infections, GN, immune complex disease
What conditions are associated with deficiency of Properdin, factor D?
Neisserial infections, other pyogenic infections
What conditions are associated with deficiency of Factor I, H, MCP, C3, factor B
Atypical HUS
What conditions are associated with deficiency of C5, C6, C7, C8?
Dissemination neisserial infections
What conditions are associated with deficiency of C9?
No clinical syndrome
What are the features of Paroxysmal Nocturnal Haemoglobinuria (PNH)?
- Aetiology
- Clinical features
- Aetiology
deficiency of membrane bound complement control proteins
C59 and C55 (DAF)
makes RBCs susceptible to lysis
- Clinical features Chronic haemolytic anaemia BM failure (pancytopenia) thrombosis (venous>arterial) Haemoglobinuria in approx 25% clonal expansion of haemopoetic stem cells in the bone marrow
What is the activity of cobra venom?
mimics C3b
binds B and converted by D to a C3 convertase
unable to be inactivated by H and I (as usual)
widespread consumption of complement
What is the aetiology of mesangiocapillary disease type 2?
antibody to C3bB (C3 nephritic factor)
stabilises it and makes it insoluble–> deposition
