Complement – Chapter 13 Summary

A system of about 30 different proteins

• Most are in the plasma (serum)
• Some are membrane bound
• Most are proenzymes – which means that they have to be ‘activated’ before they are active
• Activation generally means that they have to be ‘cleaved’ or ‘digested’ into active fragments

Complement Function

· Destroy the invader outright

· Opsonize to facilitate Antigen presentation and to facilitate clearance

· Promote inflammation – fragments that do this are called anaphylatoxins

There are three complement activation pathways (Figure 13.1)

• Classical Pathway – Activation by ‘antigen-antibody complexes’ and C-reactive protein
• Lectin Pathway – Activation by ‘Mannose Binding Lectin’ binding to mannose residues on bacterial proteins and polysaccharides
• Alternative Pathway – aggregates of many foreign ‘patterns’ such as lipopolysaccharide and fungal cell walls that act as ‘protective surfaces’ to shield C3b degradation

All three pathways lead to the production of ‘C3 convertase’!!!

• Once this happens, all three pathways are essentially the same:
• Cleave C3 into C3a (anaphylatoxin) and C3b
• C3b then binds to some of the previous components to form a ‘C5 convertase’
• This cleaves C5 into C5a (anaphylatoxin) and C5b
• C5b is the nucleating principle for the ‘terminal pathway’ which forms the ‘Membrane Attack Complex’ or ‘MAC’ which leads to the lysis of the ‘target cell’.

The major activities of complement (Fig 13.5 and 13.6)

• Target cell lysis
• Opsonization via complement receptors (CR1, CR3, CR4)
• Inflammation and chemotaxis mediated via the anaphylatoxins (C4a, C3a, C5a)
• Enhance B-cell responses – B-cells have a receptor (CR2) for C3d (a breakdown product of C3b)
• Enhance dendritic cell responses – Dendritic cells also have the C3d receptor (CR2)
• Helps with antigen clearance – keeps immune complexes small making clearance by macrophages easier. Also helps attach small immune complexes to rbc’s to assist in clearance
• Helps in the removal of dead or dying ‘host’ cells – Dead host cells activate complement. (This could be bad after a heart attack or if blood flow is cut off to an area).

There are many regulators of Complement activity

• Many regulators are cell-surface bound, but some are soluble
• C1 esterase inhibitor (C1INH) – this inhibits the activity of C1 and MBL and C3bBb – in other words this inhibits all three activation pathways.
• Inactivators of the Classical pathway/Lectin pathway C3 convertase (C4b2a) – Fig 13.4
• C4 binding protein (C4BP)
• Decay accelerating factor (DAF)
• Membrane cofactor protein (MCP)
• Complement receptor 1 (CR1)
• Factor I – which breaks up C4b
• Inactivators of the Alternative pathway C3 convertase (C3bBb) – Fig 13.4
• Factor H
• Decay accelerating factor (DAF)
• Membrane cofactor protein (MCP)
• Complement receptor 1 (CR1)
• Factor I – which breaks up C3b

Complement Deficiencies – see table 13.2

• Deficiency in C1 or C2 or C4 – Immune complex disease because of impaired clearance of immune complexes (frequently seen in lupus). Also increased pyogenic infections
• C3 deficiency -- Immune complex disease because of impaired clearance of immune complexes. Also increased pyogenic infections. (Some people have an autoantibody called C3 nephritic factor that stabilizes the alternative pathway C3bBb – this causes the uncontrolled breakdown of C3, leading to C3 deficiency.)
• Deficiency in B, D or properidin – pyogenic infections
• C1INH deficiency – hereditary angioedema – uncontrolled C1 activation