COMPLEMENT SYSTEM

COMPLEMENT SYSTEM:

These are proteins circulating in the blood and are of several types of which C3 is the most abundant and is produced in the liver. It can be converted into C3b and when stable C3b binds to a bacteria, bacterial death occurs. All the pathways of complement activation involve the conversion of C3 to C3b. it occurs in 3 ways:

1. Alternate pathway: in this C3 spontaneously converts into C3b and it happens all the time in the blood and the tissues but it is unstable and is destroyed in less than a second. But, it can be stabilized if it binds to amino and hydroxyl groups that are present commonly on the surface of pathogens. Eg: bacterial lipopolysaccahrides (LPS), fungal cell walls and viral envelopes. Stable C3b is so effective because it can form more copies of it via the positive feedback loop. It binds to a complement protein B and is clipped by another complement protein D forming C3bBb which is a C3 convertase. Factor H blocks the alternate pathway preventing excess production of C3b and it accelerates decay of C3 convertase and cleaves and inactivates C3b. it is sometimes used by the cancer cells and bacteria to avoid the complement system. It is an example of innate immunity.

2. Lectin pathway: in blood there is protein called mannose-binding lectin which is produced in the liver and it circulates with MASPs (Mannose Associated Serine Proteases). These complexes binds to the surfaces with mannose (many microbes) and cleave C2 into C2b and C4 into C4b and these to combine to form C2b4b which is a C3 convertase. It is an example of innate immunity.

3. Classical pathway: some antigen-antibody complexes can bind to C1 which can then cleave C2 into C2b and C4 into C4b which then bind together and form C2b4b which is a C3 convertase. It is a part of the adaptive immunity.

C1: It is a very large complex and consists of C1q, C1s, C1r, & C1-inhibitor. For the C1 portion to bind to the complex it must bind to 2 Fc portions that are close together and then the C1 inhibitor falls off and the C1s & C1r are activated and can cleave C2 & C4

MEMBRANE ATTACK COMPLEXES is the major way to fight the capsulated bacteria. There are some membrane proteins that protect us from our own membrane attack complexes. The 2 most imp ones are: decay accelerating factor (CD55/DAF), MAC inhibitory protein (CD59).

DAF disrupts C3b attachment. CD59 disrupts MAC. If they are deficient in a person he will suffer with haemolysis. And this condition is termed as paroxysmal nocturnal haemoglobinuria.

The other conditions such as this are, inherited C3 deficiency (are subjected to recurrent infections by encapsulated bacteria). And children with this deficiency get infected with glomerulonephritis from IC (Immune complex) deposition and other type 3 hypersensitivity disorders. Another one is the deficiencies of C5-C9 and is called as terminal complement pathway deficiency. Children with this deficiency have impaired defence against encapsulated bugs and experience recurrent Neisseria infections.

The other condition is hereditary angioedema. It occurs due to the deficiency of C1 inhibitory protein. And it has to do with higher levels of bradykinin which causes oedema or swelling. It can be diagnosed by measuring the C4 levels in the blood as they have lower levels of C4 as the C1 is always present in them. And these patients should never be given ACE (Angiotensin Converting Enzyme) inhibitors as they not only block the conversion of angiotensin 1 to 2 but also block the breakdown of bradykinin.

There is also C3 nephritic factor because it stabilizes C3 convertase and leads to the overactivity of classical pathway. It is found in >80% patients suffering with membrano proliferative glomerulonephritis 2 (MPGN2).

The complement system is tested by using:

1. CH50: tests classical pathway. Normal range is from 150-250 units/ml.

2. C4 & C3 levels: lower levels in lupus and lupus nephritis, MPGN & post-streptococcal glomerulonephritis.