Complement System In Immunity And Pathways

Complement System 

The Compliment refers to a system of some nonspecific proteins present in normal human and animal serum which are activated characteristically by antigen-antibody reaction and subsequently lead to a number of biological significant consequences.

The compliment constitutes 10-15 percent of total human serum globulins. C ordinary does not combine with either free antigen or antibody but only with antigen-antibody complex. The complement system consists of about 20 proteins which include the complement of the properdin system and the control proteins.

A. Components of Complement 

There are nine components of a compliment called C1 to C9. The component C1 is made up of three protein subunits named C1q, C1r, and C1s. In normal serum C3 is present in the highest concentration 1.2 mg/ml whereas C2 in the lowest concentration 0.015mg/ml.
Complement is normally present in the circulation in an inactive form, but when it is activity is included by antigen-antibody reaction or other stimuli, complement components react in a specific sequence as a cascade either through the classical or alternative pathway.

Both the pathway have the same result lysis or damage to the target cell. The classical pathway is triggered by a specific antigen-antibody complex, the alternative pathway can be initiated by endotoxin, lipopolysaccharide, or zymosan. 

B. Classical Pathway

Complement components react in a specific sequence, following activation by antigen-antibody complex, and results in immune cytolysis. This is known as the classical pathway of compliment.
The traditional model used to explain C activity for immune cytolysis is the lysis of erythrocyte E antibody A complex named EA and later on, when C components are attached to EA, it is called EAC. Immune cytolysis is initiated by the binding of component C1 to EA. C1q is the recognition unit of C1, hence C1q reacts with the Fc piece of a bound antibody molecule(IgM or lgG) in the erythrocyte-antibody complex.
The binding of C1q in the presence of calcium ions leads to the activation of C1r and C1s. The activated C1s is an esterase which splits C4 into C4a and C4b, of which C4b join the cascade. C14b in the presence of magnesium ions act on C2 and forms C2a and C2b. The larger fragment C2a attaches to C4 to form C42 which has enzymatic activity and is called C3 convertase. The other C2 fragments posses kinin like activity and increase vascular permeability. C 42 splits C3 into C3a and C3b,  of which C3b joins the cascade. C3a has chemotactic and anaphylatoxin properties.
 C14b2a3b has enzymatic activity and is referred to as C5 convertase.  It acts on C5, to split it onto C5a (anaphylatoxin and chemotactic) and C5b which joins the cascade. C6 and C7 join to form C567, some of which binds to the cell membrane and prepares the cell for lysis by C8 and C9. Most of C567 absorb to unsensitised ‘bystander’ cells and making them susceptible to lysis by C8 and C9.
In this way, C567 serves to amplify the reaction. The unbound C567 complex has chemotactic and leucocyte activating properties. The lysis is done by producing ‘holes’ approximately 100A ° in diameter in the cell membrane.  This disrupts the osmotic integrity of the cell membrane which results in the release of the contents of the cell.

C. Alternative Pathway of Complement Activation

The activation of C3 has a major role in the complement cascade. In the classical pathway, C3 activation occurs by classical C3 convertase (C142). This activation of C3 without the help of C142 is known as the ‘alternative pathway. The alternative pathway contributes to antimicrobial defense without requiring specific antibodies.
Bacterial endotoxins, yeast cell walls, IgA, and D, the cobra venom factor, and nephritic factor (a protein present in the serum of glomerulonephritis patient) are some substances (activators) which may activate the alternative pathway. The binding of C3b to an activator is the unsensitised first step in the alternative pathway.
Although C3b is present in the circulation in the free state it is rapidly inactivated by the serum protein factors H and I however bound C3b is protected from such inactivation. The bound C3b, in the presence of Mg, interacts with plasma protein factor B forming C3bB. The factor B portion of the C3bB complex is split by factor D into Ba and Bb.
Bb fragment binds to C3b forming C3bBb. This C3bBb is a C3 convertase of the alternative pathway. This enzyme is extremely liable. The properdin or factor F helps to stabilize the enzyme C3 convertase. C3 convertase splits more C3 to C3a and C3b. The newly formed C3b binds more factor B. The alternative pathway then proceeds from C3 to C9 in the same way as that occurs in the classical pathway.

D. Biological Effects of Complement 

1. Bacteriolysis and Cytolysis

Complement mediates immunological membrane damage.  This results in bacteriolysis and cytolysis.

2. amplification of Inflammatory Response 

C3a and C5a are anaphylatoxins by degranulation of mast cells to release histamine and other mediators. 

3. Hypersensitivity Reaction 

Complement participates in Type 2 cytotoxic and Type 3 immune complex hypersensitivity reaction.

4. Endotoxin Shock

Endotoxic can activate the alternative pathway of the complement cascade.

5. Immune Adherence 

Complement bound to antigen-antibody complexes adheres to erythrocytes or to platelets. This is called immune adherence. Adherence Particle is rapidly phagocytosed and thus helps in eliminating the pathogenic microorganisms.

6. Opsonisation 

Phagocytic cells(macrophages, monocytes,  neutrophils, and others ) possess surface receptors for C3b. If immune complexes have activated the complement system, the C3b bound to them stimulates phagocytosis and removal of immune complexes. This facilitated phagocytosis is referred to as optimization.

7. Autoimmune Disease 

Serum complement levels are decreased in many autoimmune diseases. They may, therefore, be involved in the pathogenesis of autoimmune diseases. 

E. Biosynthesis of Compliment

The rise in the complement level occurs in response to acute inflammation. Complement along with some other plasma proteins(CRP) are collectively known as acute phase substance which shows a rise in acute inflammation.

2. Deficiencies Of The Compliment

Deficiency of complement leads to poor host resistance against infection and fungal infection and collagen disorders.
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