complement system effects on the human body

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Introduction:

The word complement means additional effect, here it means that there is additional immunity to our human body. It was discovered by Jules Bordet in 1895, in sheep antiserum to the bacterium Vibrio cholerae. He found that the bacterium cell wall was lysed and found out that there is a loss of lysing ability when the serum is heated and regained its ability when fresh serum is added to it. He described correctly that the bacterial lysis required two things namely the antibodies and heat sensitive component responsible for the bacterial lysis. He named the compound as alexin and the term " complement " was coined by Paul Ehrlich.

They are normal serum proteins found in an inactive state unless or until they are activated by invading pathogens. There are nine important proteins which constitute the complement system which are designated by numerals as C1, C2, C3..C9. They are heat labile β - globulins. They are neither antigens nor antibodies and found as proenzymes. They activate as cofactors for the antibodies to exhibit full activity of cell lysis. They do not increase after immunisation. On activation they become active, acquire enzymatic esterase activity and activation is designated by drawing a horizontal bar over them. There are about 20 different β - globulins are seen, out of which 16 are active in complements. Complement C1 has 3 sub units such as C1q, C1r, C1s.

Biosynthesis of Complements:

C1 is synthesised in intestinal epithelium.

C2 and C4 are synthesised by macrophages.

C3, C6 and C9 are synthesised in the liver.

The site of C7 is not known.

Complement proteins action:

Complement

Active protein /

split product

Immunological function

C1

C1q

Binds to Fcportion of IgM(1) and IgG(2)

C1r

Serine protease: enzymically activates C1s

C1s

Serine proteases: enzymically activates C4and C5

C4

C4a

Peptide mediator of inflammation (anaphylotoxin)

C4b

Binds C2forming complex that is cleaved by C1s to yield activated C4b2a

C2

C2a

Serine protease: activated C4b2aacts as C3convertase

C2b

Unknown function

C3

C3a

Peptide mediator of inflammation (anaphylotoxin)

C3b

Binds to activated C4b2ato form C5 convertase; major opsonin

Complement Activation:

There are 3 types of activation is seen in the complement namely

Classical pathway (activated by Ag-Ab complex, Gram -ve bacteria and animal viruses)

Alternative pathway (activated by aggregated IgG or IgM, Bacterial endotoxin)

Lectin pathway.

Pathogens recognization by Complement system:

COMPLEMENT

PATHOGEN EPITOPES

RECOGNIZATION VIA

Classical Pathway

Multiple epitopes

Antibody ( 2 molecules ) IgG /(one molecule) IgM (adaptive/ specific immunity)

Lectin Pathway

Phosphoryl Choline,

Fungal Cell walls,

LPS (lipopolysaccharides)

Mannose

C - reactive protein (Innate)

MBL (Mannose Binding Protein)

Alternative Pathway

Non-self Surfaces

C3b(Innate)

Classical Pathway:

This activation begins with the formation of soluble antigen - antibody complexes or after the binding of the antibody to antigen on suitable target such as bacterial cell. IgM(1) and IgG(2) molecules activates classical pathway. Complement system has particular sequence to react, C1q, C1r, C1s, C4, C2, C3, C5, C­6, C7, C8 and C9.

The complexing of the antibody with antigen induces conformational changes in the Fc region of the of the IgM molecule that expose the binding surface for the C1 component of the complement system.

C1 in serum is a macro molecular compound with subunits such as C1q and two molecules of C1r and C1s held together by Ca2+ ions.

The C1q identifies the antigen-antibody complex and reacts with Fc region of the receptor. This process of binding is called complement fixation. Ca2+ is essential for the binding of C1q.

Attachment causes the C1r activation functions as serine histidine esterase and activates C1s.

Then C1s activates the C4 and C2 in the presence of Mg2+.

C4 activation causes the splitting up to form fragment called C4a and C4b. Activated C4b attaches to the Ag-Ab complex or on the surface of the microbe.

Activated C2 forms two fragments namely large C2a and small C2b. C2a reacts with C4b to form complex called C4b2a.

Activated C4b2a is called as C3 convertase and acts on C3 to form C3a and C3b and C3b binds to form C4b2a3b.

The complex C4b2a3b acts as C5 convertase. Macrophages and phagocytes has binding sites for C3 and hence the above complex attaches on their surface and helps in phagocytosing the bacteria and viruses.

The activated C5 forms the two fragments namely C5a and C5b and the C5b is separated and incorporated in the lipid bilayer.

This activates the formation of complex by addition of complements C6, C7, C8 tetrameric complex called C5b678.

This complex has binding site for the C9 and forms the complex called C5a6789.

This complex forms a pore in the lipid bilayer in the surface of the bacteria causing the cell to lysis. When the bacterial cell lysis then it is called Bacteriolysis and when the RBC lysis occurs then it is called haemolysis.

Complement Chemotoxins:

Fragments such as C3a, C4a and C5a acts as Chemotoxins to attract inflammatory cells and causes degranulation of mast cells and blood basophils. C3a, C5a induce monocytes and neutrophils to the site of infection. C3b acts as opsonin. They also acts as anaphylotoxins on mast cells to degranulate the histamine and other vascular permeable substances to form the increased permeability which helps in the vascular permeability.

Alternative Pathway:

In this method activation of C3 compound occurs without the activation of C1, C4 and C2 and hence it is called alternative pathway.

It is activated by aggregated IgG or IgA antibodies, Bacteria endotoxin, lipopolysaccharides from gram -ve bacteria, teichoic acid from gram +ve bacteria, fungal and yeast cell walls(zymosan).

They do not depend on the Fc region of antibodies for activation.

About 4 complement factors are involved namely C3, B, D and P.

Activation of C3 is done by the presence of the zymosan and Mg2+ and they form C3a and C3b by spontaneous reaction.

Then to this C3a compound B reacts to form Ba and Bb and the compound Bb forms a complex called C3aBb which is unstable C3 convertase.

To this complex compound D reacts to cleave the Ba from the above complex.

In order to stabilize that properdin compound P is added to form the stable C3 convertase.

This C3 convertase acts on the C3 to form C3a and C3b and this C3b reacts with the C3 convertase complex to form C3bBb3b to form the stable C5 convertase.

After the formation of the C5 the reaction is same as that of the classical pathway and forms MAC (Membrane Attacking Complex).

Lectin pathway:

In this pathway there is no need for antibodies to activate the complement system. Instead of that mannose and C-reactive protein are involved for their activation.

In this process after binding of the CRP or Mannose Binding Lectin with that of the micro organisms causes the activation of the C4 as the classical pathway.

MBL is acute phase protein produced during the inflammatory responses.

After the binding of the MBL the MBL associated serine proteases binds to it, this causes the cleavage of the C4 and follows the classical pathway and forms MAC's.

Functions of the complement system:

Lysis of the bacteria and viruses.

Opsonisation promotes the phagocytosis of the particulate antigens.

Binding to the specific complement receptors on the cells of the immune system triggers the activation of the immune responses such as inflammation and secretion of the immunoregulatory molecules that amplify or alter specific immune responses.

Immune clearance, which removes immune complexes from the circulation and deposits them in the spleen.

Helps in the coagulation of the blood. Blood platelets adhere to activated C3 are lysed. Lysed platelets release factor for the conversion of the prothrombin to the thrombin.

Inhibitors of the Complement system:

Protein

Type of Protein

Pathway inhibited

Immunologic function

C1 inhibitor

Soluble

Classical

Serine protease inhibitor: causes dissociation of C1q

C4bbinding protein

Soluble

Classical and Lectin

Blocking formation of C3convertase by binding with C4b

Factor H

Soluble

Alternative

Blocks the formation of C3 convertase by binding with C3b

S protein

Soluble

Terminal

Binds to C5b678on autologous cells, blocks the binding of C9

Complement-receptor factor

Type 1 (CR1)

Membrane-Cofactor Protein

(MCP)

Membrane bound

Classical, Alternative, Lectin

Blocks the formation of C3 convertase by binding with C4bor C3b

Factor I

Soluble

Classical, Alternative, Lectin

Serine protease: Cleaves C4bor C3bby using CR1, MCP

Decay-accelerating factor

(DAF)

Membrane bound

Classical, Alternative, Lectin

Accelerated the dissociation of C4b2aand C3bBb

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