The Complement System-Immunology

Complement is an essential component of our innate host defences. Complement is a collective term used to designate a group of plasma proteins at least 20 in number, that are present in average human (and other animals) serum. The term “complement” refers to the ability of these proteins to complement, i.e., augment, the effects of different components of the immune system, e.g., antibody.

Activation of the Complement System

The activation of the complement system.
Activation of Complement

***Note that the nomenclature of the cleavage products
of C2 is undecided. Some call the large fragment C2a and others call it C2b.

Several complement components are proenzymes, which must be cleaved to form active enzymes. Activation of the complement system can be initiated either by antigen-antibody complexes or by a variety of nonimmunologic molecules, e.g. endotoxin.
Sequential activation of complement components occurs via one of three pathways: the classic pathway, the lectin pathway, and the alternative pathway.

Of these pathways, the lectin and the alternative pathways are
more important the first time we are infected by a microorganism because the antibody required to trigger the classic pathway is not present. The lectin pathway and the alternative pathway are, therefore, participants in the innate arm of the complement system.

The Classical Pathway

In the classic pathway, antigen-antibody complexes bind to C1 which activates C1 to form a protease, which cleaves C2 and C4 to form a C4b,2b complex which is also called the C3 convertase.

The C3 convertase, which cleaves C3 molecules into two fragments, C3a and C3b. C3a, an anaphylatoxin, is discussed below.

C3b forms a complex with C4b,2b (C3 convertase), producing a new enzyme, C5 convertase (C4b,2b,3b).

The C5 convertase cleaves C5 to form C5a and C5b. C5a is an anaphylatoxin and a chemotactic factor (see below).

C5b binds to C6 and C7 to form a complex that interacts with C8 and C9 to produce the membrane attack complex(C5b,6,7,8,9), which causes cytolysis.

** Note: the “b” fragment continues in the main pathway, whereas the “a”
fragment is split off and has other activities.

The Lectin Pathway

In the lectin pathway, mannan-binding lectin (MBL) (also known as mannose-binding protein) binds to the surface of microbes bearing mannan (a polymer of the sugar, mannose).

This activates proteases associated with MBL that cleave
C2 and C4 components of complement and activate the classic pathway.

*** Note that this process bypasses the antibody requiring step and so is protective early in infection before antibody is formed.

The Alternative Pathway

In the alternative pathway, many unrelated cell surface substances, e.g., bacterial lipopolysaccharides (endotoxin), fungal cell walls, and viral envelopes can initiate the process by binding C3(H2O) and factor B. This complex is cleaved by a protease, factor D, to produce C3b,Bb. This acts as a C3 convertase to generate more C3b.

Now the C3b,Bb,C3b also C5 convertase cleaves the C5 producing the same result as the Classical pathway.

*** NOTE

Only IgM and IgG fix complement. One molecule of IgM can activate complement; however, activation by IgG requires two cross-linked IgG molecules. C1 is bound to a site located in the Fc region of the heavy chain. Of the IgGs, only IgG1, IgG2, and IgG3 subclasses fix complement; IgG4 does not.
C1 is composed of three proteins, C1q, C1r, and C1s. C1q is an aggregate of 18 polypeptides that binds to the Fc portion of IgG and IgM. It is multivalent and can cross-link several immunoglobulin molecules. C1s is a proenzyme that is cleaved to form an active protease. Calcium is required for the activation of C1.

Regulation of Complement System

The first regulatory step in the classic pathway is at the level of the antibody itself. The complement-binding site on the heavy chain of IgM and IgG is unavailable to the C1 component of complement if the antigen is not bound to these antibodies. This means that complement is not activated by IgM and IgG despite being present in the blood at all times. However, when
an antigen binds to its specific antibody, a conformational shift occurs and the C1 component can bind and initiate the cascade.

Several serum protein regulate the complement system in different stages.

  1. C1 inhibitor is an important regulator of the classic pathway. It inactivates the protease activity of C1. Activation of the
    classic pathway proceeds past this point by generating sufficient C1 to overwhelm the inhibitor.
  2. Regulation of the alternative pathway is mediated by the binding of factor H to C3b and cleavage of this complex by factor I, a protease. This reduces the amount of C5 convertase available. The alternative pathway can proceed past this regulatory point if sufficient C3b attaches to cell membranes. Attachment of C3b to cell membranes protects it from degradation by factors H and I. Another component that enhances activation of the alternative pathway is properdin, which protects C3b and stabilizes the C3 convertase
  3. Protection of human cells from lysis by the membrane attack complex of complement is mediated by the decay-accelerating factor (DAF, CD55)—a glycoprotein located on the surface of human cells. DAF acts by binding to C3b and C4b and limiting the formation of C3 convertase and C5 convertase. This prevents the formation of the membrane attack complex.

Biological Effects of the Complement system

Opsonization:

Microbes, such as bacteria and viruses, are phagocytized much better in the presence of C3b and C3b are the receptor in the surface of many phagocytes.

opsonization
opsonization by complement C3b

Chemotaxis

C3a and C5a and the C5,6,7 complex have chemotactic activity and attract neutrophils. Neutrophils migrate towards especially towards C5a. C5a also enhances the adhesiveness of neutrophils to the endothelium.

Anaphylatoxin

C3a, C4a and C5a cause degranulation of mast cell with the release of mediators. i.e histamine leading to increased vascular
permeability and smooth muscle contraction, especially contraction of the bronchioles leading to bronchospasm.
Anaphylatoxins can also bind directly to smooth muscle cells of the bronchioles and cause bronchospasm. C5a is, by far, the most potent of these anaphylatoxins. Anaphylaxis caused by these complement components is less common than anaphylaxis caused by type I (IgE-mediated) hypersensitivity

Cytolysis

Insertion of the C5b,6,7,8,9 complex into the cell membrane leads to killing or lysis of many types of cells including erythrocytes, bacteria, and tumour cells. Cytolysis is not an enzymatic process; rather, it appears that insertion of the complex results in the disruption of the membrane and the entry of water and electrolytes into the cell.

Enhancement of Antibody Production

The binding of C3b to its receptors on the surface of activated B cells greatly enhances antibody production compared with that by B cells that are activated by antigen alone. The clinical importance of this is that patients who are deficient in C3b produce significantly less antibody than do those with normal amounts of C3b. The low concentration of both antibody and C3b significantly impairs host defences, resulting in multiple, severe pyogenic infections.

Inflammation

Mainly C5a and to a lesser extent C3a and C5a play a role in Inflamation.

Immune adherence

C3b is responsible for immune adherence.

Virus neutralization

C1 and C4 play a role in neutralization of viruses.

Removing harmful immune complexes from the body

C3b and to a lesser extent, C4b helps to remove harmful immune complex from the body.

Clinical Aspects of Complement System

  1. Inherited (or acquired) deficiency of some complement components, especially C5–C8, greatly enhances susceptibility to
    Neisseria bacteremia and other infections. A deficiency of MBL also predisposes to severe Neisseria infections.
  2. A deficiency of C3 leads to the severe, recurrent pyogenic sinus and respiratory tract infections.
  3. Inherited deficiency of C1 esterase inhibitor results in angioedema. When the amount of inhibitor is reduced, an overproduction of esterase occurs. This leads to an increase in anaphylatoxins, which cause capillary permeability and oedema.
  4. Acquired deficiency of decay-accelerating factor on the surface of cells results in an increase in complement-mediated hemolysis. Clinically, this appears as the disorder paroxysmal nocturnal hemoglobinuria.
  5. In transfusion mismatches, e.g., when type A blood is given by mistake to a person who has type B blood, antibody to
    the A antigen in the recipient binds to A antigen on the donor red cells, complement is activated, and large amounts of
    anaphylatoxins and membrane attack complexes are generated. The anaphylatoxins cause shock, and the membrane attack complexes cause red cell hemolysis.
  1. Immune complexes bind complement and thus complement levels are low in immune complex diseases, e.g., acute glomerulonephritis and systemic lupus erythematosus. Binding (activating) complement attracts polymorphonuclear leukocytes, which release enzymes that damage tissue.
  2. Patients with severe liver disease, e.g., alcoholic cirrhosis or chronic hepatitis B, who have lost significant liver function
    and therefore cannot synthesize sufficient complement proteins, are predisposed to infections caused by pyogenic bacteria.

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