Regulation of Complement, Biological Effects of Complement and Deficiency of Complement System

Regulation of Complement, Biological Effects of Complement and Deficiency of Complement System

 

Regulation of Complement System

  • The complement system involves the formation of many biologically active substances, there are several regulatory systems to prevent unwarranted injury to the human host.
  • The activities of the various complement components activated at every stage of the cascade are regulated by several mechanisms.

The regulators of the complement system are as follows:

  1. Level of antibody
  2. C1 inhibitors
  3. Other inhibitory or repressor
  4. Decay-accelerating factor (DAF)
  5. Regulation of the alternative pathway

Level of antibody:

  • The level of antibody itself is the initial regulatory step within the classical pathway.
  • If antigen isn’t bound to the antibodies, the complement binding sites on the heavy chains of IgG and IgM are unavailable to the C1 part of the complement.
  • This means that complement isn’t activated even if IgM and IgG are present in the blood at all times.
  • However, once antigen binds with specific antibodies, a conformational shift happens that allows the C1 component to bind and initiate the cascade reaction.

C1 inhibitors:

  • These inhibitors play a important performance in limiting unnecessary complement activation.
  • These inhibit the formation and function of C1qrs complex by causing C1s to dissociate from C1qrs.
  • The C1 inhibitors might also aid in the removal of the complete C1 complex from the antigen–antibody complexes.

Other inhibitory substances:

  • Multiple substances have restrictive effects over different steps of the activation sequence of the classical pathway.
  • These are considered as host cell protecting mechanisms.
  • These mechanisms probably help to shield the host cells from the possible bystander damage or injury initiated by activated complement fragments (C3b and C4b) being formed on close to its surface.

Decay-accelerating factor (DAF):

  • It is another inhibitory or repressing substance located in a large variety of host cell membranes.
  • It is therefore termed as a result of it will accelerate the dissociation of active C4b2a complexes, turning off their ability to activate native C3.
  • In addition, DAF remains attached to membrane bound C4b and C3b, and prevents the following interaction with C2a and factor B, severally.
  • As a consequence, the two types of C3 convertases, C4b2a and C3bBb, are not formed; hence, the rate of C3 breakdown is reduced and the host cells are spared from complement-mediated membrane damage.

Regulation of alternative pathway:

  • The alternative pathway has its own set of regulative proteins and mechanisms.
  • It is initiated by the binding of factor H to C3b and cleavage of this complex by specific plasma inhibitor factor I, a protease.
  • This reduces the amount of C5 convertase available.

Biological Effects of Complement

  • The main role or importance of complement is to amplify the humoral immunologic response.
  • The complement and its various products participates within the inflammatory response, opsonization of antigen, viral neutralization, and clearance of immune complexes as follows:
    • Chemotaxis
    • Opsonization
    • Hypersensitivity Reactions
    • Cytolysis
    • Enhancement of Antibody Production

Chemotaxis:

  • C5a could be a chemotactic molecule specifically recognized by polymorphonuclear leukocytes, somatic cells or phagocytic cells.
  • This substance causes leukocytes to migrate to a tissue in which an antigen–antibody reaction is taking place in the tissue.
  • At that site, a phagocytic cell observe or recognizes opsonized particles and ingests them.
  • C5a not only has a chemotactic effect on neutrophils, However it also activates these cells causing their reversible aggregation and release of stored enzymes, as well as proteases.
  • C5a also enhances the adhesiveness of neutrophils to the endothelium tissue.

Opsonization:

  • Complement plays a very important role in opsonization of pathogenic bacteria and viruses or any microorganisms.
  • Bacteria and viruses are simply or easily phagocytosed by phagocytic cells within the presence of complement component C3b.
  • This is because the receptors for the C3b component are present on the surface of phagocytes.

Hypersensitivity Reactions:

  • Complement takes participate in type II (cytotoxic) and type III (immune complex) hypersensitivity reactions.
  • The C3a, C4a, and C5a components helps in degranulation of mast cells with release of mediators, such as histamine.
  • The C3a fragments bind to receptors on basophils and mast cells and induce the release of stored vasoactive amines (e.g., histamine) and heparin.
  • The release of histamine into the tissues results in increased capillary permeability and smooth muscle contraction. 
  • Fluids which is released into the tissue, therefore causing edema and swelling.
  • There is some proof that C3a and C5a can also act directly on endothelial cells, causing increased vascular permeability.
  • The end result is like classical anaphylactic reaction which takes place when IgE antibodies bound to the membranes of mast cells and basophils react with the corresponding antigens.
  • For this reason, C3a and C5a are refered as anaphylatoxins.

Cytolysis:

  • Complement mediates cytolysis. Insertion of C5b–9 complex (MAC) into the cell membrane results in killing or lysis of erythrocytes, bacteria, and tumor or cancerous cells.
  • The insertion of the MAC complex results in disruption of the membrane, there by resulting in entry of water and electrolytes into the cell.

Enhancement of Antibody Production:

  • The binding of C3b to the surface receptors on the activated B cells, which enhances the production of antibodies in comparison to that of B cells activated by antigen alone.
  • Hence, deficiency of C3b results in reduced production of antibodies.
  • Therefore, low concentration of each C3b and antibodies may affects host defense, resulting in severe pyogenic infections.

Deficiency of Complement

Complement plays a vital role in the well being of humans. Deficiency of various components may lead to many diseases as follows:

  • Inherited deficiency of C1 esterase inhibitors causes angioedema.
  • The low level of C1 esterase inhibitors results in over production of esterase.
  • This results an increase in release of anaphylatoxins, that cause capillary permeability and edema.
  • Acquired deficiency of DAF leads to an increase in complement mediated hemolysis.
  • The condition manifests clinically as paroxysmal nocturnal hemoglobinuria.
  • Inherited or acquired deficiency of C5–8 components greatly enhances susceptibility to Neisseria bacteremia and other infections.
  • Deficiency of C3 results in severe recurrent pyogenic sinusitis and respiratory infections.
  • The synthesis of enough quantities of complement is reduced within the patients with severe disease, such as chronic infectious disease or alcoholic liver disease.
  • These patients, therefore, are extremely liable to infections caused by pyogenic bacterium.

Deficiency of complement components and diseases related with these complement deficiency are summarized in Table:

Deficiency Disorder Salient features
C1 esterase inhibitor Hereditary angioedema Transient but recurrent localized edemain the skin, gastrointestinal
tract, and respiratory tract
C1q Associated with hypogammaglobulinemia and severe combined immunodeficiency disease Repeated infections
C2 and C4 Similar to SLE Due to failure in clearance immune-mediated complexes
C3 Severe recurrent pyogenic infections Streptococcus pneumoniae infections
C5 Impaired chemotaxis Increased susceptibility to bacterial infection
C5–C8 Bacteremia Gram-negative diplococci and toxoplasmosis

Regulation of Complement, Biological Effects of Complement and Deficiency of Complement System

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