Regulation of Complement System

Regulation of Complement System

Since the complement system involves the formation of many biologically active substances, there are many regulatory systems to prevent unwarranted damage to the human host. The activities of the different complement components activated at each stage of the cascade are regulated by several mechanisms. The following are regulators of the complement system:

1. Level of antibody: The level of antibody itself is the firstregulatory step in the classical pathway. If antigen is not bound to the antibodies, the complement-binding sites on the heavy chains of IgG and IgM are unavailable to the C1 component of the complement. This means that complement is not acti-vated even if IgM and IgG are present in the blood at all times. However, when antigen binds with specific antibodies, a con-formational shift occurs and that allows the C1 component to bind and initiate the cascade reaction.

2.  C1 inhibitors: These inhibitors play a critical role inlimiting unnecessary complement activation. These prevent the formation and function of C1qrs complex by causing C1s to dissociate from C1qrs. The C1 inhibitors may also aid in the removal of the entire C1 complex from the antigen–antibody complexes.

3. Other inhibitory substances: Multiple substances haveinhibitory effects over different steps of the activation sequence of the classical pathway. These are considered to be host cell protective mechanisms. These mechanisms probably help to protect the host cells from the possible bystander damage initi-ated by activated complement fragments (C3b and C4b) being formed on and near its surface.

4.        Decay-accelerating factor (DAF): It is another inhibitorysubstance located in a large variety of host cell membranes. It is so termed because it can 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 subsequent interac-tion with C2a and factor B, respectively. 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.

5.        Regulation of alternative pathway: The alternative path-way has its own set of regulatory proteins and mechanisms. It is mediated 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.