Complement cascade

Primary immunodeficiencies are uncommon, and may occur in 1 in 10,000 individuals (6). Many primary immunodeficiencies are hereditary and congenital, and first appear in infants and children. Primary immunodeficiencies are classified into four main groups (7) relating to the lymphocytes (B-ceUs, T-ceUs, or both), phagocytes, or the complement cascade (8). Primary deficiency diseases result from B-ceU defects in 50% of cases, from T-ceU defects in ca 10%, and from combined B- and T-ceU defects in ca 20%. Phagocytic disorders account for 18% and complement defects occur in 2% of all cases. 

Serum concentrations lie between 0.5 and 2.5mgml. IgM can fix complement and a single molecule can initiate the complement cascade. IgM (with IgD) is the major immunoglobulin expressed on the surface ofB cells where it acts as an antigen receptor. 

Complement is not a single protein but comprises a group of functionally linked proteins that interact with each other to provide mar of the effector functions of humoral immunity and inflammation. Most of the components of the system are present in the serum as proenzymes, i.e. enzyme precursors. Activation of a complement molecule occurs as a result of proteolytic cleavage of the molecule, which in itself confers proteolytic activity on the molecule. Thus, many components of the system serve as the substrate of a prior component and, in turn, activate a subsequent component. This pattern of sequential activation results in the system being called the complement cascade. ... 

Evidence for a neuroimmunological involvement in Alzheimer s disease is accumulating. Activation of the complement cascade by beta amyloid (Rogers et al., 1992), the recruitment, proliferation and activation of microglia in intimate juxtaposition to the senile plaques (Davis et al., 1992), and the increased synthesis of microglia-derived pro-inflammatory cytokine interleukin-1 (Griffin et al., 1989) is indicative of a chronic inflam-... 

Over 20 infectious agents have been incriminated as etiologic agents for many the causal relationship has been disproved, and for others there is conflicting evidence. Human herpesvirus 6 (HHV-6) is currently the most likely causative virus. HHV-6 may initiate the autoimmune processes of MS in one of two ways. First, HHV-6 is structurally similar to myelin basic protein. When T cells become sensitive to HHV-6, the cells may attack myelin basic protein. Second, HHV-6 may directly stimulate the complement cascade, activating autoimmune processes.5 Infection with HHV-6 alone cannot fully explain MS, because HHV-6 is found in 75% of all people, but MS is much more rare. 

B cells likely cross previously damaged sections of the blood-brain barrier to arrive in the CNS, an area normally free of B cells. Autoreactive T cells cause B cells to form autoantibodies to myelin. B-cell antibodies also initiate the complement cascade which causes myelin degradation.7... 

The complement cascade may become activated via two pathways the classical pathway or the alternative pathway. 

Interaction with Other Cascade Systems. Interactions between the complement system, the kinin, and the coagulation and fibrinolytic systems have repeatedly been reported (S37, PI9). Activation of one system induces activation of the other systems. The reciprocal activation of the various cascade systems may have an important role in the pathogenesis of ARDS and MODS as complications of sepsis. Nevertheless, until now no convincing prophylactic or therapeutic effects of intervention in the complement cascade system on the severity of septic complications have been reported. 

Cl Binds with IgG or IgM on membrane of the target cell to initiate activation of complement cascade... 

The complement system which functions as part of the immune response is composed of about twenty proteins which circulate in the blood stream as inactive precursors. The complement cascade is functionally divided into two arms called the classical and alternative pathways, reflecting their different initiating events but which converge at C3. A simplified scheme is shown in Figure 5.25. 

Figure 5.25 Complement cascade. The classical pathway requires antigen antibody (Ag Ab) interaction to activate Cl, the alternative pathway is antigen independent...

C-reactive protein, which binds to bacteria and activates the complement cascades. It also binds and removes host proteins which are released from damaged tissues which, if allowed to persist, could induce an autoimmune response. 

The reactions that take place in the complement system can be initiated in several ways. During the early phase of infection, lipopoly-saccharides and other structures on the surface of the pathogens trigger the alternative pathway (right). If antibodies against the pathogens become available later, the antigen-antibody complexes formed activate the classic pathway (left). Acute-phase proteins (see p. 276) are also able to start the complement cascade lectin pathway, not shown). 

Released into the blood, antibodies lock onto matching antigens. The antigen-antibody complexes are then cleared by the complement cascade or by the liver and spleen. 

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