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Complement system

German: Komplementsystem

1 Definition

The complement system is a part of the humoral immune system, which contributes to the elimination of cellular antigens (e.g. bacteria (unspecific immune response).

2 Structure & effects

More than 20 different proteins form the complement system together. The activation mechanism is similar to the coagulation. Upon activation, a cascade-like proteolytic mutual activation and binding of the complement factors leads to the formation of a lytic complex (membrane attack complex).

Comment: At first, the individual steps of activation are consciously not reflected to the smallest detail, in order to not impair the understanding of the principle due to the inflation of abbreviations.

The individual complement factors are represented and abbreviated by CX-a/b (X=numerical identifier, a/b=fragment). The active form of the complement system, the lytic complex, is to be morphologically understood as a pore inside the cell membrane of the foreign cell to be lysed. This pore is formed by the complement factors C5b and C6-C9. By the dissolution of the integrity of the cell, it enables the destruction of the cell.

Further functions of the complement system are:

  • Alteration of the vessel wall permeability (by the local effects of activated complement factors)
  • Induction of an increased chemotaxis
  • Improved opsonization of antigens

3 Pathways of activation

Basically, there are the classical, the alternative and the MBL (mannose-binding lectin) pathways of activation. For that, the activation from C5 to C5b is crucial.

3.1 Classical complement activation

In classical complement activation, at first, factor C1 binds to an antigen-antibody-complex (cell marked with antibodies - IgG or IgM). C1 is a trimer of a binding subunit C1q and two proteolytic subunits C1r and C1s. After a successful binding, C1r activates the subunit C1s, which serves the binding and activation of C4. For that, the peptide fragment C4a is split off. C2 binds to the activated components of C4. Due to the effects of C1s, C2 is activated by splitting-off the peptide fragment C2a.

C4b and C2a together, as C3 convertase (C4bC2a), can activate the complement factor C3 by splitting-off an a-fragment. Activated C3b is a potent marker for antigenic cells (opsonization). The compound of C4b2a3b (C5-convertase) catalyzes the activation of complement factor C5 to C5b. C5b induces the formation of the lytic complex.

3.2 Alternative complement activation

The alternative pathway of complement activation acts without the help of antibodies. By proteases in the plasma, a small portion of C3 is always activated to C3b. The binding of factors C3b and B to bacterial lipopolysaccharides (endotoxins) enables the splitting of B by factor D, in order to obtain another form of C3-convertase C3bBb.

After a series of redistributions and activations, the C3b,Bb-complex results from the influence of the protease. This complex can activate C5 and thereby induce the formation of the lytic complex.

Conclusion: In the end, the enzyme as C5-convertase is structured as C4b2a3b or C3bBbC3b as per way of complement activation, in order to split C5 into C5a and C5b.

3.3 MBL activation

Another form of complement activation can be found in the binding of mannose (which is located on the surface of bacteria) by a serum-based, mannose-binding lectin. It activated the MBL-associated serine proteases MASP-1, MASP-2, and MASP-3. It catalyzes the same reaction as in the classical complement activation pathway.

4 Complement defects

Genetic defects can be the origin of defective complement factors. Complement defects are described for almost every factor. Generally, complement defects favor bacterial infections, especially Cocci. Defects of the terminal complement factors of the classical activation pathway (eg. C9) lead to an increased susceptibility for the Neisseria genus. A special deficiency of C1-esterase-inhibitor leads to an heredetary angioneurotic edema.

Within the framework of an SLE, immune complexes activate the complement system and contribute to pathogenesis. Also in some forms of glomerulonephritis (eg. membranoproliferative glomerulonephritis), errant activations of the complement system contribute to the disease progress.

4.1 Diagnostics

Diagnostic tests to detect complement defects are the CH50 test (classical pathway) or the APCH50 test.

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