Bibliothek.pdf

SUMMARY
summary
Upon infection and/or injury several different parts of the innate immune system become
immediately activated in human blood. Besides the complement also the kallikrein-kininsystem,
the coagulation system and the fibrinolysis are induced to restrict infection and
tissue damage. Thereby one system can modulate also the other to ensure a fast and
efficient reaction. The complement system plays an important role in the defence against
infectious agents. Once activated, C3, the central protein of the complement system, is
cleaved into the opsonin C3b and the anaphylatoxin C3a. In addition to the newly formed
complement C3 convertases, plasma proteases that are not part of the complement system
such as kallikrein (contact activation) and plasmin (fibrinolysis) can act on C3. In this work a
clear function of both kallikrein and plasmin in the complement system is demonstrated.
However, while kallikrein exerts complement activating functions, plasmin has a complement
inhibitory function. For the first time C3 cleavage by kallikrein is shown that releases active
C3b and C3a. Furthermore kallikrein cleaves factor B to Bb and Ba. The resulting cleavage
products C3b and Bb form an active C3 convertase. Thus kallikrein which is generated from
Präkallikrein by factor XI after contact activation also can induce formation of an active C3
convertase C3bBb. This kallikrein mediated complement activation is shown to be regulated
by factor H, the complement regulator of the alternative pathway. These results show a new
complement activation pathway (the kallikrein way) that is activated by recognition of
extrinsic surfaces and the generation of kallikrein which subsequently activates C3 and factor
B to form an active C3 convertase which is regulated by factor H. In contrast to kallikrein the
central enzyme of fibrinolysis plasmin is confirmed to act as a complement inhibitor. Plasmin
in addition to C3 and C3b degrades and inactivates factor B as well as the C3 convertase of
the alternative pathway C3bBb. Besides plasmin further “non-complement proteins” are able
to act on the complement response. In this study the plasma protein β2GPI, that has
regulatory functions in the coagulation system and fibrinolysis, is identified as a new
complement inhibitor. The experiments demonstrate that the β2GPI I-IV fragment binds to
C3b and in the presence of factor H increases the C3b inactivation by factor I. In addition
β2GP I-IV also regulates the assembly of the terminal complement complex (TCC).
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