Compliments from complement: a fourth pathway of complement activation?

The immune system of vertebrates is known to be composed of innateand acquired defense. While the innate immune system should potentially be sufficient for the defense against most pathogens, antibodies and activated T-lymphocytes strongly enhance our capacities for defense against a plethora of pathogens. The innate immune system is composed of a large number of defense molecules, including the complement system. The complement system is a major player in innate immunity and is strongly involved in a large number of biological processes, including the initiation and amplification of acquired immunity. Most of these biological activities are achieved by two mechanisms: first, the deposition of opsonic fragments especially of the components C3 and C4 on pathogens or other targets and second, the initiation or induction of inflammatory responses following release of small fragments e.g. from C3, such as C3a. Three pathways of complement activation exist, namely the classical pathway, the alternative pathway and the lectin pathway (Figure 1). They merge at the level of C3, leading to the activation of a common terminal sequence and generation of the C5b-C9 membrane attack complex that can insert itself into membranes and cause cytolysis. The lectin pathway of complement is activated following the recognition of specific carbohydrate patterns by molecules like mannan-binding lectin (MBL) and ficolins 1, 2 and 3 (Figure 2). Once, binding of these molecules to target structures has occurred, the MBL-associated serum protease-2 (MASP-2) is activated and then cleaves its natural substrates C4 and C2, leading to the formation of C4b2a, a C3-convertase that cleaves C3 into C3b and C3a. C3b can attach itself in a covalent fashion to the activator and act as an opsonin. Activation of C3 can also take place, independently of the lectin pathway, by the classical pathway which is known to be initiated e.g. by antigen antibody complexes, but also by dying cells and substances like DNA. Here, the recognition unit of the classical pathway, the complement component C1q, binds to specific sites on the activator, and then induces activation of the C1q-associated proenzymes C1s and C1r leading again to the activation of C4 and C2 and formation of the C3-convertase C4b2a. So, both activation of the lectin pathway and the classical pathway merge at the level of C4 and C2. The third pathway of complement, the alternative pathway, is based on the continuous low-grade hydrolysis of C3 leading to the formation of an enzyme complex composed of C3 and activated B