Complement is a complex system containing more than 30 various glycoproteins present in serum in the form of components, factors, or other regulators and/or on the surface of different cells in the form of receptors. It is a highly sophisticated host defence system designed to destroy pathogens. Once the complement system is activated, a chain of reactions involving proteolysis and assembly occurs, resulting in destruction of the membranes of pathogens. The cascade up to the cleavage of C3
(Complement component-3), which plays a central role in the complement system, is called the activation pathway. There are three categories of complement pathway; the classical pathway, alternative pathway and lectin pathway (Ref.1).
The recently discovered lectin pathway (also called MBL pathway or MBLectin pathway) can activate the complement system in an antibody-independent fashion. It is activated by the binding of MBL
(Mannose-Binding Lectin), also known as MBL
(Mannose-Binding Protein-1) to carbohydrates on the surfaces of pathogens. MBL
is an oligomer of subunits composed of identical polypeptide chains each of which contains a cysterine-rich, a collagen-like, a neck, and a carbohydrate-recognition domain. MBL
consists of several sizes of oligomers. Activation of the lectin pathway begins when MBL
binds to the mannose groups of microbial carbohydrates (Ref.2). In this pathway, the C-type lectin domain of MBL
recognizes mannose or N-acetylglucosamine structures on the surfaces of pathogens in a calcium-dependent manner, leading to the activation of MASP
(Mannan-Binding Lectin Serine Protease), which is present as a proenzyme complexed with MBL
. In humans, three types of MASP
(MASP1, MASP2 and MASP3) and sMAP (small MBL-associated protein, or called MAp19) form complexes (MBL-MASP) with MBL
share domain structures (two CUB domains, an EGF-like domain, two CCP domains and a serine protease domain) and thus constitute a subfamily of the serine protease family. In serum, MASPs
are present as proenzymes consisting of a single polypeptide chain. Upon cleavage of a peptide bond, MASPs
are converted to their activated forms consisting of two polypetides linked by a disulfide bridge. Activated MASP1
, while activated MASP2
. The function of MASP3
is not known. sMAP is a truncated protein, which is derived from the MASP2
gene by alternative polyadenylation. Its function remains unknown. MBL
is thought to bind to MASPs
and sMAP through its collagen-like domain. However, the stoichiometry of the complexes and the activation mechanism has not been fully elucidated (Ref.3).
The activated MASP
activates the classical pathway by proteolytically cleaving C4
to form C4BC2B, the C3
convertase capable of enzymatically splitting hundreds of molecules of C3
. Once formed the C3
convertase cleaves and activates the remaining complement factors leading ultimately to formation of a pore in the bacterial membrane by the MAC (Membrane Attack Complex) that lyses the bacterial cell. MBL
show structural similarity to C1Q
, respectively, indicating that gene duplication events were also responsible for generating the classical and lectin pathways (Ref.4).
Recently it has been shown that MBL
is the main opsonin in the human blood serum. MBL
has been found to initiate complement-mediated lysis of mannan-coated erythrocytes. This new lectin pathway of complement activation is important not only for the killing of microorganisms through the interaction of carbohydrates on their surfaces and MBL
or other collectins (humoral lectins found in humans and other mammals) but also for the opsonizing activity. The discovery of the lectin pathway has raised a broad interest within the medical community as this defense route maintains immunity under situations where the adaptive immune response is dysfunctional, i.e. in the very young, the very old and the very ill patients, in patients undergoing cytostatic therapy and transplantation. On the other hand, overshooting responses of the lectin pathway may significantly contribute to the pathophysiology of cerebral, myocardial and gut infarction, septic shock syndrome and perhaps to autoimmune disease. Modulation of the innate immune response has therefore a high therapeutic potential in the treatment of human morbitity and mortality (Ref.5).