Lectin Pathway of the complement system


The lectin pathway of the complement system is a type of cascade reaction that involves the recognition and elimination of a wide range of pathogens and apoptotic cells by the innate immune system. The lectin pathway is similar to the classical pathway in that it activates the C3 convertase and the membrane attack complex (MAC) through the cleavage of C4 and C2 by serine proteases. However, unlike the classical pathway, which is triggered by antibodies bound to antigens, the lectin pathway is initiated by carbohydrate-binding proteins called lectins that bind to specific sugars on the surface of microbes or altered self-cells.

Lectins are a group of proteins that have at least one domain that can bind to carbohydrates in a specific and reversible manner. Lectins can be classified into different families based on their structural and functional characteristics. Some of the major families of lectins involved in the lectin pathway of the complement system are:

  • Mannose-binding lectin (MBL): This is a soluble protein that circulates in the blood plasma and binds to mannose, glucose, N-acetylglucosamine, and other sugars with 3- and 4-hydroxyl groups in equatorial positions on the surface of bacteria, fungi, viruses, and protozoa. MBL can also bind to apoptotic cells and necrotic cells that expose these sugars. MBL is structurally similar to C1q, the recognition molecule of the classical pathway, as it has a collagen-like region and six globular heads that can interact with multiple ligands.
  • Ficolins: These are also soluble proteins that circulate in the blood plasma and bind to acetylated residues such as N-acetylglucosamine, N-acetylgalactosamine, and N-acetylneuraminic acid on the surface of bacteria, fungi, viruses, and apoptotic cells. Ficolins have a collagen-like region and a fibrinogen-like domain that forms a trimeric structure with six binding sites for ligands. There are three types of ficolins in humans: Ficolin-1 (M-ficolin), Ficolin-2 (L-ficolin), and Ficolin-3 (H-ficolin). Ficolin-1 is mainly expressed by monocytes, macrophages, and granulocytes, while Ficolin-2 and Ficolin-3 are mainly synthesized by the liver and secreted into the blood.
  • Collectin 11 (CL-K1): This is another soluble protein that circulates in the blood plasma and binds to oligomannose structures on the surface of bacteria, fungi, viruses, and apoptotic cells. Collectin 11 has a collagen-like region and a C-type lectin domain that forms a hexameric structure with six binding sites for ligands. Collectin 11 is also expressed by endothelial cells, epithelial cells, and mesangial cells in various tissues.

When these lectins bind to their ligands on the surface of pathogens or altered self-cells, they activate a series of enzymatic reactions that lead to the formation of C3 convertase and MAC, which mediate various effector functions such as inflammation, opsonization, phagocytosis, and lysis of target cells. The lectins form complexes with mannose-binding lectin-associated serine proteases (MASPs), which are soluble serine proteases that cleave C4 and C2 upon activation by lectin-ligand interactions. There are four types of MASPs in humans: MASP-1, MASP-2, MASP-3, and MASP-4. MASP-1 and MASP-2 are homologous to C1r and C1s of the classical pathway, respectively, while MASP-3 and MASP-4 are unique to the lectin pathway. MASP-1 can activate MASP-2 and cleave C2, while MASP-2 can cleave both C4 and C2. MASP-3 can activate pro-factor D into factor D, which is involved in the alternative pathway of complement activation. MASP-4 can cleave prothrombin into thrombin, which is involved in blood coagulation.

The lectin pathway of complement activation is an important part of innate immunity that provides an effective defense against invading pathogens and apoptotic cells without requiring prior exposure or antibody production. The lectin pathway also interacts with other pathways of complement activation and other components of innate and adaptive immunity to modulate immune responses.