Complement: Classical and Lectin Pathways

Abstract

The classical and lectin pathways of complement are major recognition systems of innate immunity that are found in mammals and other animal species. By means of several multimolecular proteases – C1 , the mannan‐binding lectin (MBL)– MBL‐associated serine protease 2 (MBL–MASP‐2) and the ficolin– MASP‐2 complexes – each comprising a recognition protein and a protease component, they detect pathogens and other targets and thereby trigger proteolytic reactions. Both pathways converge to the formation of C3 convertase , a complex protease that cleaves C3 , the central component of the complement system. Proteolytic cleavage of C3 generates a series of fragments and elicits various effector mechanisms, including inflammation and phagocytosis. These mechanisms contribute to the elimination of pathogenic microorganisms and altered host cells from blood and tissues and modulate the adaptive immune response. Key Concepts: C1q, MBL and ficolins are pattern‐recognition molecules able to sense conserved motifs on pathogens and altered self‐cells. C1q is a major sensor of apoptotic cells and regulator of immune tolerance. Proteolytic cleavage of C3 is pivotal for amplification of the complement response and labelling of the target particles. Target recognition, proteolysis and complex formation generate conformational changes that underlie complement functioning. Complement activation and activity are tightly regulated to avoid noxious side effects on normal host cells and tissues.

Properdin and Factor H: Opposing Players on the Alternative Complement Pathway “See-Saw”

“…The classical pathway is activated when its recognition component C1 binds to a target, via C1q. C1q recognizes targets mainly by surface charged clusters, and binds directly to many bacteria, apoptotic cells, or surfaces which have IgG or IgM attached (Kishore and Reid, 1999; Arlaud and Thielens, 2010). The complement protein complex C1 is made up of three proteins, C1q, C1r, and C1s.…”

Cell microencapsulation with synthetic polymers

“…In essence, microcapsules can prevent activating the direct pathway, but not the indirect pathway: the antigens shed by xenogeneic grafts diffuse through the membrane activating systemic CD4 T‐cells and other complement components, which are cytotoxic to the xenogeneic cells . As complement components include proteins ranging in size from 74 to 460 kDa, it is likely that the 100 kDa MWCO HEMA–MMA microcapsules fail to restrict certain complement proteins, resulting in the destruction of xenogeneic cells . Thus, rather than adding immunosuppressants, another approach to increasing xenogeneic graft viability should include reducing the MWCO of the HEMA–MMA membranes.…”