title: A molecular basis of activation of the alternative pathway of human complement.
abstract: The fluid phase interaction of native C3, B, D and P continuously generates C3b; C3b complexes with B to permit cleavage-activation by D, thereby generating C3b, Bb, the amplification C3 convertase. C3b, Bb formed in the fluid phase or on a non-activating surface for the alternative pathway undergoes decay-dissociation through release of Bi, and the residual C3b undergoes cleavage inactivation by the C3b inactivator (C3bINA). The capacity of P to stabilize C3b, Bb and therby augment C3 cleavage is counterbalanced by beta 1H, which inactivates the convertase by displacing Bi and facilitates the inactivation of residual C3b by C3bINA. Transition to amplified C3 cleavage is achieved because the surface characteristics of an activating particle protect C3b from inactivation by C3bINA in the presence of beta 1H, and the stabilized alternative pathway convertase, P, C3b, Bb, from extrinsic decay-dissociation by beta 1H. Natural activating surfaces such as zymosan (Zy) and rabbit erythrocytes are relatively deficient in sialic acid residues as compared to non-activating surfaces such as sheep erythrocytes (Es). Sialic acid residues on C3b-bearing particles augment binding of beta 1H to favor competition with B, inactivation of C3b and decay-dissociation of C3b, Bb. The absence of this carbohydrate on the membrane in the environment of C3b results in low affinity binding of beta 1H, a circumstance that permits uptake of B to form the amplification convertase and impairs extrinsic decay of the C3-cleaving enzyme. This natural humoral host resistance reaction based on the relative content of sialic acid on target particles has a cellular counterpart in the capacity of human monocytes to engage in antibody-independent phagocytosis of sialic acid-deficient cells. Thus, the non-immune host may respond to such cells by dual humoral and cellular recognition mechanisms and this response may represent a primordial basis for protection against microbial invasion.
mesh_terms: D000818:Animals; D003176:Complement C3 / Q000378:metabolism*; D003179:Complement C3b / Q000378:metabolism*; D003180:Complement C3b Inactivator Proteins; D004912:Erythrocytes / Q000502:physiology; D006801:Humans; D007700:Kinetics; D051379:Mice; D010587:Phagocytosis; D011817:Rabbits
chemical_list: D003176:Complement C3; D003180:Complement C3b Inactivator Proteins; D003179:Complement C3b