Few Complement-Activation Pathways

OTHER COMPLEMENT-ACTIVATION PATHWAYS

A. Proteolytic Enzymes as Nonspecific Activators of Individual Complement Components

A variety of proteolytic enzymes, some released by microbes at the site of an infection and others released from host cells in areas of inflammation or necrosis, are capable of activat-ing the complement system. For example, polymorphonuclear leukocytes (PMN) leak ox-idative products and lysosomal proteolytic enzymes into the extracellular fluids during the phagocytosis process. Oxidation of native C5 increases its susceptibility to conversion by proteases and increases C5a formation. Also, within inflamed or traumatized tissue, dam-aged host cells release lysosomal proteases during their degeneration. Plasmin, a fibri-nolytic enzyme activated during the clotting process, also activates certain complement components. These bacterial and/or host proteases are able to directly cleave and thereby activate C1, C3, and C5. As a consequence of direct cleavage and activation of C3 and C5, biologically active peptides (C3a and C5a) are generated, contributing to a local inflam-matory reaction by their direct action and by attracting and activating additional PMNs to the area of tissue damage.

B. The Lectin Pathway of Complement Activation

A newly discovered pathway for activating the second and fourth complement components is the lectin complement pathway, which involves the serum mannan-binding lectin (MBL), sometimes termed mannose-binding lectin. MBL is an acute phase reactant, mean-ing that its concentration increases during infection/inflammation. Structurally, MBL is a member of the collectin family (C-type lectin) characterized by having a collagen-like se-quence that resembles the structure of C1q and several Ca2+ -dependent carbohydrate recognition domains. Mannan, a constituent of the polysaccharide capsules of pathogenic fungi and yeasts (e.g., Cryptococcus neoformans and Candida albicans) is one of several polysaccharide substances to which human MBL binds via Ca2+ -dependent interactions. The activation of the lectin pathway does not require antigen-antibody interactions.

The initiation of the lectin pathway has several features that parallel C1 of the classi-cal complement pathway. The first step in the lectin pathway requires the direct binding of serum mannan-binding lectin to polysaccharides (e.g., mannan) on the surface of microor-ganisms. In addition to carbohydrate motifs of microorganisms, MBL can bind to glyco-proteins on the envelope of certain viruses such as influenza A. MBL inhibits infectivity by three different mechanisms:

1.           Direct neutralization and agglutination

2.           Deposition of complement through the lectin pathway

3.           Opsonization via collectin receptors on phagocytes (receptors for the collagen-like region of MBL and of C1q).

The lectin complement pathway is initiated by microorganism-bound MBL as it as-sociates with two human MBL-associated serine proteases (MASP-1 and -2) that cleave and activate C4 and C2. Similar to the action of C1, the MBL complex generates deposi-tion of C4b2a with subsequent C3b deposition and terminal component activation. It is im-portant to realize that classical pathway activation by immune complexes is much more ef-ficient and powerful than activation by the lectin pathway.