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Figure 1: The three pathways of the complement cascade

the lectin (mannose-binding) pathway, a complement a parallel pathway of direct cerebral injury via iron
pathway triggered when MBL or Ficolin bind to toxicity. [78,79]
terminal mannose groups on the surfaces of microbes.
This binding allows MBL to associate with circulating A link exists between the complement and coagulation
MASPs, which then cleave C4 and C2 to form the cascades, as kallikrein and thrombin may also cleave C3
C4bC2a C3 convertase. [76,77] In both the classical and and C5. [80,81] In addition, C-reactive protein (CRP) may
lectin pathways, C3b may then bind to C4b2a to form either activate complement by recruiting C1q to the surface
the C5 convertase, C4b2a3b. This is different from the of damaged cells or regulate the cascade by recruiting
C5 convertase in the alternative pathway, where C2 complement inhibitors. [82,83] Cholesterol-containing
and C4 do not play a major role. lipids and enzymatically-modified or oxidized LDLs
in atherosclerosis can activate complement via C1, [84-87]
The alternative pathway is triggered by carbohydrates and these also play a role in the pathogenesis of coronary
or proteins found on self and nonself surfaces. [10] In atherosclerotic plaques. [88]
the plasma, C3 is spontaneously hydrolyzed (but not
cleaved) at a low rate to form iC3, which is amplified MODULATORS OF THE COMPLEMENT SYSTEM
in the environment near pathogens due to these
carbohydrates or proteins. iC3 binds to Factor B, which The complement system is highly regulated by
Factor D then cleaves into to Bb and Ba, producing the activators and inhibitors so as to confine the
fluid-phase C3 convertase (iC3Bb). The fluid-phase destructive mechanisms of the complement system
C3 convertase cleaves C3 to C3a and C3b, creating to nonhost surfaces while protecting the healthy
sufficient C3b to bind with Bb and form C3bBb, which, tissue, and alteration of these modulators plays a
when stabilized by Properdin on a microbial surface, role in a variety of disease processes. [57] As noted the
acts as the principal C3 convertase of the alternative alternative pathway C3 convertase (C3bBb) is stabilized
complement pathway. The “alternative” C3 convertase on the microbial cell surface by Properdin, [89] which
C3bBb may then associate with an additional C3b is released by a variety of leukocytes, [90-92] some of
to form the C5 convertase, C3bBbC3b. [75] The C5 which, as mentioned, are present in aneurysm walls.
convertases from any of the three pathways may In addition to microbial surfaces, Properdin can also
then facilitate the assembly of the MAC. In addition, bind to apoptotic and necrotic cells and facilitate a
several of the cleavage byproducts, chiefly, C3a and complement response. [89] Regulators of complement
C5a, known as anaphylatoxins, initiate a cascade of activation inhibit the complement system at two
signals which induces leukocyte chemotaxis, [57] the predominant steps: either at the level of convertases,
effects of which include degranulation and resulting or in the assembly of the MAC. [57,93] Factor I acts at the
smooth muscle contraction and increased vascular convertase level by cleaving C3b into its inactive form,
permeability. [55,56] Cleavage products of C3 also cause iC3b, which is unable to form an active C3 convertase

96 Neuroimmunol Neuroinflammation | Volume 2 | Issue 2 | April 15, 2015