There are three distinct pathways that activate the complement system: the classical, lectin, and alternative pathways (Figure 1). The classical pathway is initiated by C1q complex formation when C1q recognizes antigen–antibody complex [78]. The lectin pathway is analogous to the classical pathway, which begins from the binding of mannose residues by mannose-binding lectin (MBL). C1q complex and mannose-binding lectin associated proteases (MASPs) cleave C2 and C4 into C2a and C4b, followed by C3 convertase (C4b–C2a) formation [79,80]. The alternative pathway can be initiated from C3 hydrolysis or from C3b directly. Once factor B binds with C3(H₂O) or C3b, it is cleaved by factor D to become C3(H₂O)Bb or C3b-Bb as another C3 convertase, which further produces more C3b to amplify the complement cascade [81]. Thus, the alternative pathway accounts for around 80–90% of complement activation [9,10,12,13]. C3 convertases cleave C3 into C3a and C3b; C3a can induce downstream activation by binding to C3aR, and C3b binds to CR3 or CR4 to mediate phagocytosis [82]. C3b can further combine with C4b–C2a and C3b-Bb to generate C5 convertases (C4b–C2a–C3b and C3b–Bb–C3b) and activate the terminal pathway which is regarded as the effector pathway of the complement system [6,10,11,13]. Similar to C3, C5 convertases cleave C5 into C5a and C5b; C5a is another important chemotactic protein similar to C3a, and C5b assembles with C6–9 to generate the membrane attack complex (MAC) [79,80].

The appropriate activation of the complement cascades rely on a series of tightly regulated soluble and membrane-bound complement inhibitors. Such complement inhibitors have been shown to successfully control complement activation in animal models with CNS disorders [4]. Soluble complement inhibitors include C1 inhibitor (C1INH), complement inhibitor C4b binding protein (C4BP), factor H (FH) and factor I (FI) while complement receptor type 1 (CR1), CRIg, CD55, and CD59 belong to the membrane-bound complement inhibitors [83]. C1INH, also known as SERPING1, inactivates the proteolytic effects of the C1 complex, MASP1, and MASP2, to inhibit the classical and lectin pathways [79,84]. Deficiency of C1INH can affect normal neurodevelopment, indicating that appropriate complement system function is important to the CNS [1]. C4BP can bind to C4b and act as a decay-accelerating factor [83]. Moreover, FH is the dominant regulatory factor of the alternative pathway and by competitively binding to C3b, it destabilizes C3 and C5 convertase both on cell surfaces and in plasma [79]. FI can permanently inactivate C3b and iC3b and degrade C3 convertase by cleaving the C4b component aside by cofactors such as FH, C1INH, and C4BP [79]. CR1 is a single-pass membrane glycoprotein expressed on different cells and acts as a cofactor to FI in accelerating the dissociation of C3 convertase [79,81]. Rodents bear only the complement receptor type-1 related protein (Crry) in place of CR1 [85]. Another potent inhibitory factor CRIg converts C3a or C5a into inactive forms, which impairs signal transmission through the C3a or C5a receptors [79]. An inactive C3b product (iC3b) also interacts with CR1 or CRIg for further degradation [78,79]. CD55 is widely expressed on various cells and inhibits the formation of and accelerates the dissociation of C3 convertases among all three complement pathways [78,83]. Different from other complement inhibitors, CD59 binds to C5b-8 on the host cell surface and blocks the binding and polymerization of C9 to prevent MAC formation [79].

It is well-known that 90% of soluble serum complement components are derived from the liver constitutively and activated immune cells are an important source of inducible complement protein [81]. However, the CNS may not be exposed to the same composition of complement components as in the periphery due to selective restriction of the BBB [1,2,17]. Recent studies reveal that complement components could be synthesized locally by resident cells in the CNS that provide “immunosurveillance” to maintain normal functionality in the brain [86].

3. Complement System in the Developing Brain