The complement system in schizophrenia

Abstract

Several lines of evidence suggest that immunological factors contribute to schizophrenia. Since 1989, the role of complement, a major effector of innate immunity and an adjuvant of adaptive immunity, has been explored in schizophrenia. Increased activity of C1, C3, C4 complement components in schizophrenia has been reported by two or more groups. Two studies on different subject cohorts showed increased MBL-MASP-2 activity in patients versus controls. More then one report indicated a significant high frequency of FB*F allotype and low prevalence of the FS phenotype of complement factor B in schizophrenia. From the data reported, it is likely that the disorder is accompanied by alterations of the complement classical and lectin pathways, which undergo dynamic changes, depending on the illness course and the state of neuro-immune crosstalk. Recent findings, implicating complement in neurogenesis, synapse remodeling and pruning during brain development, suggest a reexamination of the potential role of complement in neurodevelopmental processes contributing to schizophrenia susceptibility. It is plausible that the multicomponent complement system has more than one dimensional association with schizophrenia susceptibility, pathopsychology and illness course, understanding of which will bring a new perspective for possible immunomodulation and immunocorrection of the disease.

Fig 1

The complement activation pathways. The sequence of classical pathway activation is shown at the bottom, with immunoglobulin (Ig) G antibodies bound to a bacterial surface as an example of a target. Clq binds to the surface (bottom left). Cl binding activates CIr then Cls. which then cleaves C4 and C2. The C4b2a complex (C3 convertase) forms on the bacterial surface and cleaves C3. One C3b binds to C4b2a, and forms a binding site for C5. C5 is cleaved, then the C5b6789 complex (the MAC, membrane attack complex) assembles and causes membrane damage. At the top of the figure, the lectin pathway is shown. MBL (mannan-binding lectin) or a ficolin binds directly to a bacterial surface, and MASP-2 (MBL-associated serine protease) is activated. This then cleaves C4 and C2, and the pathway follows the same sequence as the classical pathway. At the left, the alternative pathway is shown. C3b (derived from the classical or lectin pathway, or by activation by C3(H₂O)Bb, as discussed in the text, binds to the surface, then binds factor B (FB). which is activated by factor D (FD), forming the C3 convertase, C3bBb. More C3 is cleaved by C3bBb, then C5 activation and MAC assembly follows, as for the classical pathway. On the right, the host cell and its mechanisms for protection against complement attack are shown. CD59 binds the C5b678 complex and prevents binding of C9. CD35 (CR1), CD46 (MCP) and CD55 (DAF) all destabilize the C3 convertases or inhibit their formation. Soluble regulators like factor H (FH) may become transiently bound on the surface, and also regulate convertase formation.