The complement system consists of 30 proteins that interact in a carefully regulated manner to destroy invading bacteria and prevent the deposition of immune complexes in normal tissue. This complex system can be activated by diverse mechanisms proceeding through distinct pathways, yet all converge on a final common pathway in which five proteins assemble into a multimolecular complex, the membrane attack complex (MAC). The MAC inserts into cell membranes to form a functional pore, resulting in ion flux and ultimately osmotic lysis. Immunohistochemical evidence of the MAC decorating neurons in cortical gray matter has been identified in multiple CNS diseases, yet the deleterious consequences, if any, of MAC deposition in the cortex of mammalian brain in vivo are unknown. Zhi-Qi Xiong et al. demonstrate that the sequential infusion of individual proteins of the membrane attack pathway (C5b6, C7, C8, and C9) into the hippocampus of awake, freely moving rats induced both behavioral and electrographic seizures as well as cytotoxicity. The onset of seizures occurred during or shortly after the infusion of C8/C9. Neither seizures nor cytotoxicity resulted from the simultaneous infusion of all five proteins premixed in vitro. The requirement for the sequential infusion of all five proteins together with the temporal relationship of seizure onset to infusions of C8/C9 implies that the MAC was formed in vivo and triggered both seizures and cytotoxicity. Deposition of the complement MAC in cortical gray matter may contribute to epileptic seizures and cell death in diverse diseases of the human brain.
Due to the multiple functions of the MAC, it is no surprise that the membrane attack complex has been implicated in an impressive number of diseases, evident via its detection in diseased tissues or its elevated levels in the blood, and that so many different clinically relevant microorganism have adopted numerous different techniques to escape the destructive action of complement.
Deficiencies of the membrane attack complex / MAC cascade predispose to meningococcal infections, indicating that its cytolytic properties are of particular importance in host defence against Neisseria, for which there appears to be no sufficient back-up. Neutrophils can only provide partial protection, although they can kill meningococci when incubated in terminal complement deficient serum, and this effect increases after vaccination so that this may represent an alternative treatment option in addition to, or instead of, vigilance and antibiotic prophylaxis.
Typically, membrane attack complex / MAC deficient subjects present in adolescence or in young adulthood, and suffer from recurrent meningococcal infections with especially the rarer serogroups. By way of example, the index case of a report in this journal issue by Vazquez-Bermudez et al. was ascertained because of three meningococcal disease episodes in a 15-year-old-boy.
1. Xiong, Z. Q., Qian, W., Suzuki, K., & McNamara, J. O. (2003). Formation of complement membrane attack complex in mammalian cerebral cortex evokes seizures and neurodegeneration. The Journal of neuroscience, 23(3), 955-960. 2. Würzner, R. (2003). Deficiencies of the complement MAC II gene cluster (C6, C7, C9): is subtotal C6 deficiency of particular evolutionary benefit?. Clinical & Experimental Immunology, 133(2), 156-159.