Inhibition of Complement (C) System
The C system is the core of innate immunity and is capable of inducing release of MP, especially in immune mediated disorders [153-155]. It can also degrade otherwise healthy cells expressing antibodies or damaged self-proteins and plays a major role in the clearance of many MP phenotypes. Accordingly, the C system may be a target of therapy in selected neurological disorders.
Fluitier et al., using a mouse model of traumatic brain injury (TBI) and an inhibitor of C6 made in their laboratory, were able to significantly promote neurological recovery and reduce secondary neuronal injury post-TBI by inhibiting the terminal membrane attack complex (MAC) . At least three C inhibitors are approved for humans: compstatin [157, 158], the C1 inhibitor (C1-INH) , and eculi- zumab, approved for paroxysmal nocturnal hemoglobinuria (PNH) . PNH can have neurological complications . However, that the C system is also known to exert many effects favorable to tissue repair and recovery.
Pilzer et al. provide new insight on C-mediated MP generation, showing that a specific cellular protein, mortalin/GRP75, is responsible for shedding of MP with bound MAC, this being a mechanism for eliminating MAC from the cell surface [71, 155]. Sims et al. had earlier shown that cells can recover their membrane potentials after shedding MAC . Mortalin is also known as the heat shock protein, HSPA9.
Elward et al. cast new light on C-mediated clearance of senescent cells and MP and underlying mechanisms which may in future allow manipulation of MP levels in blood or CSF. Their main finding was a key role for clustering of CD46, which then binds C1q or C opsonins . (CD46 is also known as “membrane cofactor protein,” a C regulator, along with CD55 and CD59.)