(A) A model for astrocyte-microglia interaction in precytolytic tissue injury in NMO. (i) AQP4-specific IgG1 is produced in secondary lymphoid tissue outside the CNS. AQP4-specific antibodies bind to AQP4 on astrocytic endfoot processes, leading to AQP4 internalization, reduced cell surface AQP4 expression, and astrocytic activation. (ii) Activated astrocytes produce elevated C3 that is cleaved to C3a and C3b. (iii) Secreted C3a binds C3aR on resting microglia, promoting microglial activation, production of C1q, and convergence toward astrocytes. (iv) C1q promotes localized injury to neurons and oligodendrocytes. (B) Activation of the classical complement cascade leads to sustained CNS tissue damage in NMO. (i) C1q binds the framework constant (Fc) region of adjacent AQP4 antibodies bound to AQP4 in close proximity, attracting C1r and C1s. (ii) This C1 complex activates C4 and C2 components that lead to formation of C3 convertase, producing C3b, which together with C4b and C2b create the C5 convertase. Eculizumab (Soliris), a C5-convertase inhibitor, is approved for treatment of NMO. (iii) C5b, one of the 2 C5 cleavage products, together with C6–C9 proteins form the membrane attack complex (MAC), which leads to astrocyte lysis and tissue necrosis. This figure was adapted with permission from Kenneth Probst (Xavier Studio).