## 6 Molecular Mechanism of NMOSD
### Complement-Mediated Pathology  
Other immune pathways, such as complement-dependent cytotoxicity (CDC), complement-dependent cell-mediated cytotoxicity (CDCC), and antibody-dependent cellular cytotoxicity (ADCC), also initiate astrocyte injuries. CDC produces a membrane attack complex (MAC) by triggering the complement pathway [127; 128]. The complement cascade is activated by binding AQP4-IgG onto AQP4, which recruits the complementfactors and forms the membrane attack complex formation that attacks the astrocytes, oligodendrocytes, and neurons, leading to demyelination and neuronal cell death [127]. The complement factor C3a is quite elevated in NMOSD patients and is found to be responsible for the disease activity, presence of neurologic disabilities, and AQP4-IgG [147]. ADCC mainly involves binding neutrophils, macrophages, and NK cells with the Fc region of the AQP4-IgG antibody [148]. CDC pathways induce membrane permeability, cause AQP4-IgG antibody influx into the BBB, and accelerate inflammation [149]. Another MAC inhibitory protein, CD59, constrains the accumulation of MACs on the AQP4-expressing tissues. A study demonstrated that rats lacking CD59 are highly prone to NMO pathology, and that CD59 is responsible for protecting AQP4 tissues. In CD59 \({}^{-/-}\) rats, the MAC gets activated, targets the AQP4 channels, and causes astrocyte damage, inflammation, and injury. CD59, the regulatory complement protein, protects AQP4 seropositive NMOSD cases [150]. The levels of complement factors C3 and C4 in the plasma of patients with MS, MOGAD, and AQP4-IgG\({}^{+}\) NMOSD and healthy controls were examined. AQP4\({}^{+}\) NMOSD and MOGAD patients have the lowest C3 and C4 levels compared to other participants, suggesting that C3 and C4 might be diagnostic markers for AQP4-IgG\({}^{+}\), NMOSD, and MOGAD [143]. Another study demonstrated the association of the levels of complement factors C3 and C4 with AQP4-IgG titers, indicating the involvement of AQP4-IgG clones in activating the complement [149]. Purinergic receptors (P2 Rs) were used to treat inflammatory diseases that protect against complement-mediated cell injury. P2 Rs interact with AQP4-IgG and cause misfolding of antibodies, which disrupts the complement involvement and activation. The interaction of AQP4-IgG antibodies is of vital clinical importance because its interactions determine the complement activation and BBB permeability [151]. In particular, C5 initiates the terminal cascade reactions, and a C5 inhibitor (eculizumab) can neutralize C5 and inhibit MAC formation by blocking the CDC [152]. Complement activation requires aggregation of AQP4 monomers (OAPs). AQP4-IgGs bind to OAPs and C1q, a multiple interaction reaction in which a single C1q molecule binds to six AQP4-IgG molecules [42]. The binding of C1q to AQP4-IgG activates the CDC, recruits pro-inflammatory anaphylaxis, forms a MAC, and induces cellular injury. In ADCC, the cascade gets activated by binding effector leukocytes onto the Fc region of AQP4-IgG. This can cause further cellular injury by degranulation and local cell death by infiltrating NK cells, neutrophils, eosinophils, and macrophages [148]. Thus, the injury creates an inflammatory response in astrocytes and produces other cytokines, disturbing the BBB and damaging oligodendrocytes, microglial cells, and nearby neurons [37,153]. The cell types involved in ADCC also participate in CDCC through enhanced phagocytosis and anaphylaxis-induced degranulation of cells. The anaphylaxis produced by NMO lesions act as chemoattract for the nearby circulating eosinophils, neutrophils, monocytes, and macrophages [154]. [PERSON] and her team histopathologically analysed autopsies and brain biopsies of patients with MOGAD. They observed that MOG-IgG activates the complement and complement deposition in all white matter lesions and that MOGAD pathology is dominated by perivensous and confluent white matter demyelination.