## 6 Molecular Mechanism of NMOSD
### MOG-IgG-Dependent Pathology  
Myelin oligodendrocyte glycoprotein (MOG) is present on the outer surface of myelin sheaths [47] that consist of 218 amino acid residues spanning twice across the cell membrane and having IgG-like domains in the extracellular N-terminal-end [129]. In AQP4-ab seronegative NMO cases, autoantibodies against MOG (MOG-IgG) have been detected. The AQP4-IgG type of NMOSD primarily affects astrocytes and causes astrocytopathy, whereas MOG-IgG causes demyelination, as it expresses mostly in the oligodendrocytes and outermost myelin sheaths [49]. AQP4-ab and MOG-IgG are the two different target-mediated entities of NMOSD. The characteristics of this two-antibody-mediated NMOSD are different. AQP4-ab positive cases showed loss of AQP4 and dystrophic astrocytes. In the MOG-IgG type of NMOSD, the pathology is differentiated by the expression of AQP4, perivencous and primary demyelination, reactive gliosis in the white and grey matter, and numerous lesions in cortical regions [48]. The clinical features of MOGAD differ from AQP4-IgG seropositive NMOSD. Even though ON is a common feature in AQP4-IgG NMOSD and MOGAD, the phenotypic difference can be seen in the length of optic nerve involvement, optical disc morphology, and the ganglion cell inner plexiform layer pattern in OCT [130; 131]. The clinical characteristics of MOGAD and AQP4+ NMOSD were compared with CSF analysis and peripheral T/B lymphocytes during active and chronic phases. The results showed that the protein level in MOGAD was significantly lower than in AQP4+ NMOSD. The level of myelin basic protein was significantly lower in MOGAD. Furthermore, the albumin and IgG reflecting BBB permeability and intrathecal IgG production were significantly lower in MOGAD patients compared to AQP4+ NMOSD patients. The increased permeability of the BBB in AQP4+ NMOSD was observed more than in MOGAD. Concurrently, the BBB allows AQP4-IgG to promote IL-6 production from AQP4-positive astrocytes. T/B lymphocyte subset plasmablasts are also normal in MOGAD and higher in AQP4+ NMOSD, and the B cell subsets differ in both conditions. Transitional B cells were higher in MOGAD than AQP4+ NMOSD and healthy controls, but there was no significant difference in memory B cells [132]. Figure 3: AQP4- dependent NMOSD pathology. NMOSD pathogenesis is initiated through various etiological factors such as genetic reasons, environmental factors, genetic-environment context, low levels of vitamins, medications, and so on. NMOSD pathogenesis involves the synthesis of autoantibodies against AQP4, a water channel transmembrane protein present in the astrocyte end feet of the BBB. AQP4 antibodies moved from the plasma into the CSF through the BBB. The presence of more AQP4 autoantibodies circulating in the plasma results in inflammation and causes the production of pro-inflammatory cytokines, interleukins, and complement factors. Thus, produced cytokines, complement factors, and granulocytes breach into the BBB and CSF of NMOSD patients. The cytokines activate the complement cascade factors, activating NK cells and the MAC. The MAC targets the astrocytes’ AQP4 channels, leading to astrocyte damage and neuroinflammation [123; 124; 125; 126; 127; 128]. (Figure created using BioRender.com; accessed on 12 February 2023). In MS, MOGAD, and AQP4\({}^{+}\) NMOSD, the primary phenomenon is the neurodegeneration of myelin deficient retina. Analyzing the degeneration of retinal neurons is a frequently used diagnostic tool in MOGAD and NMOSD. The retinal nerve fibre layer was significantly reduced in NMOSD patients, and visual impairment was observed in MOGAD [131]. The inflammation and visual system degeneration were evaluated using spectral domain OCT and electroretinography in transgenic spontaneous opticospinal encephalomyelitis mice. The results revealed that the damage to the retina and optical nerve, which could affect the retinal functions, caused inflammation, complement factors activation, and degeneration (Figure 4).