## 6 Molecular Mechanism of NMOSD
### IL-6 Pathophysiology  
IL-6 is an important pathogenic factor of NMOSD, a pleiotropic cytokine and regulator of acute and chronic inflammation, and is responsible for the survival of plasmablasts, which is essential for AQP4-IgG production [133]. The survival of plasmablasts and B memory cell maturation are modulated by IL-6 signalling. Alternatively, IL-6 inhibits the differentiation of Th17 cells [134]. IL-6 initiates the pathophysiological processes and disease activity of NMOSD by stimulating AQP4-IgG secretion, disturbing BBB integrity, enhancing proinflammatory T cell differentiation and activation [135], and regulating the balance between Th-17 and regulatory T (Treg) cells. Studies have revealed that enhanced IL-6 levels inhibit regulatory T cell differentiation and induce B cell differentiation in NMOSD conditions. Levels of IL-6 and soluble IL-6 receptors are increased more in the CSF and serum of NMOSD patients during relapse than during the remission period [136; 137].  
IL-6 enhances BBB permeability, enhances the entry of antibodies into the CNS, and induces pro-inflammatory cell infiltration, leading to the binding of AQP4-IgG with AQP4 [135]. It was previously reported that NMO-IgG enhances the expression of the IL-6 gene [136]. The production of IL-6 in astrocytes depends on the Janus Kinase/Signal transducer and activator of the transcription 3 protein (JAK/STAT3) pathway and NFxB pathway [136; 138]. Under usual circumstances, the IL-6 level is low in the CNS. CNS lesions could stimulate IL-6. T cells, B cells, endothelial cells, monocytes, and glial cells can produce IL-6 in different situations such as inflammation, antigen-specific immune responses, and during the use of host defence mechanisms [139]. In multiple neuroinflammatory diseases, the injured neurons, astrocytes, and microglial cells produce IL-6, which is helpful in differential diagnosis [140], oligodendrocyte and axonal injury, and demyelination [135].  
The levels of IL-2 and interferon-\(\gamma\) (INF- \(\gamma\)) in the CSF remain unchanged in NMOSD [141; 142]. The cytokines IL-1B, IL-6, IL-17, and TNF-\(\alpha\) and other complement factors C1s, C3a, C4a, C4d, and C5 are elevated in NMOSD [30]. NMOSD pathogenesis can be promoted through IL-6-dependent Th-17 cells and Th-17-associated cytokines [143]. IL-6 induces the naive T cells and differentiates them into Th-17 inflammatory cells, which initiates further inflammation and disturbs BBB integrity. IL-6 also induces B cells to differentiate into plasmablasts and produce AQP4-IgG antibodies [144]. The increased IL-6 levels in the serum and CSF correlate with expanded the disability status scale (EDSS) score [137; 139; 140] and relate to the levels of AQP4-IgG and GFAP, which are directly proportional to the degree of astrocyte damage [141]. Thus, high levels of IL-6 in serum and the CSF can be marked as an indication of NMOSD relapse. Blocking the IL-6 receptors with the help of monoclonal antibodies might inhibit IL-6-associated humoral immune response mechanisms, T cell activation and pathways, BBB dysfunctions, recruitment and activation of the complement system, and macrophage activities [135].  
Pro-inflammatory cytokine IL-6 levels remain high in the serum of NMOSD patients, which remains an important prognostic biomarker and a potential target for NMOSD therapy because the IL-6 initiates the production and maintenance of Th17, a kind of CD\({}^{4+}\) T helper cell, which further induces other pro-inflammatory markers, neutrophil deposition, and organ-specific autoimmunity, enhancing AQP4-IgG secretion even more [135; 137]. In addition to IL-6, the granulocyte-macrophage stimulating colony-forming factor (GM-CSF) could stimulate the function of Th17 cells [145]. Apart from IL-6, the other cytokines IL-1, IL-8, IL-10, IL-13, IL-17, IL-21, and IL-23 were found in higher levels in the serum and CSF of NMOSD patients [146].