## 4 Etiology of NMO  
The genetic risks for NMO are the class I and II alleles of the human leukocyte antigen (HLA). Demyelinated lesions found in the cervical spinal cord showed that these lesions were associated with HLA alleles DRB1 and DQB1 [18]. HLA plays an important role in genetic risk for NMO, MS, and other demyelinating diseases, facilitating understanding of its pathogenesis and differential diagnosis [19]. The contribution of HLA alleles in NMO pathogenesis and the profile of HLA in NMOSD patients have been detailed by [PERSON] and [PERSON] (2014) [19]. Different specific alleles were present in the different populations of people from various countries; such as the HLA-DRB1*03 allele marked for NMO in French, Brazilian, and Afro-Caribbean populations [20; 21], the HLA-DRB1*05:01 allele for NMO in African-American, Latino, and Japanese populations [19; 22; 23], and DRB1*1602 for NMO in Chinese populations [24]. The single nucleotide polymorphism (SNP) at several sites of the gene AQP4 is the risk factor for NMO in the Chinese population [25]. In NMO AQP4 seropositive cases, the interleukin 17 (IL-17) gene polymorphism was found compared to healthy controls. Increased production of inflammatory cytokines IL-17, IL-6, and IL-32 in the plasma was found [26]. Polymorphism in the allele programmed death-1 receptor is highly present in NMO conditions [27]. An expression study comparing NMO cases and normal controls showed more than 700 mRNAs differentially expressed in NMO subjects. The genes responsible for IL-23, INF-\(\gamma\), NFkB, and T cell-related genes showed changes in NMO subjects [28]. Small RNAseq analysis from the whole blood of rituximab-responsive NMO patients before and after six months following treatment and healthy controls showed that 32 and 14 miRNAs were downregulated and upregulated, respectively, after rituximab treatment. In comparison, untreated NMO patients and healthy controls showed that 17 and 25 miRNAs were upregulated and downregulated, respectively. Thus, miRNAs could be a potential circulating biomarker for NMO [29]. Understanding the complexity of NMO requires knowledge about the biomarkers. Proteomic and metabolomic evaluations were used to avoid misdiagnosis and to differentiate NMOSD from other diseases such as multiple sclerosis, longitudinally extensive transverse myelitis (LETM), and relapsing-remitting multiple sclerosis (RRMS). The discovery of NMOSD biomarkers would support diagnosing and differentiating seropositive and seronegative AQP4-ab and MOG-Ab NMO cases and other related disorders [30]. The involvement of T follicular helper (Tfh) cells and chemokine CXC receptor 5 (CXCR5) in reducing the disease progression and necovcurrence of NMOSD was studied. The function of Tfh cells on B cell mediated humoral immunity is modulated by the serum C-X-C motif ligand 13 (CXCL-13). The correlation between gut microbiome-CXCL-13 and Tfh could facilitate understanding NMOSD [31; 32]. NMO patients with high recurrence rates showed higher levels of CXCR5, and NMO patients with low annual relapse rates showed reduced CXCL13 in their serum and CSF. The results indicated that CXCL13 and CXCR5 in the CSF are directly related to NMO disease-related nerve defects [31]. The effects of gut microbiota and its metabolites in causing NMO pathology are described by certain studies [33; 34]. AQP4 is an osmotically driven water channel present in the glial cells, responsible for the extracellular osmolality stabilisation, glutamate homeostasis, and balance of the metabolic load in the blood-brain barrier (BBB) [35]; thus, regulating the CNS in response to injury could influence synaptic plasticity as well as behaviour [36]. AQP4-ab causes inflammation and complement-dependent immune cytotoxicity [37]. AQP4 stabilizes the extracellular osmolality during neuronal activity, thus maintaining the BBB's glutamate homeostasis, energy, and metabolic loads [35].