Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune central nervous system (CNS) inflammatory disorder that can lead to serious disability and mortality. Females are predominantly affected, including those within the reproductive age. Most patients develop relapsing attacks of optic neuritis; longitudinally extensive transverse myelitis; and encephalitis, especially brainstem encephalitis. The majority of NMOSD patients are seropositive for IgG autoantibodies against the water channel protein aquaporin-4 (AQP4-IgG), reflecting underlying aquaporin-4 autoimmunity. Histological findings of the affected CNS tissues of patients from in-vitro and in-vivo studies support that AQP4-IgG is directly pathogenic in NMOSD. It is believed that the binding of AQP4-IgG to CNS aquaporin-4 (abundantly expressed at the endfoot processes of astrocytes) triggers astrocytopathy and neuroinflammation, resulting in acute attacks. These attacks of neuroinflammation can lead to pathologies, including aquaporin-4 loss, astrocytic activation, injury and loss, glutamate excitotoxicity, microglial activation, neuroinflammation, demyelination, and neuronal injury, via both complement-dependent and complement-independent pathophysiological mechanisms. With the increased understanding of these mechanisms underlying this serious autoimmune astrocytopathy, effective treatments for both active attacks and long-term immunosuppression to prevent relapses in NMOSD are increasingly available based on the evidence from retrospective observational data and prospective clinical trials. Knowledge on the indications and potential side effects of these medications are essential for a clear evaluation of the potential benefits and risks to NMOSD patients in a personalized manner. Special issues such as pregnancy and the coexistence of other autoimmune diseases require additional concern and meticulous care. Future directions include the identification of clinically useful biomarkers for the prediction of relapse and monitoring of the therapeutic response, as well as the development of effective medications with minimal side effects, especially opportunistic infections complicated by long-term immunosuppression.
Highlights
Aquaporin-4 (AQP4) is a transmembrane water channel highly expressed in the endfeet of central nervous system (CNS) astrocytes, which is essential for normal functioning of the blood−brain barrier (BBB) and for maintenance of CNS water homeostasis [2]
AQP4-immunoglobulin G (IgG) can originate from the pool of autoreactive naïve B cells that develop as a consequence of impaired early B cell tolerance checkpoints in Neuromyelitis optica spectrum disorder (NMOSD) patients [40]
Similar findings were observed in another retrospective study involving 103 AQP4-IgG-seropositive NMOSD patients, showing that 89% of patients had a significant reduction in median annualized relapse rate (ARR) from 1.5 to 0, 61% remained relapse free at a median follow-up of 18 months, and neurological function improved or stabilized in 78% with azathioprine treatment
Summary
It is clear that NMOSD seropositive for AQP4-IgG is not multiple sclerosis, but an autoimmune disorder affecting predominantly CNS astrocytes (astrocytopathy), and the detection of AQP4-IgG in the serum of patients greatly facilitates the diagnosis of NMOSD. A small proportion of patients with typical neurological features of NMOSD are seronegative for AQP4-IgG, and their pathogenesis is uncertain. Converging lines of evidence support that CNS inflammatory demyelinating disorders associated with MOG-IgG have different pathophysiologies and pathologies from AQP4-IgG-seropositive NMOSD, and are considered as a separate entity termed myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD), which phenotypically can mimic NMOSD [10]. We focus on the treatments of NMOSD only, not MOGAD
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