Clinical and Experimental Neuroimmunology最新文献

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease of the central nervous system, characterized by severe relapses that can lead to blindness or paralysis. However, NMOSD presents with a broad spectrum of symptoms, including optic neuritis, transverse myelitis, and area postrema syndrome, along with distinctive findings on magnetic resonance imaging. In Japan, where the prevalence of NMOSD is relatively high, nationwide surveys and regional studies have revealed its detailed epidemiological and clinical characteristics. The discovery of aquaporin-4 autoantibodies has not only distinguished NMOSD from multiple sclerosis but also provided critical insights into its immunopathogenesis, resulting in the development of molecular-targeted therapies capable of inhibiting key immune pathways, including the complement system, interleukin-6 signaling, and B-cell-mediated immunity. Several biological agents, such as eculizumab, ravulizumab, satralizumab, inebilizumab, and rituximab, have demonstrated high efficacy in preventing relapse in clinical trials. Although long-term safety data remain limited for most agents, Japanese real-world data support their effectiveness and safety. This review summarizes the clinical features, imaging characteristics, and current treatment strategies for NMOSD, with a particular focus on the therapeutic mechanisms of biological agents and the insights they provide into disease pathophysiology.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system characterized by recurrent inflammation, primarily targeting the optic nerves and spinal cord. The presence of anti-aquaporin 4 antibodies has revealed core aspects of its immunopathology, but growing evidence suggests that genetic factors also contribute to individual susceptibility, clinical heterogeneity, and treatment response. Recent advances in genome-wide association studies (GWAS), whole exome sequencing (WES), and Mendelian randomization (MR) have identified genetic variants associated with NMOSD. These findings span human leukocyte antigen (HLA) class II alleles, non-HLA immune-related genes, and somatic mutations acquired by clonal hematopoiesis. Importantly, genetic associations vary by ethnicity and may underlie the disparities seen in disease prevalence and phenotype. In addition, MR studies are revealing potential causal pathways involving immune mediators, cytokines, and metabolites, providing a new perspective on the disease mechanism. These genomic findings are accelerating our understanding of NMOSD and are expected to lead to risk stratification, refinement of diagnostic classification, and development of targeted therapies. This review provides an integrated overview of current genetic research in NMOSD and identifies implications for future precision medicine.

In Japan, five biologics (eculizumab, ravulizumab, satralizumab, inebilizumab, and rituximab) are currently available for treating neuromyelitis optica spectrum disorder (NMOSD). These biologics have dramatically suppressed the disease relapse rate; however, a big problem remains: there are no useful biomarkers or sufficient evidence in drug selection and drug switch for each patient. Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) has been recently identified, and its therapeutic strategy is still under investigation. To solve these problems, the Japan NMOSD/MOGAD Registry was launched in December 2023. In this paper, we summarize the current clinical problems of NMOSD and MOGAD in Japan and review the Japan NMOSD/MOGAD Registry project.

Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing autoimmune/inflammatory disease of the central nervous system (CNS) that causes severe neurological deficits, including optic neuritis and longitudinally extensive myelitis. The autoantigen of NMOSD is the water channel “aquaporin-4 (AQP4),” which is highly expressed in the endfeet of astrocytes, the ependymal cell lining of the ventricles, and Müller cells in the retina throughout the CNS. AQP4-IgG autoantibodies produced by peripheral plasmablasts/plasma cells can cross the blood–brain barrier and primarily damage astrocytes, leading to secondary demyelination and axonal injury. The mechanism of AQP4 antibody-guided CNS injury ‘AQP4-opathy’ in NMOSD is mainly complement-dependent cytotoxicity, but it can also be attributed to antibody-dependent cellular cytotoxicity or AQP4 internalization. Moreover, recent research has demonstrated that stage-dependent immune dynamics orchestrate AQP4 antibody-guided lesions as follows: adaptive immune elements, including AQP4 autoantibodies with activated T_H17 cells, could form AQP4-opathy specific to NMOSD, synchronizing with the activation of innate immune dynamics, including complements, granulocytes, and microglia/macrophages in active phases. In particular, activated neutrophils with extracellular traps and tissue-resident memory T cells expressing granzyme B infiltrate during the initial and early active phases of NMOSD. These immune cells may be involved in lesion expansion and trigger relapses in cooperation with active AQP4 antibody-guided NMOSD pathology. These newly identified insights will lead to a better understanding of innate immunology and novel therapeutic strategies for NMOSD.