[PubMed] [CrossRef] [Google Scholar] 19

[PubMed] [CrossRef] [Google Scholar] 19. optic neuritis and transverse myelitis, however can also present with cerebral syndromes [1C3]. Approximately three-quarters of patients with NMOSD have antibodies against aquaporin-4 (AQP4), a water-channel protein abundantly expressed in astrocyte foot processes [4, 5]. However, the spectrum of NMOSD has expanded with the identification of novel autoantibodies, including those against myelin oligodendrocyte glycoprotein (MOG) [6]. B cells play a central role in the pathogenesis of NMOSD [7]. They are generated in the bone marrow from Rabbit Polyclonal to CFI hematopoietic stem cells and proceed through stages of maturation by expressing unique surface markers, including CD19, a pan B cell marker expressed throughout the life span of a B cell, and CD20, which is usually expressed starting at the pre-B cell stage, before being downregulated at the stage of plasma cells and plasmablasts (Fig.?1) [8]. Immune activation is initiated in the peripheral immune system where pathogenic AQP4 antibodies are generated by plasmablasts in an interleukin-6-dependent manner [7C9]. AQP4 autoantibodies enter the CNS and bind to AQP4 in foot processes of blood-brain barrier (BBB) astrocytes (Fig. ?(Fig.1)1) [7, 9]. The antibody-antigen complexes activate the proteolytic classical complement cascade, resulting in generation of complement C5, a component of the membrane attack complex that causes astrocyte death and demyelination (Fig. ?(Fig.1)1) [10, 11]. Open in a separate window Fig. 1 NMOSD pathogenesis and therapeutic targets in the peripheral immune and central nervous systems. B cells undergo maturation in the bone marrow, spleen, and lymph nodes, ultimately to generate anti-AQP4-expressing plasmablasts. Pathogenic AQP4 antibody enters the CNS via the defective blood-brain barrier to target astrocytes with resultant neuroinflammation and demyelination. Conventional (blue), new maintenance (green), and emerging (gray) therapies are depicted in respective checkpoints involved in NMOSD pathogenesis. AQP4 aquaporin 4, BBB blood-brain barrier, C complement factor, CD cluster of differentiation, IgG immunoglobulin G, IL interleukin, MAC membrane attack complex, NK natural killer cell. Created with BioRender.com. T cells also contribute to the immunopathogenesis of NMOSD; however, their functions are less well defined [12]. Animal models provide evidence that AQP4-specific T cells cause inflammatory CNS lesions [13]. NMO IgG is usually primarily of the IgG1 subclass [14], and T helper cells are crucial for immunoglobulin class switching to generate IgG1 subclass AQP4 antibodies [15]. In addition, patients with NMOSD have higher proportions of Th17 cells compared to healthy controls [16]. Studies suggest that high IL-6 expression 3,4-Dihydroxybenzaldehyde in NMOSD patients may enhance the reciprocal activation of Th17 cells [17] and upregulation of Th2-related cytokines [18, 19]. Conventional therapies In contrast to multiple sclerosis (MS), functional decline and permanent disability in NMOSD are primarily impacted by severe, often life-threatening clinical relapses [20, 21]. Therefore, the treatment strategy for patients diagnosed with NMOSD [22C24] consists of aggressive management of acute relapses followed by long-term preventative immunosuppressive therapies, as layed out in Fig.?2. Open in a separate windows Fig. 3,4-Dihydroxybenzaldehyde 2 Recommended treatment algorithm for acute and long-term management of aquaporin 4 antibody positive (AQP4+) and myelin oligodendrocyte glycoprotein antibody positive (MOG+) NMOSD. Acute management does not differ by serostatus, but there are more specific long-term treatments for patients based on antibody status. Conventional therapies can be used for AQP4+, MOG+, or seronegative patients. New therapies 3,4-Dihydroxybenzaldehyde have shown efficacy in AQP4+ patients. inebilizumab 3,4-Dihydroxybenzaldehyde and satralizumab may be considered for use as first-line therapies. Eculizumab has proven effectiveness as an add-on therapy but may.