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Fig. 2 | Journal of Neuroinflammation

Fig. 2

From: Neuromyelitis optica spectrum disorders: from pathophysiology to therapeutic strategies

Fig. 2

Pathophysiologic mechanisms and therapeutic targets for approved and experimental treatment options in NMOSD. AQP4-specific B cells differentiate in the periphery to plasma cells capable of producing anti-AQP4 antibodies (1), which penetrate the CNS and are deposited mainly on the feet of astrocytes. Specific T cells interact with B cells or dendritic cells, and in the presence of IL-6, IL-23, and TGF-β differentiate into Th17 cells. These in turn penetrate the CNS, facilitate the passage of AQP4-ab into the CNS via opening the blood brain barrier (BBB), and contribute to the recruitment of neutrophils (2). This inflammatory environment activates complement through C1q which binds to anti-AQP4-ab, induces C5 cleavage into activated fractions C5a and C5b, causing astrocyte injury through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). When C1q binds to conformational Fc determinants on IgG or IgM antibody–antigen complexes, it produces cellular injury by formation of the pore-like membrane attack complex (MAC) (3). In addition to MAC formation, complement activation produces factors C3a and C5a, which together with VEGF increase vascular permeability and provide a chemotactic gradient, resulting in recruitment of neutrophils, eosinophils, basophils, mast cells, NK cells and macrophages (4). These cells produce complement-independent damage of astrocytes through ADCC or degranulation involving Fc receptors. Mechanisms described above may also generate cytotoxicity in neighboring cells including oligodendrocytes and neurons through bystander effects (5). Experimental treatments or those in ongoing studies are represented in dotted line spaces. AQP4 aquaporin-4, CCP cytotoxic cationic proteins, IL interleukin, NE neutrophil elastase, NOS nitric oxide species, VEGF vascular endothelial growth factor

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