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Page 2 of 16 Zhang et al. Neuroimmunol Neuroinflammation 2019;6:8 I http://dx.doi.org/10.20517/2347-8659.2019.06

underlying MS is an autoimmune reaction to myelin or oligodendrocytes, but no MS-specific autoantigen
has been identified.

NMO/NMOSD typically manifest as optic neuritis and longitudinally extensive transverse myelitis, and can
lead to severe disability. The prevalence of NMOSD rarely exceeds 5/100,000, and is comparatively similar
[4]
[6]
globally . In 2004, Lennon et al. discovered NMO autoantibodies, which clearly differentiated NMO
from MS. Up to 80% of NMO patients test positive for antibodies against aquaporin4 (AQP4), which is a
[7]
water channel protein found in many organs of the body . In the CNS, AQP4 is expressed in a perivascular
[6]
distribution on astrocytic foot processes . The distinctive immunopathology of NMO lesions supports a
central role for AQP4-IgG in the pathogenesis of this disease. AQP4-IgG damages the blood-brain barrier
(BBB) through complement-dependent astrocytic damage. AQP4-IgG-positive NMOSD is not a classic
[8,9]
demyelinating disease as MS, marked by secondary demyelination due to astrocyte loss . In addition to
the optic nerve and spinal cord, areas of high AQP4 expression around the ventricles are often involved, such
as the area postrema of the medulla oblongata, thalamus, peripheral area of the third and fourth ventricles,
corpus callosum, and white matter of the cerebral hemisphere. The high specificity of AQP4-IgG extends the
study of NMO and its related diseases. Previously, the diagnostic criteria for NMO required optic nerve and
[10]
spinal cord involvement. In 2007, Wingerchuk proposed the concept of NMOSD . In 2015, the International
Panel for NMO Diagnosis removed the separate definition of NMO and integrated NMO into the broader
[11]
term of NMOSD . NMOSD are a class of antigen-antibody-mediated CNS inflammatory demyelinating
[12]
diseases that are primarily mediated by humoral immunity, with or without AQP4 positivity .

PATHOGENESIS OF MS AND NMOSD
MS is considered a classic autoimmune disease mediated by autoreactive T-lymphocytes, specifically
CD4+ T-helper (Th)1 cells and Th17 cells. Th1 cells produce interferon (IFN)-γ, while Th17 cells are a T-cell
subgroup producing IFN-γ and interleukin (IL)-17 [13,14] . Activated T-cells can express a variety of adhesion
molecules that combine with receptors on the vessel wall. Furthermore, vascular endothelial cells express
selectins that bind to T-cells, and chemokines can induce T-cells to enter the CNS. Additionally, T-cells
secrete matrix metalloproteinases that degrade the collagen component of blood-vessel walls, destroying the
BBB and facilitating the entry of T- and B-lymphocytes and monocytes into the brain. In the CNS, T-cells
secrete inflammatory cytokines and chemokines, which cause the activation of other inflammatory cells,
resulting in a series of complex cascades of immune responses that finally lead to damage to the myelin
sheath and even axons [13-16] . IL-4 stimulates the differentiation of CD4+ T-cells into anti-inflammatory Th2
cells and inhibits Th1 and Th17 cells. IL-2 and transforming growth factor (TGF)-β stimulate the production
[17]
of regulatory T cells, which can inhibit Th17, Th1, and CD8+ T-cells in the CNS . Th1 cells can recognize
major histocompatibility complex (MHC) class II molecules, cross the BBB, and induce CNS autoimmunity.
And Th17 lymphocytes are capable of crossing the BBB, and their secretion damages the BBB and promotes
[18]
the entry of other inflammatory cells into the CNS . In recent years, it has been found that B-cells also
play an important role in the pathogenesis of MS. In most MS patients, oligoclonal bands and B-cell clonal
proliferation occur in the CSF, and B-cell proliferation and germinal-center formation may occur in the
[19]
meningeal follicles .

NMOSD are humoral immune-mediated autoimmune diseases. B-lymphocytes secrete specific antibodies
that bind to complement, then deposit and destroy AQP4, which is expressed on the surface of astrocytes.
However, the role of B-cells in the pathogenesis of NMOSD may not be limited to the production of AQP4-
IgG, and an imbalance between pro-inflammatory and anti-inflammatory B-cell functions may also be
[20]
involved . Other inflammatory cells such as macrophages, eosinophils, and neutrophils are then attracted
[21]
towards the injured tissue and secrete inflammatory factors that cause myelin loss and axonal damage .
[22]
A study has shown that peripheral blood neutrophils show a primed phenotype in NMOSD . In some