Neuromyelitis optica spectrum disorder (NMOSD) is a rare, autoimmune disorder that is distinguishable from multiple sclerosis. It is caused by the autoantibody, NMO immunoglobulin G (IgG), attacking aquaporin-4 (AQP4) channels. Inflammatory lesions along specific nerves within the central nervous system (CNS) develop as a result, causing symptoms such as vision loss, disability, and, in severe cases, death.1
AQP4 is a bidirectional, osmosis-driven water channel expressed on the foot processes of astrocytes and ependymal cells in the CNS.1 Astrocytes are the most numerous glial cells located in the CNS. They play important roles, including axon guidance, synaptic support, and control of the blood brain barrier (BBB) and blood flow.2 In the CNS, AQP4 channels are predominantly found in the retina, optic nerves, hypothalamus, spinal cord, cerebellum, and periventricular and periaqueductal regions.1
NMO IgG Autoantibodies
The autoimmune antibody, NMO IgG, has a high specificity (99%) and moderate sensitivity (56% to 73%) for NMOSD, with higher sensitivities in cases of relapsing NMOSD.1
NMO IgG autoantibodies are synthesized outside of the CNS, only entering the CNS when the BBB is disrupted and becomes permeable to IgG autoantibodies, which ordinarily would not easily pass through.
The IgGs bind with AQP4 channels, resulting in complement-mediated necrosis of astrocytes via the lytic complex C5b-9.3 This, in turn, leads to extensive inflammatory demyelination and loss of astrocytes in specific regions of the CNS, especially the optic nerves and central grey matter of the spinal cord.1
Mechanisms of Blood Brain Barrier Disruption
BBB disruption results from either a systemic inflammatory response or a localized pathological process within the CNS.
In one study, researchers evaluated the medical literature between 1975 and 2009 and identified 25 NMO cases – 11 following viral infection and 14 following bacterial infection (predominantly varicella zoster and Mycobacterium tuberculosis, respectively).4 In another study, vaccination against human papilloma virus preceded the onset of NMO in 4 teenage girls.5 Rarely, cancers such as B-cell lymphoma, lung carcinoma, and breast carcinoma preceded the onset of NMO.6
Another hypothesis involves an initial localized CNS disease process potentially affecting BBB permeability, causing an accumulation of B-cells and sensitizing them to AQP4 channels. Further research is required to determine the exact cause of autoantibody production in NMO cases.1
Other Triggers for Autoimmunity
In addition to viral and bacterial infections and pre-existing CNS pathologies, non-Caucasian heritage and female sex are potential genetic predispositions.1 A small number of cases (3%) have a familial history with a complex pattern of inheritance. As of 2010, there were 12 families with 25 known affected individuals who inherited familial NMO recorded in the medical literature.1,7
Another study conducted in 2011 analyzed AQP4 gene mutations to see if they contributed to NMO manifestation. Only a very small number of NMO cases (3 of 191) demonstrated AQP4 mutations leading to a problem transcribing arginine.8 Researchers speculated that the loss of arginine in the transcribed protein might negatively impact the palmitoylation of AQP4 channels.9 This may increase the size of AQP4’s orthogonal arrays of intramembranous particles, thereby impacting the structure and function of the water channels themselves.1,10
T helper cells, cytokines, and B-cells are necessary for the systemic synthesis of NMO IgG autoantibodies. Researchers in one study identified elevated Th2- and Th17-related cytokines, in particular interleukin (IL)-6, without the presence of the signature Th2, Th17, or IL-17 in the cerebrospinal fluid (CSF) of participants with NMO.11 Conversely, investigators in other studies did identify elevated IL-17 levels in the CSF of patients with NMO.12,13 Therefore, it can be deduced that Th17 cells, given their association with both IL-6 and IL-17, play an important role in the widespread CNS inflammation of patients with NMO.1
- Bukhari W, Barnett MH, Prain K, Broadley SA. Molecular pathogenesis of neuromyelitis optica. Int J Mol Sci. 2012;13(10):12970-12993. doi:10.3390/ijms131012970
- Blackburn D, Sargsyan S, Monk PN, Shaw PJ. Astrocyte function and role in motor neuron disease: a future therapeutic target? Glia. 2009;57(12):1251-1264. doi:10.1002/glia.20848
- Kinoshita M, Nakatsuji Y, Moriya M, et al. Astrocytic necrosis is induced by anti-aquaporin-4 antibody-positive serum. Neuroreport. 2009;20(5):508-512. doi:10.1097/wnr.0b013e32832776f4
- Sellner J, Hemmer B, Mühlau M. The clinical spectrum and immunobiology of parainfectious neuromyelitis optica (Devic) syndromes. J Autoimmun. 2010;34(4):371-379. doi:10.1016/j.jaut.2009.09.013
- Menge T, Cree B, Saleh A, et al. Neuromyelitis optica following human papillomavirus vaccination. Neurology. 2012;79(3):285-287. doi:10.1212/WNL.0b013e31825fdead
- Pittock SJ, Lennon VA. Aquaporin-4 autoantibodies in a paraneoplastic context. Arch Neurol. 2008;65(5):629-632. doi:10.1001/archneur.65.5.629
- Matiello M, Kim HJ, Kim W, et al. Familial neuromyelitis optica. Neurology. 2010;75(4):310-315. doi:10.1212/WNL.0b013e3181ea9f15
- Matiello M, Schaefer-Klein JL, Hebrink DD, Kingsbury DJ, Atkinson EJ, Weinshenker BG; NMO Genetics Collaborators. Genetic analysis of aquaporin-4 in neuromyelitis optica. Neurology. 2011;77(12):1149-1155. doi:10.1212/WNL.0b013e31822f045b
- Suzuki H, Nishikawa K, Hiroaki Y, Fujiyoshi Y. Formation of aquaporin-4 arrays is inhibited by palmitoylation of N-terminal cysteine residues. Biochim Biophys Acta. 2008;1778(4):1181-1189. doi:10.1016/j.bbamem.2007.12.007
- Wolburg H, Wolburg-Buchholz K, Fallier-Becker P, Noell S, Mack AF. Structure and functions of aquaporin-4-based orthogonal arrays of particles. Int Rev Cell Mol Biol. 2011;287:1-41. doi:10.1016/B978-0-12-386043-9.00001-3
- Uzawa A, Mori M, Arai K, et al. Cytokine and chemokine profiles in neuromyelitis optica: significance of interleukin-6. Mult Scler. 2010;16(12):1443-1452. doi:10.1177/1352458510379247
- Tanaka M, Matsushita T, Tateishi T, et al. Distinct CSF cytokine/chemokine profiles in atopic myelitis and other causes of myelitis. Neurology. 2008;71(13):974-981. doi:10.1212/01.wnl.0000326589.57128.c3
- Ishizu T, Osoegawa M, Mei FJ, et al. Intrathecal activation of the IL-17/IL-8 axis in opticospinal multiple sclerosis. Brain. 2005;128(Pt 5):988-1002. doi:10.1093/brain/awh453
Reviewed by Debjyoti Talukdar, MD, on 10/6/2021.
Reviewed by Debjyoti Talukdar, MD, on 10/6/2021.