Roemer, S. F. et al. Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain 130, 1194-1205

Department of Neurology, Mayo Clinic, College of Medicine, 200 First St. SW, Rochester, MN 55905, USA.
Brain (Impact Factor: 9.2). 06/2007; 130(Pt 5):1194-205. DOI: 10.1093/brain/awl371
Source: PubMed


Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that typically affects optic nerves and spinal cord. Its pathogenic relationship to multiple sclerosis (MS) is uncertain. Unlike MS, NMO lesions are characterized by deposits of IgG and IgM co-localizing with products of complement activation in a vasculocentric pattern around thickened hyalinized blood vessels, suggesting a pathogenic role for humoral immunity targeting an antigen in the perivascular space. A recently identified specific serum autoantibody biomarker, NMO-IgG, targets aquaporin-4 (AQP4), the most abundant water channel protein in the CNS, which is highly concentrated in astrocytic foot processes. We analysed and compared patterns of AQP4 immunoreactivity in CNS tissues of nine patients with NMO, 13 with MS, nine with infarcts and five normal controls. In normal brain, optic nerve and spinal cord, the distribution of AQP4 expression resembles the vasculocentric pattern of immune complex deposition observed in NMO lesions. In contrast to MS lesions, which exhibit stage-dependent loss of AQP4, all NMO lesions demonstrate a striking loss of AQP4 regardless of the stage of demyelinating activity, extent of tissue necrosis, or site of CNS involvement. We identified a novel NMO lesion in the spinal cord and medullary tegmentum extending into the area postrema, characterized by AQP4 loss in foci that were inflammatory and oedematous, but neither demyelinated nor necrotic. Foci of AQP4 loss coincided with sites of intense vasculocentric immune complex deposition. These findings strongly support a role for a complement activating AQP4-specific autoantibody as the initiator of the NMO lesion, and further distinguish NMO from MS.

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Available from: Hans Lassmann, Dec 12, 2013
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    • "While spinal cord or optic nerve attacks in NMOSD commonly result in severe clinical disability [17], clinical brain symptoms resolved markedly in 87% of our patients, consistent with the seemingly reversible brain lesions on MRI. The clinical and radiological resolution of brain attacks has been reported in previous case series [2], [18]–[20]. The mechanism of reversibility has been attributed to vasogenic edema, secondary to disruption of water transport during AQP4-directed autoimmune reactions [3], [7], [19]. "
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    ABSTRACT: Brain involvement is commonly seen in patients with neuromyelitis optica spectrum disorder (NMOSD). However, little is known about the chronic changes of acute brain lesions on MRI over time. Here, our objective was to evaluate how acute brain MRI lesions in NMOSD changed on follow-up MRI. We reviewed the MRIs of 63 patients with NMOSD who had acute brain lesions and follow-up MRI over an interval of at least 3 months. Of the 211 acute brain lesions, 24% of lesions disappeared completely on T2-weighed images (WI) and a decrease in size ≥50% on T2-WI was observed in 58% of lesions on follow-up MRI. However, 47% of lesions revealed focal T1-hypointensity and, in particular, 18% showed focal cystic changes. Cystic changes were observed most commonly in corticospinal tract and corpus callosal lesions whereas the vast majority of lesions in the cerebellum, basal ganglia and temporal white matter resolved completely. MRI remission on T2-WI occurred in 82% of lesions, while approximately half of the lesions presented foci of T1-hypointensity, which may be considered a severe tissue injury over time. The extent of brain injury following an acute brain lesion in NMOSD may depend on the location of the lesion.
    PLoS ONE 09/2014; 9(9):e108320. DOI:10.1371/journal.pone.0108320 · 3.23 Impact Factor
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    • "There is strong evidence for a central role of complement in NMO pathogenesis and hence for the utility of complement-targeted therapeutics. Inflammatory lesions in human NMO show prominent vasculocentric deposition of activated complement [11]–[13]. In vitro, addition of NMO-IgG and complement to AQP4-expressing cells, including astrocytes, produces complement-dependent cytotoxicity (CDC) [14]–[17]. "
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    ABSTRACT: Neuromyelitis optica (NMO) is an autoimmune demyelinating disease of the central nervous system in which binding of anti-aquaporin-4 (AQP4) autoantibodies (NMO-IgG) to astrocytes causes complement-dependent cytotoxicity (CDC) and inflammation resulting in oligodendrocyte and neuronal injury. There is compelling evidence for a central role of complement in NMO pathogenesis. Here, we evaluated the potential of C1-esterase inhibitor (C1-inh) for complement-targeted therapy of NMO. C1-inh is an anti-inflammatory plasma protein with serine protease inhibition activity that has a broad range of biological activities on the contact (kallikrein), coagulation, fibrinolytic and complement systems. C1-inh is approved for therapy of hereditary angioedema (HAE) and has been studied in a small safety trial in acute NMO relapses (NCT 01759602). In vitro assays of NMO-IgG-dependent CDC showed C1-inh inhibition of human and rat complement, but with predicted minimal complement inhibition activity at a dose of 2000 units in humans. Inhibition of complement by C1-inh was potentiated by ∼10-fold by polysulfated macromolecules including heparin and dextran sulfate. In rats, intravenous C1-inh at a dose 30-fold greater than that approved to treat HAE inhibited serum complement activity by <5%, even when supplemented with heparin. Also, high-dose C1-inh did not reduce pathology in a rat model of NMO produced by intracerebral injection of NMO-IgG. Therefore, although C1r and C1s are targets of C1-inh, our in vitro data with human serum and in vivo data in rats suggest that the complement inhibition activity of C1-inh in serum is too low to confer clinical benefit in NMO.
    PLoS ONE 09/2014; 9(9):e106824. DOI:10.1371/journal.pone.0106824 · 3.23 Impact Factor
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    • "Formation of AQP4:AQP4-IgG immune complexes, with subsequent complement-mediated destruction of astrocytes, is paralleled by loss of AQP4 and GFAP staining in perivascular lesions in histological sections. This loss is localised in the same areas that exhibit accumulation of eosinophils and plasma cells as well as vasculocentric deposits of immunoglobulins and products of complement activation (Jarius et al., 2008; Lucchinetti et al., 2002; Roemer et al., 2007). These characteristics also resemble the histopathological features of murine brain lesions induced by injection of human AQP4-IgG with human complement into the brain (Saadoun et al. 2010). "
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    ABSTRACT: The role of complement has been demonstrated in experimental models of neuromyeltis optica (NMO), however, only few studies have analysed complement components longitudinally in NMO patients. We measured serum or plasma concentrations of anti-C1q antibodies and complement split products C3a, C4a and soluble C5b-9 in patients with NMO, multiple sclerosis and healthy controls. NMO patients had higher levels of C3a and anti-C1q antibodies than healthy controls. C3a levels correlated with disease activity, neurological disability and aquaporin-4 IgG in NMO patients suggesting a role of the alternative pathway of complement in the pathogenesis of NMO and supporting the strategy of therapeutic complement inhibition.
    Journal of Neuroimmunology 09/2014; 274(1-2). DOI:10.1016/j.jneuroim.2014.07.001 · 2.47 Impact Factor
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