Neuromyelitis optica IgG and natural killer cells produce NMO lesions in mice without myelin loss.

Department of Medicine, University of California, San Francisco, 1246 Health Sciences East Tower, San Francisco, CA 94143-0521, USA.
Acta Neuropathologica (Impact Factor: 9.73). 04/2012; 123(6):861-72. DOI: 10.1007/s00401-012-0986-4
Source: PubMed

ABSTRACT The pathogenesis of neuromyelitis optica (NMO) involves targeting of NMO-immunoglobulin G (NMO-IgG) to aquaporin-4 (AQP4) on astrocytes in the central nervous system. Prior work provided evidence for complement-dependent cytotoxicity (CDC) in NMO lesion development. Here, we show that antibody-dependent cellular cytotoxicity (ADCC), in the absence of complement, can also produce NMO-like lesions. Antibody-dependent cellular cytotoxicity was produced in vitro by incubation of mouse astrocyte cultures with human recombinant monoclonal NMO-IgG and human natural killer cells (NK-cells). Injection of NMO-IgG and NK-cells in mouse brain caused loss of AQP4 and GFAP, two characteristic features of NMO lesions, but little myelin loss. Lesions were minimal or absent following injection of: (1) control (non-NMO) IgG with NK-cells; (2) NMO-IgG and NK-cells in AQP4-deficient mice; or (3) NMO-IgG and NK-cells in wild-type mice together with an excess of mutated NMO-IgG lacking ADCC effector function. NK-cells greatly exacerbated NMO lesions produced by NMO-IgG and complement in an ex vivo spinal cord slice model of NMO, causing marked myelin loss. NMO-IgG can thus produce astrocyte injury by ADCC in a complement-independent and dependent manner, suggesting the potential involvement of ADCC in NMO pathogenesis.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Myelin-oligodendrocyte glycoprotein antibody (MOG antibodies) was found in various demyelinated diseases. This is the first report of a patient with longitudinally extensive transverse myelitis with an extremely high titer of MOG antibodies after an influenza infection. This case supports the view that MOG antibodies are linked to longitudinally extensive transverse myelitis and that influenza infection might trigger the MOG antibodies.Case presentationA 32-year-old healthy male developed high fever, dysesthesia and paraesthesia below the C2 area, muscle weakness of the bilateral lower extremities, and urinary retention ten days after an influenza type A infection. Magnetic resonance imaging revealed a longitudinal lesion in the spinal cord extending from C2 to the spinal conus. There were no lesions in the brain or optic nerves. Established cell-based immunoassays revealed that he was positive for MOG antibodies (titer =65,536) and negative for anti-aquaporin 4 antibodies (AQP4 antibodies). He fully recovered after steroid pulse therapy followed by 60 mg prednisolone.Conclusion This is the first report of influenza A-associated longitudinally extensive transverse myelitis with a high titer anti-MOG antibodies. Our case report supports a relationship between anti-MOG antibodies and longitudinally extensive transverse myelitis, which was triggered by influenza infection. Further studies are needed to establish the clinical significance of anti-MOG antibodies for diagnosis, treatment, and prognosis.
    BMC Neurology 11/2014; 14(1):224. · 2.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Neuromyelitis optica (NMO) is an autoimmune disease of the CNS that is characterized by inflammatory demyelinating lesions in the spinal cord and optic nerve, potentially leading to paralysis and blindness. NMO can usually be distinguished from multiple sclerosis (MS) on the basis of seropositivity for IgG antibodies against the astrocytic water channel aquaporin-4 (AQP4). Differentiation from MS is crucial, because some MS treatments can exacerbate NMO. NMO pathogenesis involves AQP4-IgG antibody binding to astrocytic AQP4, which causes complement-dependent cytotoxicity and secondary inflammation with granulocyte and macrophage infiltration, blood-brain barrier disruption and oligodendrocyte injury. Current NMO treatments include general immunosuppressive agents, B-cell depletion, and plasma exchange. Therapeutic strategies targeting complement proteins, the IL-6 receptor, neutrophils, eosinophils and CD19-all initially developed for other indications-are under clinical evaluation for repurposing for NMO. Therapies in the preclinical phase include AQP4-blocking antibodies and AQP4-IgG enzymatic inactivation. Additional, albeit currently theoretical, treatment options include reduction of AQP4 expression, disruption of AQP4 orthogonal arrays, enhancement of complement inhibitor expression, restoration of the blood-brain barrier, and induction of immune tolerance. Despite the many therapeutic options in NMO, no controlled clinical trials in patients with this condition have been conducted to date.
    Nature Reviews Neurology 08/2014; · 15.52 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Animal models of neuromyelitis optica (NMO) are needed for drug testing and evaluation of NMO disease pathogenesis mechanisms. We describe a novel passive-transfer model of NMO in which rats made seropositive for human anti-aquaporin-4 (AQP4) immunoglobulin G antibody (NMO-IgG) by intraperitoneal (IP) injections were subject to intracerebral needle injury. Following a single IP injection, NMO-IgG distributed rapidly to peripheral AQP4-expressing cells (kidney collecting duct, gastric glands, airways, skeletal muscle) and area postrema in brain, but not elsewhere in the central nervous system; however, no pathology was seen in brain, spinal cord, optic nerve or peripheral tissues. After testing various maneuvers to produce NMO-IgG-dependent pathology in brain, we found that transient puncture of brain parenchyma with a 28-gauge needle in NMO-IgG seropositive rats produced robust NMO pathology around the needle track, with loss of AQP4 and glial fibrillary acidic protein, granulocyte and macrophage infiltration, centrovascular deposition of activated complement, and blood-brain barrier disruption, with demyelination by 5 days. Pathology was not seen in rats receiving control (non-NMO) human IgG or in NMO-IgG-seropositive rats made complement-deficient by cobra venom factor. Interestingly, at 1 day a reversible, multifocal astrocytopathy was seen with loss of AQP4 and GFAP (but not myelin) in areas away from the needle track. NMO-IgG-seropositivity alone is not sufficient to cause NMO pathology in rats, but a single intracerebral needle insertion, without pre-existing inflammation or infusion of pro-inflammatory factors, was sufficient to produce robust NMO pathology in seropositive rats.
    Acta neuropathologica communications. 04/2014; 2(1):48.

Full-text (2 Sources)

Available from
May 29, 2014