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

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

Aquaporin-4 and brain edema.

Aquaporin-4 (AQP4) is a water-channel protein expressed strongly in the brain, predominantly in astrocyte foot processes at the borders between the brain parenchyma and major fluid compartments, including cerebrospinal fluid (CSF) and blood. This distribution suggests that AQP4 controls water fluxes into and out of the brain parenchyma. Experiments using AQP4-null mice provide strong evidence for AQP4 involvement in cerebral water balance. AQP4-null mice are protected from cellular (cytotoxic) brain edema produced by water intoxication, brain ischemia, or meningitis. However, AQP4 deletion aggravates vasogenic (fluid leak) brain edema produced by tumor, cortical freeze, intraparenchymal fluid infusion, or brain abscess. In cytotoxic edema, AQP4 deletion slows the rate of water entry into brain, whereas in vasogenic edema, AQP4 deletion reduces the rate of water outflow from brain parenchyma. AQP4 deletion also worsens obstructive hydrocephalus. Recently, AQP4 was also found to play a major role in processes unrelated to brain edema, including astrocyte migration and neuronal excitability. These findings suggest that modulation of AQP4 expression or function may be beneficial in several cerebral disorders, including hyponatremic brain edema, hydrocephalus, stroke, tumor, infection, epilepsy, and traumatic brain injury

Evolving trends in the surgical, anaesthetic, and intensive care management of acute spinal cord injuries in the UK.

PURPOSE: We surveyed the treatment of acute spinal cord injuries in the UK and compared current practices with 10 years ago. METHODS: A questionnaire survey was conducted amongst neurosurgeons, neuroanaesthetists, and neurointensivists that manage patients with acute spinal cord injuries. The survey gave two scenarios (complete and incomplete cervical spinal cord injuries). We obtained opinions on the speed of transfer, timing and aim of surgery, choice of anaesthetic, intraoperative monitoring, targets for physiological parameters, and drug treatments. RESULTS: We received responses from 78.6% of UK units that manage acute spinal cord injuries (33 neurosurgeons, 56 neuroanaesthetists/neurointensivists). Most neurosurgeons operate within 12 h for incomplete (82%) and complete (64%) injuries. There is a significant shift from 10 years ago, when only 61% (incomplete) and 30% (complete) of neurosurgeons operated within 12 h. The preferred anaesthetic technique in 2022 is total intravenous anaesthesia (TIVA), used by 69% of neuroanaesthetists. Significantly more intraoperative monitoring is now used at least sometimes, including bispectral index (91%), non-invasive cardiac output (62%), and neurophysiology (73-77%). Methylprednisolone is no longer used by surgeons. Achieving at least 80 mmHg mean arterial blood pressure is recommended by 70% neurosurgeons, 62% neuroanaesthetists, and 75% neurointensivists. CONCLUSIONS: Between 2012 and 2022, there was a paradigm shift in managing acute spinal cord injuries in the UK with earlier surgery and more intraoperative monitoring. Variability in practice persists due to lack of high-quality evidence and consensus guidelines

Photonic Analogue of Two-dimensional Topological Insulators and Helical One-Way Edge Transport in Bi-Anisotropic Metamaterials

Recent progress in understanding the topological properties of condensed matter has led to the discovery of time-reversal invariant topological insulators. Because of limitations imposed by nature, topologically non-trivial electronic order seems to be uncommon except in small-band-gap semiconductors with strong spin-orbit interactions. In this Article we show that artificial electromagnetic structures, known as metamaterials, provide an attractive platform for designing photonic analogues of topological insulators. We demonstrate that a judicious choice of the metamaterial parameters can create photonic phases that support a pair of helical edge states, and that these edge states enable one-way photonic transport that is robust against disorder.Comment: 13 pages, 3 figure

Aquaporin water channels in the nervous system.

The aquaporins (AQPs) are plasma membrane water-transporting proteins. AQP4 is the principal member of this protein family in the CNS, where it is expressed in astrocytes and is involved in water movement, cell migration and neuroexcitation. AQP1 is expressed in the choroid plexus, where it facilitates cerebrospinal fluid secretion, and in dorsal root ganglion neurons, where it tunes pain perception. The AQPs are potential drug targets for several neurological conditions. Astrocytoma cells strongly express AQP4, which may facilitate their infiltration into the brain, and the neuroinflammatory disease neuromyelitis optica is caused by AQP4-specific autoantibodies that produce complement-mediated astrocytic damage

Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.

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