Neuromyelitis optica (NMO) is a severe human demyelinating disorder with predilection for the optic nerve and spinal cord. Approximately 70% of affected individuals demonstrate a serum autoantibody response, NMO-IgG, against the aquaporin-4 (AQP4) water channel. NMO-IgG binding to AQP4 in astrocytes in the central nervous system (CNS) is thought to initiate a series of inflammatory events, including complement- and cell-mediated astrocyte damage, leukocyte recruitment, cytokine release, and myelin damage. Using single- cell FACS and recombinant antibody technology, we have faithfully reconstructed the intrathecal humoral immune response in NMO and demonstrated that AQP4 autoantibodies are sufficient to initiate astrocyte injury and disease pathology. To further the care of patients with human demyelinating disease, we will use our novel resources and innovative approach to address fundamental gaps in our understanding of NMO pathogenesis: 1) Are there alternative targets of the immune response in NMO? 2) Does the nature of the AQP4 immune response correlate with disease severity? 3) What are the mechanisms driving astrocyte injury and myelin damage In NMO pathology? First, to identify novel targets of the autoimmune response in NMO, we will examine non-AQP4 specific NMO recombinant antibodies (rAbs) for binding to human and murine tissue, glial cell lines and primary glial cultures. A compendium of candidate rAbs will be generated from our existing antibody repertoires as well as new cases of AQP4 seronegative disease. Second, to investigate the association between NMO-IgG specificity and clinical disease activity, we will evaluate the relationship between two distinct patterns of AQP4 epitope specificity and the frequency and severity of clinical activity. We hypothesize that the spectrum of AQP4 epitope specificity in NMO-IgG will influence antibody effector function and CNS injury. And third, we will define the mechanisms underlying AQP4-mediated astrocyte injury and myelin damage using a combination of disease models, transgenic animals, and NMO CSF rAbs. Specifically, we will use mixed glial cultures, ex vivo spinal cord explants, and intracerebral injections to evaluate th effect of complement activation, antibody-dependent cell mediated cytotoxicity, excitotoxicity, cytokine release, and astrocyte metabolism on AQP4 antibody-mediated CNS injury. The detailed characterization of the humoral immune response in NMO will aid in the diagnosis and treatment of NMO, the identification of novel target antigens in human demyelinating disease, and the elucidation of the mechanisms causing glial and neuronal injury in CNS inflammatory disease.

Public Health Relevance

Neuromyelitis optica (NMO) is an incurable demyelinating disorder that frequently results in blindness or paralysis. While the majority of NMO patients demonstrate an autoantibody response against the aquaporin-4 water channel, the target of the immune response in a significant fraction of affected individuals remains unknown and mechanism of brain injury is uncertain. Understanding the pathogenesis of NMO will allow physicians to identify at-risk individuals, diagnose patients at the earliest stages of disease, an develop novel therapies for human demyelinating disorders, the most common cause of non-traumatic neurologic disability in young adults.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Mckie, George Ann
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University of Colorado Denver
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Liu, Yiting; Harlow, Danielle E; Given, Katherine S et al. (2016) Variable sensitivity to complement-dependent cytotoxicity in murine models of neuromyelitis optica. J Neuroinflammation 13:301
Weil, Marie-Theres; Möbius, Wiebke; Winkler, Anne et al. (2016) Loss of Myelin Basic Protein Function Triggers Myelin Breakdown in Models of Demyelinating Diseases. Cell Rep 16:314-22
Yan, Yaping; Li, Yujing; Fu, Ying et al. (2016) Autoantibody to MOG suggests two distinct clinical subtypes of NMOSD. Sci China Life Sci 59:1270-1281
Herwerth, Marina; Kalluri, Sudhakar Reddy; Srivastava, Rajneesh et al. (2016) In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica-related pathology. Ann Neurol :
Bennett, Jeffrey L (2016) Finding NMO: The Evolving Diagnostic Criteria of Neuromyelitis Optica. J Neuroophthalmol 36:238-45
Cree, Bruce Ac; Bennett, Jeffrey L; Sheehan, Mark et al. (2016) Placebo-controlled study in neuromyelitis optica-Ethical and design considerations. Mult Scler 22:862-72
Kremer, Stephane; Renard, Felix; Achard, Sophie et al. (2015) Use of Advanced Magnetic Resonance Imaging Techniques in Neuromyelitis Optica Spectrum Disorder. JAMA Neurol 72:815-22
Gilden, Don; White, Teresa; Khmeleva, Nelly et al. (2015) Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis. Neurology 84:1948-55
Bennett, J L; de Seze, J; Lana-Peixoto, M et al. (2015) Neuromyelitis optica and multiple sclerosis: Seeing differences through optical coherence tomography. Mult Scler 21:678-88
Blauth, Kevin; Soltys, John; Matschulat, Adeline et al. (2015) Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid cause demyelination of spinal cord explants. Acta Neuropathol 130:765-81

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