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)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Mckie, George Ann
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
Schools of Medicine
United States
Zip Code
Mader, Simone; Brimberg, Lior; Soltys, John N et al. (2018) Mutations of Recombinant Aquaporin-4 Antibody in the Fc Domain Can Impair Complement-Dependent Cellular Cytotoxicity and Transplacental Transport. Front Immunol 9:1599
Liu, Yiting; Given, Katherine S; Owens, Gregory P et al. (2018) Distinct patterns of glia repair and remyelination in antibody-mediated demyelination models of multiple sclerosis and neuromyelitis optica. Glia 66:2575-2588
Shimizu, Fumitaka; Schaller, Kristin L; Owens, Gregory P et al. (2017) Glucose-regulated protein 78 autoantibody associates with blood-brain barrier disruption in neuromyelitis optica. Sci Transl Med 9:
Soltys, John N; Meyer, Stephanie A; Schumann, Hannah et al. (2017) Determining the Spatial Relationship of Membrane-Bound Aquaporin-4 Autoantibodies by STED Nanoscopy. Biophys J 112:1692-1702
Vogel, Anna-Lena; Knier, Benjamin; Lammens, Katja et al. (2017) Deletional tolerance prevents AQP4-directed autoimmunity in mice. Eur J Immunol 47:458-469
Liu, Yiting; Given, Katherine S; Harlow, Danielle E et al. (2017) Myelin-specific multiple sclerosis antibodies cause complement-dependent oligodendrocyte loss and demyelination. Acta Neuropathol Commun 5:25
Alberga, Domenico; Trisciuzzi, Daniela; Lattanzi, Gianluca et al. (2017) Comparative molecular dynamics study of neuromyelitis optica-immunoglobulin G binding to aquaporin-4 extracellular domains. Biochim Biophys Acta Biomembr 1859:1326-1334
Bennett, Jeffrey L; Owens, Gregory P (2017) Neuromyelitis Optica: Deciphering a Complex Immune-Mediated Astrocytopathy. J Neuroophthalmol 37:291-299
Kowarik, Markus C; Astling, David; Gasperi, Christiane et al. (2017) CNS Aquaporin-4-specific B cells connect with multiple B-cell compartments in neuromyelitis optica spectrum disorder. Ann Clin Transl Neurol 4:369-380
Peschl, Patrick; Schanda, Kathrin; Zeka, Bleranda et al. (2017) Human antibodies against the myelin oligodendrocyte glycoprotein can cause complement-dependent demyelination. J Neuroinflammation 14:208

Showing the most recent 10 out of 49 publications