# Humoral Immunity, Astrocyte Injury, and Demyelination in Neuromyelitis Optica

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $377,087

## Abstract

Project Summary
 Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disorder targeted against the
aquaporin-4 (AQP4) water channel. Central nervous system (CNS) injury in NMOSD is initiated by the binding
of AQP4 autoantibodies (AQP4-IgG) to target astrocytes and the activation of antibody effector functions;
however, serum AQP4-IgG titers do not correlate with disease relapse or severity. Therefore, identifying
factors that influence CNS access, intrathecal production, or effector function of AQP4-IgG is essential for
understanding NMOSD pathognesis. Using single-cell sorting, recombinant antibody technology, and
heavy-chain variable region repertoire analysis, we have reconstructed the intrathecal AQP4-IgG
response in NMOSD, isolated anti-endothelial antibodies that activate brain microvascular endothelial
cells (BMECs), and identified an expanded CD27-IgD- double negative (DN) memory B cell population
clonally related to intrathecal AQP4-specific plasmablasts. We are now uniquely prepared to test our
hypothesis that AQP4-IgG, autoantibodies against BMECs, and pro-inflammatory DN B cells act in
concert to propel NMOSD activity and pathology.
 In Aim 1, we will examine the contribution of glucose regulated protein-78 (GRP78) autoantibodies to
NMOSD disease activity. We will investigate the abundance and epitope specificity of NMOSD anti-GRP78
autoantibodies, evaluate the cell signaling pathways activated in BMECs, and measure their ability to increase
vascular permeability in the brain and retina. In Aim 2, we will address how the binding specificity of individual
anti-AQP4 autoantibodies affect lesion formation and CNS injury in NMOSD. We have identified multiple
species of patient-derived AQP4-specific recombinant antibodies that produce distinct effects on target
astrocytes. We will gauge AQP4 rAbs on their ability to activate complement dependent cytotoxicity, initiate
antibody-dependent cell-mediated cytotoxicity, and modulate astrocyte chemokine and cytokine production in
vitro. We will then evaluate how these parameters affect NMOSD lesion formation in animal models and
disease activity in affected patients. And in Aim 3, we will analyze an expanded population of class-switched
CD27-IgD- DN B cells in NMOSD patients and investigate their role in disease activity. The abundance and
immunoglobulin repertoire of DN B cells will be compared during NMOSD relapse and remission, and we will
assess the cytokine response and immunoglobulin production of NMOSD DN B cells in response to various
stimuli. In addition, we will investigate the potential for NMOSD DN B cells to present AQP4 to autologous T
cells. The results of these investigations will elucidate how AQP4-IgG accesses the CNS, how intrathecal B
cells contribute to NMO lesion initiation, and how discrete subpopulations of AQP4-IgG contribute to CNS
injury. The outcomes of our research will remove barriers to progress in the field and advance approaches to
the diagnosis ...

## Key facts

- **NIH application ID:** 10132323
- **Project number:** 5R01EY022936-09
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Jeffrey L Bennett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $377,087
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132323

## Citation

> US National Institutes of Health, RePORTER application 10132323, Humoral Immunity, Astrocyte Injury, and Demyelination in Neuromyelitis Optica (5R01EY022936-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10132323. Licensed CC0.

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