# Contribution of antibodies targeting PLP1-anchored membrane domains to multiple sclerosis pathogenesis

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $405,282

## Abstract

Project Summary
A role for B-cells in multiple sclerosis (MS) pathogenesis has been implicated by clinical, histopathologic and
immunologic studies. The precise role they play in pathology is debated and impact could be mediated through
antibody (Ab) production, secretion of pro-inflammatory cytokines, or antigen presentation to T cells. To study
Abs produced by MS CSF B cell clones, we developed protocols to produce recombinant antibodies that
duplicate the fidelity of CD138+ plasmablast clones expanded in the CSF compartment of early active MS
patients. We identified a subset of antibodies that bound to myelin and induced complement-mediated
oligodendrocyte cell death and demyelination in vivo. These lesions spontanelusly repair and have guided
independent studies to investigate the role of microlgia in remyelination. Myelin-specific MS rAbs bind to
membrane lipid complexes anchored by the myelin protelopid 1 protein (PLP1) that is enhanced by sulfatide and
cholesterol. We have further identified a new pathogenic MS rAb that binds myelin complexes independent of
PLP1, but still causes extensive oligodendrocyte loss and CNS demyelination. A semi-quantitiative CSF binding
assay employing PLP1 protein, myelin glcyolipids and choleserol have identified antibodies to PLP1 complexes
in approximately 60% of MS patients but not in inflammatory and neurologic disease control CSF. Hence, we
hypothesize that pathogenic myelin-specific MS rAbs encompass an array of epitope specificities targeting
PLP1 protein, myelin glycolipids and PLP1 binding partners. We further suppose that antibodies to this complex
contribute to type II MS lesions and represent a measurable and specific disease relevant response that can be
quantified in patient CSF and serum. To test our hypothesis, we propose three complementary specific aims. In
Aim 1, we will employ our quantitative PLP1 Ab binding assay to screen biobanked serum and CSF samples
collected from clinically isolated syndrome (CIS) patients, relapsing MS patients, progressive MS patients, and
healthy and inflammatory controls to determine the prevalence of PLP1 Abs across the MS disease spectrum
and to correlate positive binding and titer to clinical correlates of disease activity. Aim 2 will evaluate the
distribution of PLP1 myelin complex pathology in human MS lesions and determine association between
identification of PLP1 complex antibodies from plaques and types of MS lesion histopathology. Lastly in Aim 3
we will identify and confirm the epitopic targets of MS rAbs through a combinantion of immunochemistry and
studies in gene-targeted transgenic knockout mice. We will utilize our established models to independently
evaluate the contributions of PLP1 and glycolipids to CNS demyelination and to develop improved
immunoassays reflecting the complexity of antigen recognition. Together, our results will establish the role of
complex PLP1 antibodies in disease pathogensis and should lead to improved bioassays for dis...

## Key facts

- **NIH application ID:** 10981025
- **Project number:** 1R01NS130100-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Jeffrey L Bennett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $405,282
- **Award type:** 1
- **Project period:** 2024-09-05 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981025

## Citation

> US National Institutes of Health, RePORTER application 10981025, Contribution of antibodies targeting PLP1-anchored membrane domains to multiple sclerosis pathogenesis (1R01NS130100-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10981025. Licensed CC0.

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