# Regulation of B cell function in demyelinating disease by N-glycan branching

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $500,503

## Abstract

Abstract
 Our published work has revealed that deficiencies in Asn (N)-linked protein glycosylation
reduce inflammatory demyelination in mice and are associated with Multiple Sclerosis (MS). Deficiency
in the branching of N-glycan's attached to proteins, either induced experimentally in mice or via natural genetic
variation in humans, promotes T-cell mediated inflammatory demyelination and neurodegeneration. For
example, branching deficiency induces a spontaneous and slowly progressive MS-like disease in PL/J mice,
characterized by inflammatory demyelination, axonal damage and neuronal death. Mechanistically, the
branching and number of N-glycans per protein molecule cooperate to regulate binding to galectins, a 14-
member family of sugar binding proteins. Galectin binding to cell surface glycoproteins, via their attached N-
glycans, forms a macro-molecular lattice at the cell surface that controls the distribution, clustering and
endocytosis of surface glycoproteins in a coordinated and predictable manner. N-glycan branching markedly
inhibits T cell activity in mice and humans by reducing T cell receptor clustering/signaling at the immune
synapse, promoting surface retention of the growth inhibitor CTLA-4 and inhibiting differentiation into pro-
inflammatory TH1 and TH17 cells while promoting anti-inflammatory iTreg and TH2 cell differentiation. Although
these T cell phenotypes are important regulators of inflammatory demyelination, it has become increasing clear
that B cells also play a critical role in MS. This is best exemplified by the potent activity of B cell depleting
therapies in MS, such as the anti-CD20 monoclonal antibody ocrelizumab. B cells are unique in the immune
system by having both innate and adaptive immune activity; the former exemplified by activation via Toll-like
receptors (TLR) and antigen-presenting cell (APC) functions that trigger T cell responses. The mechanism of
action of ocrelizumab appears to primarily result from reduced innate immune activity rather than altering
antibody production, as ocrelizumab reduces T cell number but not antibody or plasma cell levels in the
cerebral spinal fluid of treated MS patients. Here we test the hypothesis that N-glycan branching serves as
a critical negative regulator of pro-inflammatory innate immune activity in B cells to suppress pro-
inflammatory T cell responses and inflammatory demyelination. To evaluate this hypothesis, the following
Aims are proposed. Aim 1 examines regulation of TLR4 and TLR2 responses by N-glycan branching in B cells.
Aim 2 examines regulation of B cell receptor signaling by N-glycan branching. Aim 3 examines whether N-
glycan branching in B cells suppresses inflammatory demyelination. Positive results will identify N-glycan
branching as a major contributor to B cell mediated regulation of inflammatory demyelination and has
implications for understanding the mechanism of action of B cell depleting therapies in MS.

## Key facts

- **NIH application ID:** 10075227
- **Project number:** 5R01AI144403-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Michael Demetriou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $500,503
- **Award type:** 5
- **Project period:** 2019-01-14 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075227

## Citation

> US National Institutes of Health, RePORTER application 10075227, Regulation of B cell function in demyelinating disease by N-glycan branching (5R01AI144403-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10075227. Licensed CC0.

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