# Myelin Autoantigens in Neuropathic Pain

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $719,586

## Abstract

We propose that pathological pain from innocuous mechanical stimulation such as light touch or slight air
movement (defined as mechanical allodynia) represents an autoimmune disorder in females. This conceptually
new view of this refractory chronic pain phenotype is the overarching thesis of our renewal application. Recent
seminal work implicates adaptive immune/T cells and innate immune system/microglia in the development of
mechanical allodynia in female and male rodents, respectively. However, the mechanisms of this sexual
dimorphism phenomenon are obscure. Our groundbreaking data suggests that a known auto-antigen, myelin
basic protein (MBP), holds the mechanistic key to sexual dimorphism in mechanical allodynia. We suggest that
any, including physical, damage to myelin sheath on mechanosensitive Aβ-afferent fibers results in proteolytic
liberation of cryptic MBP peptides normally sheltered from immunosurveillance. The peptide encoding the
central (84-104) region of MBP (MBP84-104) produces direct, robust and lasting hypersensitivity to light touch (Aβ
fiber-mediated) but not thermal (C fiber-mediated) stimulation. The conserved histidine (H)-89 site is required to
intracellular transport and the algesic activity of MBP84-104. Using biochemical and molecular tools, including
mass-spectrometry, RNA-sequencing, bioinformatics, structural modeling, and immunocapture of wildtype,
mutant and control peptides, combined with rigorous pharmacological, neuropathological, and behavioral
analyses, we identified a cluster of the MBP84-104 interactors and downstream signaling factors promoting in
females (and/or protecting males from) the development of allodynia. These MBP84-104-related leads with the
established roles in pain circuitry, such as the X-chromosome imprinted gene interleukin 6, are here linked to a
master-regulator of lipid, immune and estrogen receptor signaling pathways, liver X receptor, which is new to
the pain field. With our unique, accrued toolset and rigorous data obtained in a prolific collaboration among the
teams of the PI, Veronica Shubayev (UCSD) with Tony Yaksh (UCSD) and Alex Strongin (SBP), we aim to
identify the precise molecular events in nerve, dorsal root ganglia and spinal cord leading to the sexual
dimorphism in neuropathic pain. We expect our innovative findings will foster the development of conceptually
novel analgesic therapeutics useful in refractory types of chronic pain.

## Key facts

- **NIH application ID:** 9996561
- **Project number:** 5R01DE022757-08
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** VERONICA SHUBAYEV
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $719,586
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996561

## Citation

> US National Institutes of Health, RePORTER application 9996561, Myelin Autoantigens in Neuropathic Pain (5R01DE022757-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9996561. Licensed CC0.

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