# Collagen XVII unmasking in Parkinson's disease and scratching

> **NIH NIH R21** · RUSH UNIVERSITY MEDICAL CENTER · 2021 · $249,750

## Abstract

PROJECT SUMMARY
Bullous pemphigoid (BP) is an autoimmune disease that results in the development of severe itch and blisters.
It is the most common form of autoimmune blistering disease and is overrepresented in the elderly. Treatment
for bullous pemphigoid relies on the use of immunosuppression, which given the high prevalence of medical
comorbidities in this group, results in one-year mortality rates ranging from 13% to 27%. Bullous pemphigoid is
caused by the development of antibodies against collagen XVII leading to blister formation and the
development of inflammation. Loss of self-tolerance to collagen XVII, especially in the aging immune system, is
thought to lead to development of BP. Parkinson's disease and pre-existing pruritus both independently
impose strong predisposition towards the development of bullous pemphigoid, likely through autoinoculation
with collagen XVII. Understanding the mechanism of collagen XVII autoinoculation not only provides insight
into the pathogenesis of bullous pemphigoid, but offers significant insight into the immune response in
Parkinson's disease. We propose two discrete hypotheses, 1) that scratching induced skin barrier damage or
2) neuroinflammation seen in Parkinson's disease are sufficient to autoinoculate collagen XVII in a tolerant with
minimal T-cell tolerance. To test this hypothesis, we propose utilizing a novel animal model. We have used
CRISPR-Cas9 to develop a mouse expressing a LoxP-PolyA-LoxP sequence upstream of exon 18, the coding
region of the NC15a domain of collagen XVII. This domain corresponds with the human NC16a domain, which
serves as the principle autoantigen in BP. When crossed to a tamoxifen inducible Cre-Lox mouse model,
restoration of collagen XVII expression occurs in early adulthood, bypassing T-cell tolerance once unmasked.
With inflammation and antigen unmasking through scratching or experimentally induced Parkinson's disease,
we anticipate development of antigen-specific CD4+ T-cells and autoantibodies against collagen XVII. Two
specific aims are proposed: 1) Determine the impact of scratching behaviors on the development of anti-
collagen XVII autoantibodies, antigen-specific CD4+ T-cells, and the development of BP. 2) Determine the
effect of neuroinflammation in experimental Parkinsonism in inducing cutaneous autoimmunity against collagen
XVII. This project will provide significant insight into both the role of scratching and neuroinflammation in
antigen unmasking. This proposal is likely to have strong translational potential across several disease
processes and organ systems. Our novel approach provides a valuable tool for studying the immune response
in Parkinson's disease, as well as for studying other autoimmune diseases with well-characterized
autoantigens.

## Key facts

- **NIH application ID:** 10303975
- **Project number:** 1R21OD030057-01A1
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Kyle T. Amber
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $249,750
- **Award type:** 1
- **Project period:** 2021-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10303975

## Citation

> US National Institutes of Health, RePORTER application 10303975, Collagen XVII unmasking in Parkinson's disease and scratching (1R21OD030057-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10303975. Licensed CC0.

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