Collagen XVII unmasking in Parkinson's disease and scratching

点击翻译按钮获取中文摘要

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.