Abstract
Objective: Skin inflammation heralds systemic disease in juvenile myositis, yet we lack an understanding of pathogenic mechanisms driving skin inflammation in this disease. We undertook this study to define cutaneous gene expression signatures in juvenile myositis and identify key genes and pathways that differentiate skin disease in juvenile myositis from childhood-onset systemic lupus erythematosus (SLE). Methods: We used formalin-fixed paraffin-embedded skin biopsy samples from 15 patients with juvenile myositis (9 lesional, 6 nonlesional), 5 patients with childhood-onset SLE, and 8 controls to perform transcriptomic analysis and identify significantly differentially expressed genes (DEGs; q ≤ 5%) between patient groups. We used Ingenuity Pathway Analysis (IPA) to highlight enriched biologic pathways and validated DEGs by immunohistochemistry and quantitative real-time polymerase chain reaction. Results: Comparison of lesional juvenile myositis to control samples revealed 221 DEGs, with the majority of up-regulated genes representing interferon (IFN)–stimulated genes. CXCL10, CXCL9, and IFI44L represented the top 3 DEGs (fold change 23.2, 13.3, and 13.0, respectively; q < 0.0001). IPA revealed IFN signaling as the top canonical pathway. When compared to childhood-onset SLE, lesional juvenile myositis skin shared a similar gene expression pattern, with only 28 unique DEGs, including FBLN2, CHKA, and SLURP1. Notably, patients with juvenile myositis who were positive for nuclear matrix protein 2 (NXP-2) autoantibodies exhibited the strongest IFN signature and also demonstrated the most extensive Mx-1 immunostaining, both in keratinocytes and perivascular regions. Conclusion: Lesional juvenile myositis skin demonstrates a striking IFN signature similar to that previously reported in juvenile myositis muscle and peripheral blood. Further investigation into the association of a higher IFN score with NXP-2 autoantibodies may provide insight into disease endotypes and pathogenesis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1062-1072 |
| Number of pages | 11 |
| Journal | Arthritis and Rheumatology |
| Volume | 73 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2021 |
Funding
We would like to thank the University of Michigan Advanced Genomics and Research Histology Core for their support and equipment for processing and sequencing of skin samples. We express our many thanks to the myositis and lupus patients for generously sharing their samples for our work. We also thank Matthew Manninen for his expertise in R programming and assistance with calculation of interferon scores, and Tammi Reed for assisting with the FFPE skin biopsy processing protocol. This work was presented in part at both the 2019 and 2020 American College of Rheumatology Annual Meetings.
ASJC Scopus subject areas
- Immunology and Allergy
- Rheumatology
- Immunology