Distinct Immunological Features Compared to Lichen Planus and Oral Lichen Planus

Dong Min Lim,1 DoYeon Kim,2 Hye-Min Ju,3,4 Sung-Hee Jeong,3,4 Yun Hak Kim,5– 7 Soo-Min Ok,3,4 Hae Ryoun Park2,5,8 1Interdisciplinary Program of Genomic Data Science, Pusan National University, Yangsan, 50612, Republic of Korea; 2Department of Oral Pathology, School of Dentistry, Pusan National University, Yangsan, 50612, Republic of Korea; 3Department of Oral Medicine, Dental and Life Science Institute, Pusan National University School of Dentistry, Yangsan, 50612, Republic of Korea; 4Department of Oral Medicine, Dental Research Institute, Pusan National University Dental Hospital, Yangsan, 50612, Republic of Korea; 5Periodontal Disease Signaling Network Research Center, School of Dentistry, Pusan National University, Yangsan, 50612, Republic of Korea; 6Department of Anatomy, School of Medicine, Pusan National University, Yangsan, 50612, Republic of Korea; 7Department of Biomedical Informatics, School of Medicine, Pusan National University, Yangsan, 50612, Republic of Korea; 8Department of Periodontology and Dental Research Institute, Pusan National University Dental Hospital, Yangsan, 50612, Republic of KoreaCorrespondence: Soo-Min Ok, Department of Oral Medicine, School of Dentistry, Pusan National University, 49 Pusandaehag-ro, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, 50612, Republic of Korea, Tel +82-55-360-5243, Fax +82-55-360-5234, Email [email protected] Hae Ryoun Park, Department of Oral Pathology, School of Dentistry, Pusan National University, 49 Busandaehak-ro, Yangsan, 50612, Republic of Korea, Tel +82-51-510-8250, Fax +82-51-510-8249, Email [email protected]: Lichen planus (LP) and oral lichen planus (OLP) share clinical and histological similarities, yet their distinct immunopathological mechanisms make differentiation and management challenging. Clarifying these differences is essential for accurate diagnosis and treatment. This study aimed to investigate the systemic immune profile of OLP using single-cell transcriptomics, identifying distinct immune cell subsets and signaling pathways contributing to its chronic inflammatory state. Additionally, it sought to compare the inflammatory lesion microenvironments of OLP and LP by analyzing key immune pathways and cellular interactions.Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from 16 OLP patients and 5 healthy controls. Single-cell transcriptomic data from PBMCs and lesion tissues of OLP and LP were analyzed to profile immune and inflammatory signatures. Key molecular findings were validated using independent datasets and enzyme-linked immunosorbent assays (ELISA).Results: Prostaglandin D2 synthase (PTGDS), a pivotal enzyme in prostaglandin metabolism, emerged as a diagnostic marker with elevated expression in NK cells from OLP patients. Additionally, a novel CXCR4high–TSC22D3high CD4 cytotoxic T cell subset with enhanced cytotoxicity was identified, potentially contributing to OLP pathogenesis. OLP blood samples also demonstrated significant upregulation of TNF and TLR signaling in NK cells, indicating a heightened chronic inflammatory state. Comparative tissue analysis revealed intensified TNF-driven inflammation and a disrupted HIF1A– vascular endothelial growth factor (VEGF) interactions in OLP, contrasting with LP’s robust VEGF-mediated angiogenesis.Discussion: These findings highlight distinct immunopathogenic mechanisms between OLP and LP. The upregulation of PTGDS in NK cells and CXCR4high–TSC22D3high CD4 cytotoxic T cells in PBMCs indicates systemic immune dysregulation in OLP, while tissue-level differences suggest impaired vascular remodeling and chronic inflammation. These insights underscore the need for targeted immunomodulatory therapies.Conclusion: This study identifies distinct immune signatures that differentiate OLP from LP, highlighting potential therapeutic targets that require further validation for personalized treatment strategies. Plain Language Summary: Lichen planus (LP) and oral lichen planus (OLP) are inflammatory conditions that affect the skin and mouth. Although they appear similar, our study shows that they are driven by different immune responses, which may require distinct treatment approaches. Understanding these differences can help doctors provide better care for each condition.In this study, we analyzed blood and tissue samples from people with OLP and compared them to samples from healthy individuals and those with LP. We used tissue samples from healthy individuals undergoing orthognathic surgery as a control group. By studying gene activity at the level of individual cells, we identified a protein called PTGDS that was elevated in OLP, especially in a type of immune cell known as natural killer (NK) cells. PTGDS could serve as a valuable marker for diagnosing OLP.We also discovered a unique group of immune cells in OLP that exhibited increased activity, possibly contributing to ongoing inflammation. Additionally, OLP and LP displayed distinct microenvironments, with OLP samples showing higher activity in certain inflammation-related pathways, suggesting a more chronic and persistent immune response compared to LP.These findings reveal important differences between LP and OLP, providing insights that may lead to more effective, targeted treatments for each condition. Understanding these unique immune responses may ultimately improve patient outcomes by guiding more personalized approaches to managing LP and OLP.Keywords: single-cell RNA sequencing, lichen planus, oral lichen planus, chronic inflammation, systemic immunity