Humoral immune activation within tertiary lymphoid structures is correlated with poor outcomes in oral lichen planus and lichenoid lesions

Xiaojie Yang¹Annan Dai¹Yirao Lai¹Pan Lei¹Yiwen Deng¹Xuemin Shen¹Xiaozhe Han²Lei Sun³Yufeng Wang^1*Guoyao Tang^1,4*

• ¹Department of Oral Medicine, Shanghai 9th people's hospital, Shanghai, China
• ²Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, United States
• ³Institue of Developmental Biology and Molecular Medicine, Fudan University, Shanghai, China
• ⁴Department of Stomatology, Shanghai Jiaotong University School of Medicine Xinhua Hospital, Shanghai, China

Background: Oral lichen planus (OLP) and oral lichenoid lesions (OLL) are chronic immune-mediated mucosal disorders with heterogeneous clinical presentations. While T cell-mediated mechanisms have been extensively studied, the role of humoral immunity, particularly B cell activation and plasma cell differentiation, remains insufficiently understood. Methods: RNA sequencing datasets from healthy oral mucosa and OLP lesions were integrated and analyzed to identify differentially expressed genes. Consensus clustering based on a validated tertiary lymphoid structure (TLS) signature genes (TSGs) was used to define immune subtypes. Associations with clinical severity and recurrence were validated in an independent RNA-seq cohort. Immunohistochemistry analysis of CD20+ B cells and CD38+ plasma cells was conducted in a separate clinical cohort of OLP/OLL patients. Results: Based on TSGs, two immune subtypes were identified: Subtype A was enriched for CCL3, IL2RA, and IL1R2. Subtype B exhibited elevated expression of humoral activation markers IRF4 and TNFRSF17 and enrichment of B cell-related pathways. Transcriptomic features of Subtype B were significantly associated with erosive and recurrent OLP cases. Immunohistochemistry confirmed that CD20+ B cells were enriched in TLS-like structures (P < 0.001), whereas CD38+ plasma cells were closely linked to erosive phenotypes (P = 0.038). Conclusions: TLS-associated B cell maturation and plasma cell infiltration define a humoral activation axis linked to unfavorable clinical outcomes in OLP/OLL. The presence of activated B cells and plasma cells correlates with erosive and recurrent disease phenotypes, highlighting their potential as prognostic biomarkers and therapeutic targets for improving disease management.