Hyperactivity of B Cells and Cytotoxic T Cells Implicated in Female Pattern Hair Loss: Insights from a Paired Transcriptomic Study

Summary: Female pattern hair loss (FPHL) is a common, progressive condition rarely linked to immune dysregulation, with its transcriptomic profile remaining poorly understood. 10 paired punch biopsies from the vertex and occipital scalp were collected from patients with Sinclair grade 3 or above FPHL. Each biopsy was bisected for pathological examination and transcriptomic analysis. Differential gene expression analysis was followed by over-representation analysis and gene set enrichment analysis (GSEA). WGCNA was conducted for gene module identification and trait-module correlation. Cellular composition was evaluated with CIBERSORT, and immune repertoire was assessed using TRUST4 and Immunarch. 62 upregulated and 17 downregulated genes were identified in the affected vertex scalp compared to the unaffected. Upregulated genes were enriched in Gene Ontology (GO) terms including "immunoglobulin mediated immune response", "B cell-mediated immunity", and "B cell receptor signaling pathway". We extended our analysis using MSigDB and GSEA method to mitigate potential biases caused by thresholding criteria. GSEA also highlighted similar immune-related terms, including "B cell-mediated immunity" and "immunoglobulin-mediated response". C5 gene sets included "immunoglobulin complex" and "antigen binding", while Hallmark gene sets showed enrichment in "IFN-α/γ response" and "TNF-α signaling". 43 modules were identified using WGCNA, with modules labeled by different colors. Correlation analysis between module eigengenes and clinical traits (including hair density [HD], hair calibre [HC], hair follicle units with single hair [HFUwSH], ratio of vellus and intermediate hairs [R.VH.IH]) was conducted. Among all identified modules, only the coral1 module held a correlation coefficients ＞0.3 with statistical significance. Gene set enrichment analysis on the coral1 module identified significant enrichment in “immune response-regulating signaling pathway”, "immune response-regulating cell surface receptor signaling pathway", and "T cell activation". CIBERSORT analysis indicated a higher abundance of B cells in the vertex scalp (P = 0.0273). Notably, CD8+ T cell infiltration was also elevated in the vertex scalp, while Tregs were reduced (P = 0.0346 and 0.0472 respectively). After TRUST4 reconstruction, Immune repertoire analysis showed significantly higher richness and diversity (Chao1, true diversity, and D50 diversity index) in the vertex. Taken together, this study revealed immune-related transcriptomic changes in FPHL, with increased B cell/CD8+ T cell infiltration and associated immune-related pathways activation in the vertex scalp as key characteristics. Heightened inflammatory response was also closely related to impaired trichology parameters. Findings suggest a potential role of immune modulation in FPHL pathogenesis, offering insights that may inform future therapeutic strategies.