A systemic myeloid-driven Th1 hyper-response characterizes inflammatory oral ulceration.

BACKGROUND

Inflammatory oral ulcers (RAS, Behçet's oral lesions) severely impair quality of life. Local Th1 cytokine upregulation has been reported, yet systemic Th1 polarization, myeloid mediators and clinical correlations remain undefined. While apremilast and anti-TNF-α biologics aid systemic Behçet manifestations, no agents target isolated oral ulcers specifically.

METHODS

Thirty-five ulcer patients (22 RAS, 8 Behçet's with sole oral lesions, 5 traumatic) and 30 matched healthy controls were enrolled. We performed plasma cytokine arrays, PBMC flow cytometry, HOK epithelial functional assays, and correlated Th1 markers with the validated Oral Ulcer Severity Score (OUSS). Longitudinal Th1 changes after topical steroids were assessed in an open-label pilot cohort of 18 patients.

RESULTS

Inflammatory ulcer patients showed a dominant systemic Th1 signature (elevated IFN-γ, TNF-α, IL-12; expanded T-bet+ CD4 + T cells), absent in traumatic ulcers and controls. Mild plasma IL-17 elevation lacked matching Th17 cell expansion or epithelial toxicity; Th2 markers were unaltered. Activated CD14 + monocytes drove IL-12 release. Combined IFN-γ/TNF-α synergistically damaged keratinocytes, while IL-4/IL-17 had no effect. T-bet + CD4 + T cells correlated with OUSS (r = 0.68, p < 0.0001), and IFN-γ correlated with ulcer size (r = 0.54, p < 0.01). Post-treatment OUSS dropped by 65%, accompanied by separate significant reductions in T-bet + cells (p < 0.05) and IFN-γ (p < 0.01). Limitations include small subgroups, no ulcer biopsy validation, and uncontrolled longitudinal data prone to spontaneous remission bias.

CONCLUSIONS

Myeloid-initiated systemic Th1 hyperactivity is a lineage-dominant feature of inflammatory oral ulcers, driving epithelial injury and correlating with severity. Though causal inference is constrained by study limitations, the Th1 pathway represents a rational target for precision therapy.