Cellular Immunology and Innate/Adaptive Signals of Idiopathic Orbital Inflammation: A Systematic Review of Immunohistochemistry and Flow Cytometry Studies

PURPOSE: To review immunological studies in idiopathic orbital inflammation (IOI) to characterize immune cells, mediators and pathways to strengthen diagnostic evaluation, and identify priorities for future research. METHODS: We searched 13 literature databases on October 22, 2025. Eligible studies performed flowcytometric or immunohistochemical analyses on immune cells, mediators, or pathways in IOI. Studies were reviewed qualitatively across several themes: cellular composition of B- and T-cells, T-cell subsets, B-cells, plasma cells, immunoglobulin subclasses (IgG2, IgG4), mast cells, fibrocytes, mononuclear phagocytes, antigen-presenting cells, toll-like receptors, cytokines, chemokines, and clinical correlates of immune profiles and disease severity. RESULTS: plasma cell counts and low IgG4/IgG ratio. Overall risk of bias was moderate across studies. CONCLUSION: IOI emerges as an integrated innate-adaptive immune process. Polyclonal κ/λ and low IgG4/IgG ratios distinguish IOI from orbital lymphoma and IgG4-related ophthalmic disease. Our findings highlight TNF-α, IL-12, IL-6, and CD40-CD154 as present and future treatment modalities.