Cellular Immunology and Innate/Adaptive Signals of Idiopathic Orbital Inflammation: A Systematic Review of...

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.

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.

Twenty-five studies were included (910 participants, 511 with IOI, 109 healthy controls and 290 other orbital disease comparators). IOI tissue showed mixed, polyclonal lymphoid infiltrates, typically T-cell enriched. Innate and stromal components were implicated with mast cell accumulation and TLR-2/3/4 expression. Cytokine profiling of the lesions indicated a Th1-polarized milieu, with elevated IFN-γ, IL-12, TNF-α, IL-10, and IL-8. Peripheral blood demonstrated reduced plasmacytoid dendritic cells and type 2 conventional dendritic cells, but increased CD40+ fibrocytes with IL-6 release upon ligation. Regulatory T-cells were increased, but functionally impaired and plastic by a Th17-like phenotype in blood and Th2-like phenotype in the orbit. IOI lesions had low IgG4⁺ plasma cell counts and low IgG4/IgG ratio. Overall risk of bias was moderate across studies.

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.