Breach and restoration of retinal immune privilege: barrier failure, innate dysregulation, and adaptive autoimmunity

The retina preserves vision by tightly regulating inflammation ("immune privilege") via blood-retinal barriers, neuroglial checkpoints, and tolerogenic cues. This actively maintained-and potentially restorable-state is breached in major retinal diseases through three recurrent archetypes. We synthesize 2015-2025 advances into a framework of barrier failure, innate dysregulation, and adaptive autoimmunity. Across age-related macular degeneration (AMD), diabetic retinopathy (DR), retinitis pigmentosa (RP), and non-infectious uveitis (NIU): AMD exhibits complement-microglia para-inflammation with later outer-barrier compromise; DR exemplifies inner-BRB failure with inflammatory amplification; RP begins with degeneration-triggered innate activation and progresses to combined innate-adaptive injury; NIU represents T-cell-driven breach of the blood-retinal barrier. Interventional human evidence supports immunity as a therapeutic target: complement inhibition slows geographic atrophy; anti-VEGF reduces leak; intravitreal corticosteroids suppress inflammatory edema; and anti-TNF/IL-6R improve refractory NIU. Emerging strategies aim at privilege restoration-reinforcing myeloid checkpoints, tempering inflammasomes, and exploring tolerance-oriented approaches to re-educate adaptive immunity. Evidence from preclinical and early translational studies indicates that ocular tissues can imprint regulatory/anergic programs on pathogenic T cells, supporting mechanism-aligned, patient-tailored immunotherapy as a testable route to restore regulation, mitigate inflammation, and slow degeneration.