REVIEW article
Front. Immunol.
Sec. Immunological Tolerance and Regulation
Breach and Restoration of Retinal Immune Privilege: Barrier Failure, Innate Dysregulation, and Adaptive Autoimmunity
Provisionally accepted
Qiwei Fan1,2,3,4
Zhijie Li3,4*- 1Department of Ophthalmology, Zhongshan Torch Development Zone People's Hospital, Zhongshan, Zhongshan, Guangdong, China
- 2Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China, China
- 3International Ocular Surface Research Center, Institute of Ophthalmology, and Key Laboratory for Regenerative Medicine, Jinan University, Guangzhou, Guangdong Province, China, China
- 4Jinan University Medical School, Guangzhou, Guangdong Province, China, China
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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.
Keywords: Immune Privilege, Blood retinal barrier, Microglia, complement, Inflammasome, Th17/T cells, age-related macular degeneration, Diabetic Retinopathy
Received: 11 Sep 2025; Accepted: 10 Nov 2025.
Copyright: © 2025 Fan and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Zhijie Li, tzhijieli@jnu.edu.cn
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