Sezen Karakus, M.D., is a clinician scientist and cornea specialist at the Johns Hopkins Wilmer Eye Institute, with a focus on ocular surface inflammation and corneal nerves.
The ocular surface, which includes the cornea, conjunctiva, and tear film, is a dynamic microenvironment that interacts closely with the immune system. Constantly exposed to environmental factors like allergens, microorganisms, and pollutants, the immune system of the ocular surface plays a vital role in maintaining ocular health by defending against pathogens and preventing excessive inflammation. Unravelling the complexities of ocular surface immunology is paving the way for revolutionary advancements in ocular health and disease management.
At the forefront of this defence system lies the tear film, a complex mixture of growth factors, antimicrobial peptides, antibodies (immunoglobulin [Ig] A, IgG), vitamins, and cytokines that shields the ocular surface from external threats and promotes homeostasis.1 Additionally, the conjunctiva houses specialized immune structures known as conjunctiva-associated lymphoid tissue (CALT) beneath the lamina propria, which play a vital role in immune surveillance and response.2 Autonomic and sensory nerves at the ocular surface interact with immune cells and release neuropeptides that promote or suppress immune activation.3
Research in ocular surface immunology has provided valuable insights into the immune mechanisms operating in this delicate ecosystem. Studies have shown that various immune cells, such as dendritic cells, T cells, and B cells, populate the ocular surface and contribute to immune defence and regulation.4 Furthermore, cytokines and chemokines in the tear film orchestrate the immune response, promoting inflammation when necessary and resolving it afterward.4,5
Neural Regulation of Ocular Surface Immunity
Corneal and conjunctival sensory nerves have been implicated in modulation of immune responses in the ocular surface.1,3,4 Damage to these sensory nerves can lead to altered tear film dynamics, impaired corneal sensitivity, and dysregulation of neuroimmunological pathways, which can contribute to the development of dry eye disease, ocular surface inflammation, corneal neuropathic pain, and neurotrophic keratitis.6-8 Loss of corneal sensation will not only negatively impact the blink reflex and tear production but also result in reduced expression of neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP), which are essential in regulating both the innate and adaptive immune responses within the ocular surface.9,10 Neuropeptides, along with neurotrophins released by the nerves, support corneal epithelium renewal.11,12 Studies have highlighted the involvement of sensory nerves in the pathophysiology of ocular surface diseases, providing insights into potential therapeutic targets for managing these conditions.7-12
Several immune-mediated disorders can disrupt the delicate equilibrium of the ocular surface. Allergic conjunctivitis, atopic and vernal keratoconjunctivitis, are characterized by abnormal immune responses to environmental allergens, leading to inflammation and symptoms such as itching, redness, and eye swelling. In allergic conjunctivitis, IgE-mediated immune responses trigger the release of histamine and other inflammatory mediators, resulting in ocular discomfort. Atopic keratoconjunctivitis involves a complex interplay of immune cells and cytokines, with T-helper 2 (Th2) cells playing a crucial role. Vernal keratoconjunctivitis, primarily affecting children, is characterized by intense inflammation involving eosinophils and mast cells. Antihistamines, mast cell stabilizers, and targeted immunomodulatory therapies, such as topical corticosteroids and calcineurin inhibitors, are often employed to alleviate symptoms and improve the quality of life for affected individuals.13
Dry Eye Disease
Dry eye, another prevalent condition, results from an imbalance in tear production, composition, and evaporation, leading to ocular discomfort and visual disturbances. It is well established that in dry eye disease, there is a continuous attack by the innate and adaptive immune systems on the corneal and conjunctival epithelium, as well as goblet cells, sensory nerves, and lacrimal glands.14-16 Dysregulation of immune responses, including alterations in the cytokine profile and infiltration of immune cells, contributes to the pathogenesis of dry eye disease. The initiating event may not be identified, as multiple factors usually contribute to the vicious cycle of inflammation in dry eye from different entry points.14-16
Autoimmune diseases affecting the ocular surface, such as Sjögren’s disease, systemic lupus erythematosus, and rheumatoid arthritis, pose significant challenges due to their complex immunopathogenesis. Aberrant activation of the immune response against self-antigens leads to the destruction of lacrimal glands and epithelial cells, resulting in reduced tear production and subsequent ocular surface damage. The immune response involves lymphocyte infiltration, production of pro-inflammatory cytokines, and disruption of the delicate balance of the ocular surface.16 Similarly, ocular graft-versus-host disease (GvHD), a complication following hematopoietic stem cell transplantation, occurs when immune cells from the graft attack the ocular surface tissues.17
Research into Ocular Surface Immunology
In recent years, significant strides have been made in ocular surface immunology research, offering promising avenues for clinical intervention. Biomarkers that reflect specific immunological processes can aid in early diagnosis, monitoring of disease progression, and predicting the response to treatment. For instance, measuring tear cytokine levels or specific immune cell populations can provide valuable insights into the immunological status of the ocular surface. Topical immunosuppressive or immunomodulatory medications, including corticosteroids, calcineurin inhibitors, such as cyclosporine and tacrolimus, and lymphocyte function-associated antigen 1 (LFA-1)/ intercellular adhesion molecule 1 (ICAM-1) antagonists, such as lifitegrast, have shown efficacy in suppressing inflammation and improving ocular surface health, aiming to regulate the immune response, mitigating inflammation, and restoring ocular surface homeostasis.18
Furthermore, the transplantation of ocular surface tissues presents unique challenges that demand insights from ocular surface immunology. Procedures such as corneal and limbal stem cell transplantation require meticulous consideration of immune responses to ensure graft survival. Immunosuppressive medications, such as corticosteroids and calcineurin inhibitors, are commonly employed to prevent graft rejection and enhance the success rates of these procedures.19
As our understanding of ocular surface immunology expands, so will the potential for innovative interventions. Ongoing research endeavours to focus on unravelling the intricacies of immune tolerance mechanisms, immune cell trafficking, and the impact of the microbiome on ocular surface health. This knowledge will undoubtedly shape future strategies for disease prevention, personalized medicine, and novel therapeutic targets.
The rapid progress in ocular surface immunology has opened up exciting avenues for future breakthroughs. These include:
Ocular Surface Regeneration
Advancements in regenerative medicine offer promising prospects for the treatment of ocular surface disorders, encompassing various approaches such as cell-based therapies, extracellular matrix-based therapies such as amniotic membrane, growth-factor-based therapies, and tissue-engineering techniques.20,21 Autologous serum eye drops consist of growth factors, proteins, vitamins, and anti-inflammatory cytokines, and have been used to treat Sjögren’s or non-Sjögren’s inflammatory dry eye, ocular GvHD, and neurotrophic keratitis.22 Recently, a topical recombinant human nerve growth factor (cenegermin) has received FDA approval as a treatment for neurotrophic keratitis. Cenegermin has demonstrated the ability to regenerate corneal nerves and ocular surface epithelium, leading to the restoration of visual function.23,24 Studies applying strategies to reconstruct or bioengineer lacrimal glands are also underway.25,26 Combining these regenerative approaches with immune modulation holds great potential for pioneering treatments in the near future.
Microbiome and Ocular Surface
Exploring the ocular surface microbiome, consisting of diverse microbial communities, offers fresh insights into the interplay between ocular health and the immune system. Recent studies have highlighted the role of the microbiome in modulating immune responses and ocular health.27,28 Understanding the microbiome’s influence on ocular surface immunology could lead to innovative probiotic and prebiotic-based therapies. By delving into the intricate language and communication processes between microorganisms and deciphering their functionality through whole genome sequencing, we can unlock novel insights into the pathogenesis of various ocular surface diseases.
The era of personalized medicine presents immense opportunities in the field of ocular surface immunology. Genetic profiling and advanced immunological testing techniques make it possible to customize treatments according to an individual’s unique immune profile. This personalized approach holds great potential for optimizing therapeutic outcomes while minimizing side effects. By tailoring treatments to the specific needs of each patient, we can enhance the effectiveness of interventions and improve overall patient care.29
Nanotechnology and Drug Delivery Systems
Nanotechnology-based drug delivery systems show promise in enhancing the efficacy of ocular surface immunomodulatory therapies. Nanoparticles can efficiently deliver drugs to specific ocular tissues, improving treatment outcomes and reducing side effects.30
Conclusions and Future Work
Ocular surface immunology represents a rapidly evolving field with profound implications for eye health. The interplay between the immune system and the ocular surface has become increasingly apparent and holds the key to understanding the mechanisms underlying ocular diseases and developing innovative therapeutic interventions. By elucidating the immune processes involved, scientists and clinicians are devising targeted therapies and personalized approaches to restore ocular surface homeostasis and improve patient outcomes.
As we continue to unravel the complexities of ocular surface immunology, new avenues for preventive measures, early interventions, and personalized treatments will emerge. The collaborative efforts of researchers, clinicians, and industry stakeholders will undoubtedly shape the future of ocular surface immunology, offering new horizons for eye health and enhancing the quality of life for millions worldwide.
- de Paiva CS, St Leger AJ, Caspi RR. Mucosal immunology of the ocular surface. Mucosal Immunol. 2022;15(6):1143-57.
- Knop N, Knop E. Conjunctiva-associated lymphoid tissue in the human eye. Invest Ophthalmol Vis Sci. 2000;41(6):1270-9.
- Lasagni Vitar RM, Bonelli F, Rama P, Ferrari G. Immunity and pain in the eye: Focus on the ocular surface. Clin Exp Immunol. 2022;207(2):149-63.
- Foulsham W, Coco G, Amouzegar A, et al. When clarity is crucial: Regulating ocular surface immunity. Trends Immunol. 2018;39(4):288-301.
- Barabino S, Chen Y, Chauhan S, Dana R. Ocular surface immunity: Homeostatic mechanisms and their disruption in dry eye disease. Prog Retin Eye Res. 2012;31(3):271-85.
- Belmonte C, Acosta MC, Merayo-Lloves J, et al. What causes eye pain? Curr Ophthalmol Rep. 2015;3(2):111-21.
- Guerrero-Moreno A, Baudouin C, Melik Parsadaniantz S, Réaux-Le Goazigo A. Morphological and functional changes of corneal nerves and their contribution to peripheral and central sensory abnormalities. Front Cell Neurosci. 2020;14:610342.
- Ferrari G, Chauhan SK, Ueno H, et al. A novel mouse model for neurotrophic keratopathy: Trigeminal nerve stereotactic electrolysis through the brain. Invest Ophthalmol Vis Sci. 2011;52(5):2532-9.
- Lasagni Vitar RM, Rama P, Ferrari G. The two-faced effects of nerves and neuropeptides in corneal diseases. Prog Retin Eye Res. 2022;86:100974.
- Nishida T, Inui M, Nomizu M. Peptide therapies for ocular surface disturbances based on fibronectin-integrin interactions. Prog Retin Eye Res. 2015;47:38-63.
- Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clin Ophthalmol. 2014;8:571-9.
- Suvas S. Role of Substance P neuropeptide in inflammation, wound healing, and tissue homeostasis. J Immunol. 2017;199(5):1543-52.
- Leonardi A, De Dominicis C, Motterle L. Immunopathogenesis of ocular allergy: A schematic approach to different clinical entities. Curr Opin Allergy Clin Immunol. 2007;7(5):429-35.
- Stern ME, Gao J, Siemasko KF, et al. The role of the lacrimal functional unit in the pathophysiology of dry eye. Exp Eye Res. 2004;78(3):409-16.
- Pflugfelder SC, de Paiva CS. The pathophysiology of dry eye disease: What we know and future directions for research. Ophthalmol. 2017;124(11):S4-S13.
- Ogawa Y, Takeuchi T, Tsubota K. Autoimmune epithelitis and chronic inflammation in Sjögren’s syndrome-related dry eye disease. Int J Mol Sci. 2021;22(21):11820.
- Chiang TL, Sun YC, Wu JH, et al. The ocular graft-versus-host disease: The path from current knowledge to future managements. Eye (London). 2023;37(10):1982-92.
- Periman LM, Perez VL, Saban DR, et al. The immunological basis of dry eye disease and current topical treatment options. J Ocul Pharmacol Ther. 2020;36(3):137-46.
- Maharana PK, Mandal S, Kaweri L, et al. Immunopathogenesis of corneal graft rejection. Indian J Ophthalmol. 2023;71(5):1733-8.
- Yazdanpanah G, Jabbehdari S, Djalilian AR. Emerging approaches for ocular surface regeneration. Curr Ophthalmol Rep. 2019;7(1):1-10.
- Singh VK, Sharma P, Vaksh UKS, Chandra R. Current approaches for the regeneration and reconstruction of ocular surface in dry eye. Front Med. 2022;9:885780.
- Azari AA, Rapuano CJ. Autologous serum eye drops for the treatment of ocular surface disease. Eye Contact Lens. 2015;41(3):133–40.
- Bonini S, Lambiase A, Rama P, et al. Phase II randomized, double-masked, vehicle-controlled trial of recombinant human nerve growth factor for neurotrophic keratitis. Ophthalmol. 2018;125(9):1332-43.
- Pflugfelder SC, Massaro-Giordano M, Perez VL, et al. Topical recombinant human nerve growth factor (cenegermin) for neurotrophic keratopathy: A multicenter randomized vehicle-controlled pivotal trial. Ophthalmol. 2020;127(1):14-26.
- Veernala I, Jaffet J, Fried J, et al. Lacrimal gland regeneration: The unmet challenges and promise for dry eye therapy. Ocul Surf. 2022;25:129-41.
- Joshi VP, Singh S, Thacker M, et al. Newer approaches to dry eye therapy: Nanotechnology, regenerative medicine, and tissue engineering. Indian J Ophthalmol. 2023;71(4):1292-1303.
- Kugadas A, Gadjeva M. Impact of microbiome on ocular health. Ocul Surf. 2016;14(3):342-9.
- St Leger AJ, Desai JV, Drummond RA, et al. An ocular commensal protects against corneal infection by driving an interleukin-17 response from mucosal γδ T cells. Immunity. 2017;47(1):148-58.e5.
- Kessal K, Liang H, Rabut G, et al. Conjunctival inflammatory gene expression profiling in dry eye disease: Correlations with HLA-DRA and HLA-DRB1. Front Immunol. 2018;9:2271.
- Rodrigues FSC, Campos A, Martins J, et al. Emerging trends in nanomedicine for improving ocular drug delivery: Light-responsive nanoparticles, mesoporous silica nanoparticles, and contact lenses. ACS Biomater Sci Eng. 2020;6(12):6587-97.