Ocular immune homeostasis—mechanisms of precise regulation through coordination of the eye, visual system and beyond: a narrative review
Authors: Caitlin M Logan, A Sue Menko
Published: 2026

ABSTRACT
AbstractBackground and Objective:The visual system relies on clarity, organization, and interactivity to allow for sight. While in the past, the eye was thought to be immune-privileged, newer insights reframe this hypothesis. Recent studies demonstrate that the eye relies on a precise regulation of immunosurveillance to function. Here, we aim to highlight the multiple layers of coordination and regulation that allow for ocular immune homeostasis and how this understanding can shape future research and clinical directions.Methods:The PubMed database was utilized to find recent developments in the field of ocular immunology and immune homeostasis. This review covers research in the English language from 1 January 1980 to 20 December 2025.Key Content and Findings:Ocular immune regulation is multilevel, including systems outside the eye itself. Similar to other previously accepted immune-privileged tissues, the eye hosts a variety of tissue-resident immune cells. These cells have proven necessary for the proper development of the eye as well as the activation of a protective immune response to injury and the evolution of ocular pathology. This involves a complex system of immunoregulation aimed at global homeostasis that protects vision integrity when one eye is compromised and can also involve an immune response in the contralateral eye, further evidence of the tight coordination of the visual system. In looking at diseases of immune overactivation, models highlight the involvement of recruited inflammatory cells in the evolution of the disease, including from beyond the eye itself, as occurs in uveitis. When such inflammation occurs, regulatory T cells (Tregs) and macrophages with an immunoregulatory phenotype are necessary for the regulation and recovery of the eye. Additionally, newer studies have also demonstrated a role for the microbiome in ocular health and disease, creating yet another link between systems at play in immunoregulation of the eye.Conclusions:The future holds multiple opportunities for capitalizing on the multiple layers of immune involvement and coordination of the immune system in ocular health and disease to advance treatments and preserve vision. By understanding the interactions of the eye, the visual system and the immune system, targeted therapies can better promote homeostasis and visual recovery.Keywords: Immune cells, eye, immunoregulation, ocular microbiome, uveitis

Introduction

The eye is a unique system in which the precise interworking of different tissue types and fluid compartments allows for vision. This system heavily relies on the transparency of tissues such as the cornea and lens and fluid compartments, including the tear film, aqueous, and vitreous, for the successful transmission of light. While the eye has been previously characterized as immune-privileged (1,2), more recent studies have better characterized it as immune quiescent or tolerant (3,4). Immune privilege is characterized by a reduced or modified immune response, and historically was linked to the finding that within the eye, the expected rejection of allografts did not occur (5). This privileged state was thought to relate to a combination of factors, including lack of blood vessels and lymphatic drainage in multiple ocular tissues, high concentrations of immunosuppressive tissue immunomodulators, including both cell-surface molecules and soluble factors, and the activity of regulatory T cells (Tregs) (6).

Additionally, three ocular tissue barriers are characterized: an inner blood-retinal barrier, formed by endothelial cells in the inner layers of the neural retina, an outer blood-retinal barrier, formed by the retinal pigmented epithelial cells, and the blood-aqueous barrier in the ciliary body (7,8). Of these, the inner blood-retinal barrier is thought of as a true barrier, only infiltrated in cases of significant inflammation that breaks down the endothelial tight junctions (9,10). In contrast, the outer blood-retinal barrier is viewed more as a site for retinal immunosurveillance, with the epithelium producing and surrounded by many immunomodulatory mediators (11,12) that may actually promote resolution of inflammation. Similarly, the blood-aqueous barrier is patrolled by leukocytes and is a primary site for leukocyte infiltration preceding retinal inflammation, while the aqueous humor also has multiple immunomodulatory factors (13–15). It is through these multiple gateways that the eye communicates with the immune system as a whole to allow for not just the protection of the eye from inflammation but also for the coordination of response.

This review focuses on the precise regulation of physical barriers, immune cell monitoring and activity, and immunomodulator expression on multiple levels that allow the visual system to maintain homeostasis. Inflammation within the eye in response to injury, disease pathology, or autoimmunity can lead to significant loss of visual acuity (16). It is therefore critical to understand how this inflammation is regulated and controlled within eye tissues, both in normal tissue and disease states. This review aims to examine the various levels of immune regulation and how understanding their precise inter-coordination can lead to improved clinical outcomes. We present this article in accordance with the Narrative Review reporting checklist (available at https://aes.amegroups.com/article/view/10.21037/aes-2025-1-66/rc).

Methods

A literature review was conducted using PubMed to access published papers. Reviews and meta-analyses were considered in leading to direct publication of new studies. All papers with available English publication were considered, regardless of country of origin. Literature searches occurred from May 2025 to December 2025, with this review focusing on newer publications (within the past 25 years) to highlight advances in the field, although also referencing historical context (Table 1).

Table 1The search strategy summaryItemsSpecificationDate of searchMultiple searches performed from May 1, 2025 to December 20, 2025Database searchedPubMedSearch terms usedFree text search terms: eye immunosurveillance, eye immune privilege, immune quiescence, lens immune, cornea immune, retina immune, ocular microbiome, ocular autoimmune, eye resident immune cells, retinal microglia, uveitis, immune cell types in uveitis, eye immune disorders, eye immune therapiesTimeframe1 January 1980 to 20 December 2025Inclusion and exclusion criteriaInclusion: reviews, meta-analyses, basic research, clinical trials Exclusion: article without available English translationSelection processA literature search was conducted by the author (C.M.L.) to identify the relevant published studies and updated by new publications throughout review

The search strategy summary

Eye resident immune cells

Similar to other tissues, it has been demonstrated that ocular tissues contain resident immune cells. Like the other components of the central nervous system, the retina has microglia that are critical not only for immune response but also for development and homeostasis. These cells are first seen near the optic nerve and in the peripheral retina (17,18) before migrating throughout the retina. They develop through progressive stages with distinct transcriptional and epigenomic expression patterns (19). These microglia are essential for neuronal proliferation, survival, and differentiation within the retina (20,21) and are also necessary for maintaining synaptic integrity and function in the adult retina (22). Retinal microglia are notably limited to the inner retina under physiological conditions; however, in disease pathology and aging, these cells are seen within the outer layers (23–25). In multiple ocular diseases, including glaucoma, hereditary retinal degeneration, and age-related macular degeneration (AMD), it has been shown that microglia play a role in contributing to and advancing disease pathology (26), and it is being researched as to how this may serve as a therapeutic target (27,28). However, recent work has focused on distinguishing the long-lived microglia present in normal retina, which are generally associated with lower expression of inflammatory markers, from those macrophages recruited during injury, to better understand the roles of both in normal and disease states (29). It was found that in disease states, retinal microglia migrated to the subretinal space, underwent transcriptional reprogramming that led to reduced proinflammatory expression, and were responsible for the clearance of debris (30–32).

The cornea contains a variety of immune cells, primarily macrophages, as well as Langerhans cells (LCs), mast cells, lymphocytes, and innate lymphoid cells (33,34) that are able to migrate via both lymphatic vessels and capillaries (35,36). Studies have demonstrated the presence of immature antigen-presenting cells (APCs), such as dendritic cells, even in the central cornea (37,38), ready to mature in response to inflammation or pathogens (33). Work has distinguished that LCs are found within the corneal epithelium and are CD11c+, while the dendritic cells seen in the stroma are Langerin+ but not LCs (39). It is changes in the concentrations of other types of immune cells in the cornea that are often indicative of pathology (40–43), with multiple diseases linked to an increase in neutrophils, natural killer (NK) cells, mast cells, and/or T cells, including dry eye, keratoconus, ocular Stevens-Johnson syndrome, peripheral ulcerative keratitis (PUK), and corneal transplant rejection (44–48).

The lens, despite having no vasculature or innervation, has been shown to have resident immune cells as well (49,50). It has been shown in other systems that matrix proteins such as fibronectin and tenascin-C promote the migration and adhesion of immune cells (51–54), and in the lens, these proteins are associated with the lens capsule, with fibrillin-2-rich ciliary zonules providing a pathway for immune cell migration into the embryonic lens (50). This same pathway is used to recruit immune cells to the lens surface in response to corneal injury (55). These lens resident immune cells have been observed to be integrated within the lens epithelium across species, including chick, mouse, and human (49). It has been shown in both mock cataract surgery models and in human pediatric lens explants post-cataract surgery that the lens resident immune cells are rapidly activated and recruited to the wound edge (49). These cells have also been shown to be myofibroblast progenitors (56,57), which contribute to inflammatory and fibrotic conditions, including posterior capsule opacification (PCO).

Coordination of immune response between ocular components

It was discovered that injury or loss of homeostasis in one ocular tissue leads to an immune response in other regions of the same eye. A lens-specific conditional N-cadherin knockout leads to embryonic dysmorphogenesis of the lens that results in further postnatal degeneration and opacity formation (58). This degeneration is characterized by immune cells that populate the lens and contribute to fibrosis, but more notably, there is evidence of immune surveillance throughout the eye in response as well (58). There was an increase in immune cells seen in the vitreous, retina, and central cornea in N-cadherin lens knockout eyes compared to wildtype, emphasizing the interplay of ocular tissues and likely coordinated efforts to maintain homeostasis (58). Similarly, in response to corneal debridement, it was shown that immune cells associate with the ciliary zonules and that multiple types of immune cells, including monocytes, macrophages, and neutrophils, use these zonule fibers to migrate to the anterior surface of the lens, with some of these cells crossing the lens capsule (55). This remains true in a mouse debridement wound model, where recurrent erosions in the cornea result in recruitment of immune cells back to the anterior surface of the lens even after healing of the initial injury (59).

The eye also has a unique phenomenon of binocular coordination of inflammation. It has been noted for centuries that surgical or penetrating injury in one eye can lead to the development of inflammation in the contralateral eye, a condition known as sympathetic ophthalmia (60,61). This is characterized by a cellular immune response, primarily mediated by T-cells, and including, in addition to lymphocytes, epithelioid cells and giant cells (62). Additionally, both pro- and anti-inflammatory cytokines, such as transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α), are upregulated in contralateral eyes in response to injury (63). Interestingly, changes observed in both the inciting eye and its fellow are similar, with early infiltration of CD4 + helper/inducer T cells followed by an infiltration of CD8 + suppressor/cytotoxic T cells, despite the fact that the timeframe of sympathetic ophthalmia varies greatly (64,65). While the pathogenesis of sympathetic ophthalmia is not well understood, ocular antigen interphotoreceptor retinoid-binding antigen (IRBP) and S antigen are able to produce a similar disease phenotype in monkeys, and it appears to be linked to uveal antigen exposure to the lymphatic system (60,66,67). Additionally, the disease process bears a striking similarity to Vogt-Koyanagi-Harada syndrome, with both associated with a granulomatous panuveitis and multiple pockets of subretinal fluid, which may prove an avenue to better understand this rare disease. Research into molecular pathways involved has led to therapies specifically targeting cytokines involved in leukocyte recruitment, including chemokine ligand 2 (CCL2), and C-X-C motif chemokine ligand 12 (CXCL12) (68,69).

This phenomenon has also been seen in response to infection, with recent work demonstrating that infectious keratitis leads to not only increased immune cells in the affected eye, but a subclinical immune response in the contralateral eye (70). In the cornea, this immune response seems to be linked to additional bilateral changes to sensory nerves in response to viral infection, as well as mechanical injury (9,71,72), suggesting a connection between the immune system and nervous system that may play a role in immune regulation.

In surgical settings, it has been seen that surgery in one eye can influence the inflammatory milieu of the contralateral eye. In multiple studies, the aqueous humor was analyzed in both eyes prior to and after cataract surgery, and there was a significant increase in monocyte chemoattractant protein 1 (MCP-1) in the second eye following surgery in the fellow eye (73,74). MCP-1, a pain-related inflammatory cytokine, controls recruitment of leukocytes in inflammation and tissue injury (75). Similarly, substance P is also found to be elevated in second surgical eyes in some conditions, such as diabetes, a molecule that is known to be protective in ocular inflammation, wound healing, and tissue homeostasis (74,76). Thus, in considering immune response in the eye, one must remember that the eye is a tightly coordinated system where different tissues interact to promote global homeostasis to allow for vision.

Ocular immune dysregulation in injury and disease

In recent work, there has been an emphasis on the understanding of how immune cells and their environments change in response to disease pathologies of the eye. In multiple vascular diseases of the eye, the retina demonstrates changes in immune surveillance. In retinopathy of prematurity, oxygen deprivation leads to activation of retinal microglia and correlates with the development of neovascularization (77,78). In AMD, it has been reported that activated microglia migrate to the outer layers and contribute to this degenerative disease (26,78). Moreover, it is seen that reactive microglia accumulate on retinal pigment epithelium (RPE) cells both within and on top of drusen, and it is thought that persistent inflammation causes repetitive injury to the RPE and photoreceptors (26,79). This damage leads to a continued cascade of immune recruitment and response through the release of retinal antibodies and a form of autoimmunity (80–83). Diabetic retinopathy has also been associated with inflammation (84,85), with activation and proliferation of microglia as well as their migration and infiltration of the outer retinal layers (78,86). Insights from retinal ischemia reperfusion injury demonstrate that both resident and peripheral immune cells regulate the immune response, with resident microglia, Muller cells, and astrocytes undergoing morphological change and producing inflammatory mediators that then recruit neutrophils, monocytes, and lymphocytes (87–89). This is not simply a cellular response, but rather part of a complex system that involves pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), the complement system, and inflammasomes and combines innate and adaptive immunity (88). Injury also results in transcriptional changes in subretinal microglia, including downregulation of homeostatic genes and upregulation of neurodegeneration-linked genes, many of which have been implicated in both eye and CNS diseases (30,90–95).

In the setting of the lens, it has been shown that following mock cataract surgery, there is induction of CD83, an immunoglobulin typically expressed on the surface of activated APCs, as well as S100A4, a mediator of macrophage recruitment and chemotaxis, and mediators of immune response such as Toll-like receptor 4 and interferon (IFN) γ receptor 1 (96–100). Other studies demonstrate that following cataract surgery, there is upregulation of known innate inflammatory mediators, including CXCL1 (3866-fold), S100a9, CSF3/G-CSF, and CCL2 within 24 hours that likely promote the observed infiltration of neutrophils and macrophages (101).

In corneal debridement injuries, immune cells are seen both at the leading edge of the epithelial wound and in the area of the open wound, with primarily neutrophils and, to a lesser extent, monocyte-macrophages seen in the stroma (102). While these cells generally leave following wound closure, in corneal erosions that follow primary wound closure, there is again recruitment of immune cells to areas of the stroma underlying the denuded corneal basement membrane, which includes macrophages, neutrophils, as well as a small population of CD4+ T cells (59,102). Similar to other ocular tissues, wounding of the corneal epithelium resulted in upregulation of cytokines that promote immune response (103), including interleukin (IL)-1β, CCL2, CCL6, CXCL1, and CXCL16 that serve as chemoattractants (59,104–106). Additionally, PUK is known to be an immune-mediated keratopathy, associated with increased proinflammatory cells in the cornea, including neutrophils, mast cells, and eosinophils (45) but also antibodies directed against the cornea (107,108).

A phenomenon known as anterior chamber-associated immune deviation (ACAID) was defined in the cornea to explain the immune response to this avascular tissue. In early work by Kaplan and Streilein, it was first revealed that the anterior chamber did, in fact, respond to inoculation of antigen, resulting in a systemic immune response (109–113). ACAID is associated with the production of inflammatory cytokines, recruitment of monocytes to the anterior chamber, disbursement of ocular APCs expressing F4/80 and CD11b molecules to the thymus and spleen, and induction of Tregs (114–119). Interestingly, this response appears to be a form of mild inflammation that seems to prime the immune system to protect against a future, more damaging immune response (119–121). Preliminary work highlights a possible role for this mechanism in suppressing autoimmune uveitis (122). Thus, an understanding of the regulation and response of the immune surveillance systems in the eye is critical to understanding disease pathology and healing.

Inflammation, autoimmunity and uveitis

One of the best studied inflammatory responses in the eye is autoimmune uveitis. It is a diverse collection of intraocular inflammatory diseases of the uvea that also involves other regions of the eye and is often recurrent in nature. It is a leading cause of preventable blindness and is generally classified based on the primary anatomical site of inflammation—anterior, intermediate, posterior, or all three (123–125). Uveitis is divided into two broad categories, infectious and non-infectious, and is autoimmune in nature, and in a significant proportion of cases is related to a systemic autoimmune disorder (126). In developed countries, uveitis related to autoimmune disease is much more common, while infectious uveitis is generally more frequent in the developing world (127–129). The autoimmune nature of uveitis is supported by multiple factors, including genetic association with certain human leukocyte antigen (HLA), immunological response to ocular proteins such as retinal arrestin, interphotoreceptor retinoid-binding protein, recoverin, or uveal melanin, and the critical involvement of T-cells in the pathogenesis of the disease (130,131). However, work has demonstrated that depending on the subtype of uveitis, the type of inflammatory response can vary, from being more reliant on innate immunity as is seen in endophthalmitis, to being more associated with an adaptive immune response as is seen in idiopathic granulomatous uveitis (132–134).

Much of our understanding of uveitis comes from animal models, with experimental autoimmune uveitis (EAU) being the most explored. From these, we have learned that activated T cells responding to retinal antigens mediate EAU in animals, which corresponds to the assumption that T cells play a significant role in human uveitis as well (130). T-cell targeting therapies such as mycophenolic acid and cyclosporine that work through targeting IL-2, which is necessary to T cell activation and function, have shown efficacy in human uveitis treatment (135,136). In EAU models, there is a strong upregulation of major histocompatibility complex (MHC) class II expression in the retina and this induction significantly correlates with disease severity (137). In animal models, those with higher affinity or prevalence of retinal antigen-specific T cells were predisposed to develop uveitis, while Tregs can help decrease the likelihood or severity of EAU and may suppress other T cells (130,138–141). It has been shown that CD4+ T cells are necessary for the development of EAU, while CD8+ T cells are not and, in fact, may play more of a regulatory role (142–145). One study suggests the peripheral activation of autoreactive CD4+ T cells is critical for the induction of disease, and these cells are seen to be recruited and peak earlier in the course of uveitis (146,147). CD8+ T cell numbers do increase in models of experimental uveitis, and are often found to reside in tissues as memory cells and help prime the response to repeat infection or stimulus (143,148,149). It is seen that CD8+ cells mostly have characteristics of effector memory cells during initial inflammation, while later there is increased expression of the co-inhibitory receptor PD-1, which is generally associated with T cell exhaustion (150,151).

Roles for both Th1 effector cells, which predominantly produce IFNγ, and Th17 effector cells, which produce IL-17, in the pathogenesis of uveitis have been suggested, and there is evidence of both responses in human uveitis (152–156). These T cells then secrete cytokines and chemokines that recruit other leukocytes, with Th17 generally recruiting neutrophils whereas Th1 recruits monocytes, which then cause tissue damage (131,153). The suppression of these other leukocytes, specifically in models of removal of macrophages or suppression of myeloid activation, can decrease the severity of EAU (157–161). IFNγ-mediated macrophage activation that depends on TNF-α and functional TNFR1 results in high levels of nitric oxide, TNF-α, and IL-6, but ablation of IFNγ exacerbates clinical EAU and leads to accumulation of granulocytes (129,150,162). In contrast, targeting IL-17 markedly reduces inflammation in EAU and moreover, the transfer of Th17 cells is sufficient to penetrate the retinal barrier and trigger the onset of EAU (153). Other cytokines produced by Th17 cells, such as IL-21, may also further exacerbate inflammation; however, the Th17 response also plays a role in immunoregulation through the production of IL-10, IL-24, and TGF-β (163–167). Thus, there is a balance of inflammation and immune suppression that is regulated by Th17 cells.

Further proof of this balance of inflammation and immunoregulation has recently been highlighted in the lens. While uveitis is a known cause of tissue injury within the eye and clinically linked to cataract complications, PCO, glaucoma, macular edema, and retinal detachment, only recent work has looked at the impact of uveitis on the lens itself (168–170). A mouse model of EAU demonstrates that immune cells, including T cells, macrophages and Ly6G/Ly6C+ cells, associate with the lens surface, integrate within the lens capsule and are capable of then infiltrating the lens itself (171). Interestingly, immune cells were found to continue to associate with the lens capsule surface even as EAU models entered the phase of immune resolution (172). While certain cells, including CD11b+ myeloid cells and CD4+ T cells, were seen to persist along the lens capsule surface from the period of active inflammation through to the end of the resolution phase, the numbers of Tregs significantly increased through the resolution of active inflammation (172). Additionally, macrophages associated with the lens capsule during active inflammation and resolution had immunoregulatory properties and expressed IL-10, an anti-inflammatory cytokine (172).

It is not only those cells recruited to the eye that contribute to uveitis pathology or its resolution, however. Pharmacological depletion of microglia has been shown to prevent the breakdown of the blood retinal barrier, suppress the infiltration of inflammatory cells into the retina, and improve visual outcomes in EAU models and, similarly, inactivation of microglia also improves retinal integrity and clinical appearance (173–175). The roles of microglia, however, are diverse, and recent focus has capitalized on understanding what promotes the change of retinal microglia from the proinflammatory M1 subtype to the anti-inflammatory M2 subtype (137,176–178). It remains a critical focus to understand the balance between inflammation and immune regulation in the pathogenesis of autoimmunity.

While animal models are helpful in understanding disease pathology in vivo, they do have clinical limitations. First lies in the fact that uveitis is a heterogeneous disease pathology in its clinical severity and duration, which is difficult to replicate in an inducible system (179). Additionally, certain models, especially those of anterior uveitis, offer a very limited timeframe of study to investigate disease mechanisms or treatments (180,181). Posterior uveitis is also limited by a lack of knowledge of the autoantigens involved. In addition, the progression and severity of the disease vary depending on the species, strain and dosage amount of autoantigens used by each model, making generalized conclusions difficult (142,182). Newer models involving transgenic mice that replicate a “spontaneous” form of uveitis may be useful for translational purposes (183–186).

The influence of microbiomes on ocular immune response

There has been recent focus on the importance of the microbiota associated with skin and mucosal surfaces in the regulation of global immune stimulation and response (187,188). While there are multiple forms of protection from colonization of the ocular surface, including mechanical forces such as blinking, as well as chemical deterrents such as the lysozyme found within tears, the existence of ocular surface microorganisms has been known for decades (189,190). Multiple methods have been used to characterize the normal ocular surface microbiome, although there is some debate between different studies. Using traditional methods of culturing, Gram-positive bacteria are generally the most common found (191,192). Sequencing studies generally agree on the types of Gram-positive bacteria found, but also include some Gram-negative species (193–196). Additional studies have also identified fungal elements (197,198). The organisms of the microbiota are a source for peptidoglycans that prime neutrophils and also play a role in regulating the level of secretory IgA at the ocular surface, which neutralizes toxins, viruses, and bacteria, promotes production of IL-10, and affects maturation of dendritic cells (199–205).

Even more notable are the changes in the ocular microbiome in the setting of disease. In general, most disease states are noted to be associated with a reduction in Gram-positive organisms and an increase in Gram-negative organisms (206,207). Additionally, in considering the microbiome, there are two types of diversity: α-diversity, which is the diversity of organisms within a community, and β-diversity, which is the diversity between communities (208–210). A healthy microbiome is generally characterized by a diverse environment, and it has been noted that in ocular disease states, there is a decrease in α-diversity (206,207).

Many studies have demonstrated that ocular disease states, including diabetes, conjunctivitis, and certain autoimmune diseases, are associated with alterations in ocular surface microbiota (211–215). Additionally, some studies suggest that the ocular microbiome plays a role in ocular homeostasis and changes may lead to increased risk of eye infection (216,217). In dry eye disease, multiple studies have shown a higher likelihood of bacterial culture positivity in affected eyes (190,218–220). In Sjogren syndrome, an autoimmune condition primarily associated with dry mucosa, including the eye, there is a decrease in lactoferrin and lysozyme, both molecules that generally combat bacterial growth, while there is an increase in Staph aureus and immune cell infiltrate (221–223). In meibomian gland disease (MGD), one of the major causes of evaporative dry eye disease, it has been shown that with increasing disease severity, there are increases in certain species of bacteria as well (224–226).

In addition to the ocular surface, the gut microbiome is increasingly understood to play a role in ocular inflammation. Interestingly, studies in a uveitis model revealed the presence of activated T cells in the gut prior to their localization to the retina (227,228). In these same models, it was noted that uveitis models are associated with increased populations of Th17 cells in the intestinal lining, and that antibiotic treatment significantly decreases the numbers of these cells (228–230). Additionally, studies with both antibiotic-treated and germ-free mice reveal that in the absence or suppression of microbiota, there was a significant reduction in activated T cells and disease attenuation (188,227,229,231,232). In some studies, it appears as though short-term antibiotics can inhibit EAU development, especially if started prior to induction of uveitis, while in others, there was increased leukocyte trafficking from the intestine to the eye during EAU (231–234). Recent studies demonstrate that the transfer of the gut microbiome from animals with diseases such as Behcet’s and Vogt-Koyanagi-Harada disease, which are both characterized by multiorgan inflammation, including uveitis, exacerbates disease severity in recipient EAU mice (235,236).

While a primary focus on the role of the microbiome in ocular disease has focused on uveitis models, other disease pathologies also have associations. Some studies demonstrate that changes to the gut microbiome can also modulate dry eye disease. In antibiotic-treated and germ-free mice, the ocular surface responded worse to drying stress conditions, which was associated with lymphocyte infiltration of the lacrimal gland, increased inflammatory cytokines, and impaired barrier function of the cornea (52,215,237). For those with AMD, it has been noted that there are differences in microbial populations in the intestinal, oral, nasal, and pharyngeal mucosa compared to those without the disease (238–241). Additionally, preliminary studies suggest several intraocular bacteria are associated specifically with AMD and significantly enriched in soft drusen (242,243). Notably, the only current therapy with efficacy in slowing the progression of AMD is a combination of antioxidants (244,245). Recent work has also tied infection of Helicobacter pylori to the development of open-angle glaucoma (246–248). Similar to AMD, patients with open-angle glaucoma have distinct gut microbiome compositions compared to healthy people, and a toxin produced by the gut microbiome, trimethylamine, has been found specifically in the aqueous humor of patients with glaucoma (249–251). This work remains preliminary, but it is likely that further understanding of the connection between ocular disease pathogenesis and the microbiome will help overall understanding.

Immunomodulation as a therapeutic avenue

In light of recent work on the microbiome, there has been a pursuit of whether modulation of the gut microbiome will impact disease pathology and if this may prove an avenue for treatment. A probiotic mixture was tested for possible efficacy in immune-mediated eye diseases and did have a therapeutic effect on autoimmune uveitis and dry eye, especially in combination with pretreatment with antibiotics (234,252–254). Another avenue of approach is through the use of bioactive microbial metabolites, such as short-chain fatty acids, which are associated with attenuation of inflammation (255). One of these, propionic acid, has shown success in reducing the severity of disease in an EAU model and was associated with Treg induction, although only in certain strains (233). There are also some limited studies that direct application of certain bacteria to the tear film can improve dry eye symptoms (256). Another avenue of future research is investigating a potential role for bacteriophages in modulating the microbiome, something that is currently being studied as a treatment method for ocular infections (257–259). Overall, while this is an emerging area of investigation, studies are still limited in showing efficacy.

Traditionally, therapies for uveitis have focused on immunosuppression, either broad-spectrum or targeted. Often, the progression is topical and/or systemic treatment with oral or intravenous corticosteroids, systemic immunomodulators (i.e., T-cell inhibitors or antimetabolites), and finally, biologics. However, given the high risk of side effects and complications that come with long-term corticosteroid use, there has been movement to better target aspects of inflammation to reduce steroid dependence (260). Among these immunomodulators are T cell-targeted therapies such as rapamycin and cyclosporine, anti-TNF and IFN-α treatments, and newer studies that target the IL-2 receptor (261–264). However, there are many new avenues to consider. One of these is to promote and enhance Treg function by boosting tolerance, something that has been trialed in HLA-DR3 transgenic mice and has shown promise in controlling EAU (265–267). Additionally, neutralization of IL-17 by monoclonal antibodies has been shown to stop EAU in mouse models and there are current clinical trials focused on taking advantage of this mechanism, although results are mixed (130,153,268,269). Multiple therapies aimed at blocking Th1, Th17, or both responses are currently being used as treatment for subtypes of uveitis. These include ustekinumab, which blocks both Th1 and Th17, targeting IL-12 and IL-23, sarilumab, which inhibits Th17 differentiation, and anakinra and canakinumab, which target IL-1 or its receptor (270–272). Additionally, there has been interest in developing topical ocular immunosuppressives, using inflammation antagonists such as the neuropeptide, alpha-melanocyte-stimulating hormone (α-MSH) (273). In EAU models, α-MSH is capable of reducing inflammation, primarily by antagonizing nuclear factor-kappa B (NF-κB), ubiquitination of IFNγ, inducing Treg cells, and promoting suppressor macrophages (274–277). The next step will be to see if these treatments solely have efficacy in experimental models or if they may have application in human disease.

Beyond these approaches, one could also consider inhibiting the recruitment and migration of immune cells by focusing on adhesion molecules and chemokine/cytokine receptors. Studies have shown that blocking integrins α4β1 or αLβ2, intercellular adhesion molecule 1 (ICAM-1), chemokine receptors (CCRs; CXCR3 and CXCR5), or the hyaluronan receptor CD44, osteopontin, and matrix metalloproteinases can all inhibit EAU (278–282). Recent work has also demonstrated that the interaction of CD47, also known as integrin-associated protein (IAP), with signal regulatory protein alpha (SIRPα) is required for efficient induction of T cell-mediated inflammation (267). Additionally, deficiency of CD47 protects from autoimmune uveitis, which may also provide a target for future therapies (283,284). Some of these therapies already have approval for use in other conditions; however, there are concerns about off-target effects.

Other immune cell-mediated pathologies also reveal pathways for therapeutic intervention. CCR7 is known to play a role in immune cell trafficking, playing a pivotal role in allorecognition in corneal transplantation but also in promoting Treg suppressor function (285–287). CCR7 antagonists have shown efficacy in ocular allergy and may be beneficial in other ocular conditions (288,289). Other systems have investigated the use of hydrogels that integrate hyaluronic acid, a natural component of tears with known wound healing effects, for use in corneal wound healing (290–292). These hydrogels not only have the ability to be absorbed by the corneal stroma but also have anti-inflammatory effects, including a reduced recruitment of immune cells to the site of injury (292). It is possible that ongoing clinical trials will reveal even further applications for these in inflammatory and injury conditions.

Extreme cases may also benefit from aggressive intervention as well. CD19 chimeric antigen receptor T cells (CAR T cells) are T cells that have been engineered to recognize CD19 and eliminate all B cells in a patient (293). While typically thought of in the context of lymphoma, its use is being expanded to other autoimmune disorders such as systemic lupus erythematosus, where it has led to drug-free remission (294,295). Similarly, rituximab, which targets CD20 on B cells, has been shown to have efficacy in treating ocular cicatricial pemphigoid and other subtypes of uveitis (296–299). Thus, there is a potential opportunity to capitalize on this technology in uveitis and to highlight the role of B cells in its pathology.

Strengths and limitations

This review focuses on the interconnection of the visual system and immune system, which is unique compared to other reviews on the subject. Due to the evolving nature of the field, certain topics relied more heavily on individual studies. It is possible that relevant articles may have been missed in the literature search. A formal quality assessment of the included articles was not performed.

Conclusions

The eye has evolved significantly from its previous understanding as an immune-privileged site. There are now multiple insights into the role of the resident and adaptive immune systems in inflammation, disease pathology, and tissue recovery and regulation. Here, we demonstrate that there are multiple levels of regulation within the eye, the bilateral visual system, and the immune system as a whole that are necessary to consider when investigating disease pathology and treatment. Further research that investigates how the eye is a coordinate system in how it regulates immune response, animal models that better replicate clinical pathology and treatment avenues that leverage an understanding of immunoregulation are all essential for better clinical outcomes.

Funding:

This study was supported by National Eye Institute, NIH (R01 grant to A.S.M.: EY021784).

Conflicts of Interest:

Both authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-2025-1-66/coif). The series “Biological Mechanisms of the Eye” was commissioned by the editorial office without any funding or sponsorship. A.S.M. received funding from National Eye Institute, NIH (R01 grant: EY021784). The authors have no other conflicts of interest to declare.

Footnotes

Provenance and Peer Review: This article was commissioned by the Guest Editor (Michael Wormstone) for the series “Biological Mechanisms of the Eye” published in Annals of Eye Science. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aes.amegroups.com/article/view/10.21037/aes-2025-1-66/rc

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-2025-1-66/prf

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

References