Exploring the Role of the Immune System in Myopia

While overt inflammation is not a well-recognised feature of myopia, increasing evidence points towards sub-clinical inflammation as a potential driver of axial elongation, suggesting that the immune system might be more involved in the pathogenesis of myopia than previously thought.

Early indicators of a possible link between inflammation and myopia emerged from clinical observations relating to a higher prevalence of myopia in people with immune-mediated conditions such as Kawasaki disease,¹ and unexpected myopic shifts in people with the autoimmune condition systemic lupus erythematosus.²  In clinical observational studies, higher levels of pro-inflammatory cytokines have been found in the aqueous humour of cataract patients with high myopia, compared to those with age-related cataract and no myopia (‘controls’).^3,4 However, it could be reasoned that those undergoing cataract surgery might have experienced a lifetime of exposures to inflammatory stimuli, and to call into question the relevance of sub-clinical findings broadly related to inflammation in older people compared to younger individuals.

Complementary to this evidence are findings from a recent cross-sectional clinical study, where levels of pro-inflammatory cytokines in tear fluid were measured in young people (mean age: 12 years) with myopia, compared to those with emmetropia.⁵ The authors reported a positive relationship between myopia and tear levels of specific pro-inflammatory markers, TNF-α and ICAM-1.

In another study, comparing adults with high myopia and emmetropia, tear fluid levels of interleukin (IL)-6, IL-13, and monocyte chemoattractant protein (MCP-1) were higher in the high myopia group,⁶ reinforcing links between a higher inflammatory profile at the ocular surface and myopic refractive error.

… increasing evidence points towards sub-clinical inflammation as a potential driver of axial elongation, suggesting that the immune system might be more involved in the pathogenesis of myopia than previously thought

Are Immune Cells Involved in Ocular Axial Elongation?

Scleral thinning and ocular axial elongation are key events in the development and progression of myopia. Several mechanisms have been linked to these biochemically-related changes to scleral connective tissue, including elevated levels of matrix metalloproteinases (MMPs) (e.g., MMP-2 and MMP-9) and concomitant loss of type 1 collagen.⁷ Of relevance, MMP-2 is a gelatinase that can degrade collagen fibrils in the sclera. Macrophages, the immune cells that reside in the scleral extracellular matrix, can be recruited to tissues in response to the chemokine MCP-1. Macrophages express the MCP-1 receptor, CCR2, and can produce MMP-2. Through animal studies involving experimental models of ocular axial elongation and myopia, understanding of a well-defined signalling cascade has emerged, whereby the elevated production of scleral-derived MCP-1 acts as a chemotactic recruiter of CCR2+ macrophages. These recruited immune cells, together with resident tissue macrophages, secrete MMP-2 that degrades collagen and promotes axial elongation.⁷ Functional studies also lend support to this model. For example, inhibition of the MCP-1 chemical messenger in mice with experimental myopia prevents the recruitment of macrophages and can halt the development of myopia,⁸ providing evidence that macrophages may be central to connective tissue weakening that relates to myopia onset and progression.

Can We Evaluate Macrophages in People?

Identifying the potential contributory role of scleral macrophages in myopia development is an important scientific step towards understanding the pathomechanism of this refractive condition. In a fascinating study9 on macrophage phenotypes, it was revealed that mice with defocus-induced myopia showed a shared pro-inflammatory immune signature across multiple non-ocular tissues, including the intestines, liver, and kidneys, compared to emmetropic mice.

Single cell RNA sequencing analysis of immune cells in these myopic mice showed that most of the pro-inflammatory gene upregulation was attributed to macrophages, specifically.⁹ Moreover, interruption of the implicated inflammatory pathway (via systemic injection of Salidroside, an anti-hypoxic drug) was effective at reducing the experimental refractive error in the myopic mice, lending additional support to the proposed inflammation-myopia link. However, while evaluating macrophage activation in mice is scientifically interesting, is it clinically relevant? And can macrophages be evaluated in human eyes? The short answer to both questions, is: yes. Researchers at the University of Melbourne have developed a novel clinical imaging approach that allows for the visualisation and measurement of macrophages in the corneal stroma of the living human eye.

Videos of macrophages, inside the human cornea, are non-invasively captured using time-lapsed imaging on an in vivo confocal microscope (IVCM). With the ability to see, measure, and compare dynamic behaviours in macrophages in the corneal stroma, and T lymphocytes and dendritic cells in the epithelium, this technique enables functional investigations into immune cell behaviours in living humans.

Termed Functional IVCM (Fun-IVCM),¹⁰ this imaging method is now enabling researchers to interrogate the role of the immune compartment in a wide range of ocular and non-ocular conditions, including infectious disease,¹¹ post-refractive surgery,¹² dry eye disease, diabetes and now, myopia.⁴

Through our co-led FrontTear Research Centre (fronttear.au), we are leading several clinical research studies aimed at identifying unique corneal immune signatures that may reveal previously unappreciated links between sub-clinical inflammation and eye conditions, including in myopia. In Perth (at the Lions Eye Institute and UWA’s Department of Optometry and Vision Science), recruitment has commenced for a longitudinal study of the immune landscape in the cornea and tear fluid in the eyes of young people with myopia, compared to emmetropes. In this study, people aged 12–25 years with no history of dry eye disease, who are not taking immunomodulatory eye medications, and who have not had refractive surgery are eligible to participate. Supported by the Perth Eye Foundation, this study will collect novel data on corneal immune cell density and behaviour, and tear pro-inflammatory cytokines and chemokines in myopia, to determine whether a subclinical inflammatory phenotype is associated with axial elongation. Participants with myopia who are using atropine eye drops are also welcome to enrol. After 9–12 months, participants will attend for a second study visit, to assess whether myopic progression is associated with a particular immune signature in the cornea and ocular surface.

Associate Professor Holly Chinnery BSci Hons PhD GradCertHEd is the inaugural Constable Professorial Fellow at the Lions Eye Institute, and the Department of Optometry and Vision Science, at the University of Western Australia. Assoc Prof Chinnery’s research activities focus on understanding the biology of the corneal immune system in the context of homeostasis, inflammation, injury, and neurodegenerative diseases.

Prof Laura Downie BOptom PhD PGCertOcTher FACO FAAO GAICD is an optometrist and clinician scientist who has gained international recognition for research excellence in ocular disease, with awards, highly cited papers, patents, international speaking engagements, and appointments to key professional bodies. She is a Professor and Dame Kate Campbell Fellow for Research Excellence in the Department of Optometry and Vision Sciences at the University of Melbourne.

Jointly led by Prof Downie and Assoc Prof Holly Chinnery, the FrontTear Research Centre comprises a multidisciplinary team of clinician researchers and discovery scientists, with a common goal to advance eye care.

It integrates complementary streams of preclinical and clinical research to make discoveries about ocular surface biology, develop novel biomarkers and diagnostics to improve the detection of ocular and systemic disease, and evaluate new therapies to advance patient care. Visit: fronttear.au.

References 

1. Kung YJ, Wei CC, Wan L, et al. Kawasaki Disease Increases the Incidence of Myopia, Biomed Res Int. 2017;2017:2657913. doi: 10.1155/2017/2657913.
2. Yosar J, Whist E. Acute myopic shift in a patient with systemic lupus erythematosus. Am J Ophthalmol Case Rep. 2019 Oct 10;16:100562. doi: 10.1016/j.ajoc.2019.100562.
3. Yu Q, Wang C, Zhou J, et al. Association between inflammatory cytokines and oxidative stress levels in aqueous humor with axial length in human myopia. Exp Eye Res. 2023 Dec;237:109670. doi: 10.1016/j.exer.2023.109670.
4. Zhu X, Zhang K, Lu Y, et al. Proinflammatory status in the aqueous humor of high myopic cataract eyes. Exp Eye Res. 2016 Jan;142:13-8. doi: 10.1016/j.exer.2015.03.017.
5. Nishanth S, Bauer NJC, Berendschot TTJM, et al. A novel comparative study of inflammatory cytokines through noninvasive tear analysis in children with myopia versus emmetropia. Am J Ophthalmol. 2025 Oct;278:413-420. doi: 10.1016/j.ajo.2025.06.044.
6. Guo D, Qi J, Zhu X, et al. Tear inflammatory cytokines as potential biomarkers for myopic macular degeneration, Exp Eye Res. 2023;235:109648. doi: 10.1016/j.exer.2023.109648.
7. Zhao F, Zhou Q, Zhou X, et al. Cause and effect relationship between changes in scleral matrix metallopeptidase-2 expression and myopia development in mice. Am J Pathol. 2018 Aug;188(8):1754-1767. doi: 10.1016/j.ajpath.2018.04.011.
8. Zhao F, Wu H, Zhou X. et al. Up-regulation of matrix metalloproteinase-2 by scleral monocyte-derived macrophages contributes to myopia development. Am J Pathol. 2020 Sep;190(9):1888-1908. doi: 10.1016/j.ajpath.2020.06.002.
9. Meng J, Zhang Y, Zhu X, et al. Single-cell profiling reveals a shared proinflammatory macrophage signature across multiple organs in myopia. Cell Discov. 2025 Dec 2;11(1):97. doi: 10.1038/s41421-025-00835-8.
10. Downie LE, Zhang X, Chinnery HR, et al. Redefining the human corneal immune compartment using dynamic intravital imaging. Proc Natl Acad Sci U S A. 2023 Aug;120(31):e2217795120. doi: 10.1073/pnas.2217795120.
11. Karunaratne S, Wu M, Downie LE, et al. Altered corneal T-cell motility and sensory nerve features in older adults with human immunodeficiency virus infection. Invest Ophthalmol Vis Sci. 2025 Sep 2;66(12):23. doi: 10.1167/iovs.66.12.23.
12. Rajan R, Wu M, Downie LE, et al. Post-LASIK corneas show sub-clinical differences in sensory nerves and immune cell morphodynamics. Ocul Surf. 2026 Apr 7;41:26-36. doi: 10.1016/j.jtos.2026.04.002.