Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Redefining our vision: an updated guide to the ocular immune system

Nature Reviews Immunology volume 24, pages 896–911 (2024)Cite this article

Subjects

Abstract

Balanced immune responses in the eyes are crucial to preserve vision. The ocular immune system has long been considered distinct, owing to the so-called ‘immune privilege’ of its component tissues. More recently, intravital imaging and transcriptomic techniques have reshaped scientific understanding of the ocular immune landscape, such as revealing the specialization of immune cell populations in the various tissues of the eye. As knowledge of the phenotypes of corneal and retinal immune cells has evolved, links to both the systemic immune system, and the central and peripheral nervous systems, have been identified. Using intravital imaging, T cells have recently been found to reside in, and actively patrol, the healthy human cornea. Disease-associated retinal microglia with links to retinal degeneration have also been identified. This Review provides an updated guide to the ocular immune system, highlighting current knowledge of the immune cells that are present in steady-state and specific diseased ocular tissues, as well as evidence for their relationship to systemic disease. In addition, we discuss emerging intravital imaging techniques that can be used to visualize immune cell morphology and dynamics in living human eyes and how these could be applied to advance understanding of the human immune system.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Overview of the ocular immune landscape in the healthy human eye.
Fig. 2: Neuroimmune interactions and pathways in the cornea.
Fig. 3: Neuroimmune interactions and pathways in the retina.

Similar content being viewed by others

References

  1. Wieghofer, P. et al. Mapping the origin and fate of myeloid cells in distinct compartments of the eye by single-cell profiling. EMBO J. 40, e105123 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Downie, L. E. et al. Redefining the human corneal immune compartment using dynamic intravital imaging. Proc. Natl Acad. Sci. USA 120, e2217795120 (2023). This study is the first to show that intraepithelial lymphocytes make up a substantial portion of cells in human corneal epithelium.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hammer, D. X., Agrawal, A., Villanueva, R., Saeedi, O. & Liu, Z. Label-free adaptive optics imaging of human retinal macrophage distribution and dynamics. Proc. Natl Acad. Sci. USA 117, 30661–30669 (2020). This study characterizes the distribution and dynamics of retinal macrophages in living humans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Colorado, L. H., Edwards, K., Chinnery, H. R. & Bazan, H. E. In vivo immune cell dynamics in the human cornea. Exp. Eye Res. 199, 108168 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Loi, J. K. et al. Corneal tissue-resident memory T cells form a unique immune compartment at the ocular surface. Cell Rep. 39, 110852 (2022). This study shows the formation of tissue-resident memory T cells in the mouse cornea following viral infection.

    Article  CAS  PubMed  Google Scholar 

  6. Sim, R., Yong, K., Liu, Y. C. & Tong, L. In vivo confocal microscopy in different types of dry eye and meibomian gland dysfunction. J. Clin. Med. 11, 2349 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cavalcanti, B. M. et al. In vivo confocal microscopy detects bilateral changes of corneal immune cells and nerves in unilateral herpes zoster ophthalmicus. Ocul. Surf. 16, 101–111 (2018).

    Article  PubMed  Google Scholar 

  8. Chirapapaisan, C. et al. In vivo confocal microscopy demonstrates increased immune cell densities in corneal graft rejection correlating with signs and symptoms. Am. J. Ophthalmol. 203, 26–36 (2019).

    Article  PubMed  Google Scholar 

  9. Dehghani, C. et al. Morphometric changes to corneal dendritic cells in individuals with mild cognitive impairment. Front. Neurosci. 14, 556137 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Dick, A. D. Influence of microglia on retinal progenitor cell turnover and cell replacement. Eye 23, 1939–1945 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Vendomele, J., Khebizi, Q. & Fisson, S. Cellular and molecular mechanisms of anterior chamber-associated immune deviation (ACAID): what we have learned from knockout mice. Front. Immunol. 8, 1686 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Jiang, L. Q., Jorquera, M. & Streilein, J. W. Subretinal space and vitreous cavity as immunologically privileged sites for retinal allografts. Invest. Ophthalmol. Vis. Sci. 34, 3347–3354 (1993).

    CAS  PubMed  Google Scholar 

  13. Rosenbaum, J. T., Woods, A., Kezic, J., Planck, S. R. & Rosenzweig, H. L. Contrasting ocular effects of local versus systemic endotoxin. Invest. Ophthalmol. Vis. Sci. 52, 6472–6477 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dando, S. J., Kazanis, R. & McMenamin, P. G. Myeloid cells in the mouse retina and uveal tract respond differently to systemic inflammatory stimuli. Invest. Ophthalmol. Vis. Sci. 62, 10 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. McDermott, A. M. Antimicrobial compounds in tears. Exp. Eye Res. 117, 53–61 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Taylor, A. A review of the influence of aqueous humor on immunity. Ocul. Immunol. Inflamm. 11, 231–241 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Shin, H. et al. Changes in the eye microbiota associated with contact lens wearing. mBio 7, e00198 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Graham, J. E. et al. Ocular pathogen or commensal: a PCR-based study of surface bacterial flora in normal and dry eyes. Invest. Ophthalmol. Vis. Sci. 48, 5616–5623 (2007).

    Article  PubMed  Google Scholar 

  19. Song, H., Xiao, K., Min, H., Chen, Z. & Long, Q. Characterization of conjunctival sac microbiome from patients with allergic conjunctivitis. J. Clin. Med. 11, 1130 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang, X. et al. An ocular glymphatic clearance system removes beta-amyloid from the rodent eye. Sci. Transl. Med. 12, eaaw3210 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yin, X. et al. Compartmentalized ocular lymphatic system mediates eye–brain immunity. Nature 628, 204–211 (2024). This study shows that antigens from the posterior compartment of the eye drain to the deep cervical lymph nodes via lymphatic vasculature in the optic nerve sheath.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liu, J. & Li, Z. Resident innate immune cells in the cornea. Front. Immunol. 12, 620284 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Britten-Jones, A. C., Rajan, R., Craig, J. P. & Downie, L. E. Quantifying corneal immune cells from human in vivo confocal microscopy images: can manual quantification be improved with observer training? Exp. Eye Res. 216, 108950 (2022).

    Article  CAS  PubMed  Google Scholar 

  24. Tajbakhsh, Z. et al. Dendritiform immune cells with reduced antigen-capture capacity persist in the cornea during the asymptomatic phase of allergic conjunctivitis. Eye 37, 2768–2775 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Dou, S. et al. Single-cell atlas of keratoconus corneas revealed aberrant transcriptional signatures and implicated mechanical stretch as a trigger for keratoconus pathogenesis. Cell Discov. 8, 66 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dijkgraaf, F. E. et al. Tissue patrol by resident memory CD8(+) T cells in human skin. Nat. Immunol. 20, 756–764 (2019).

    Article  CAS  PubMed  Google Scholar 

  27. Gebhardt, T. et al. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477, 216–219 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Beura, L. K. et al. Intravital mucosal imaging of CD8(+) resident memory T cells shows tissue-autonomous recall responses that amplify secondary memory. Nat. Immunol. 19, 173–182 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yamagami, S. et al. Distinct populations of dendritic cells in the normal human donor corneal epithelium. Invest. Ophthalmol. Vis. Sci. 46, 4489–4494 (2005).

    Article  PubMed  Google Scholar 

  30. Wu, M. et al. Intravital imaging of the human cornea reveals the differential effects of season on innate and adaptive immune cell morphodynamics. Ophthalmology https://doi.org/10.1016/j.ophtha.2024.04.020 (2024).

  31. Mueller, S. N. & Mackay, L. K. Tissue-resident memory T cells: local specialists in immune defence. Nat. Rev. Immunol. 16, 79–89 (2016).

    Article  CAS  PubMed  Google Scholar 

  32. Strobl, J. & Haniffa, M. Functional heterogeneity of human skin-resident memory T cells in health and disease. Immunol. Rev. 316, 104–119 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Arnous, R. et al. Tissue resident memory T cells inhabit the deep human conjunctiva. Sci. Rep. 12, 6077 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Schenkel, J. M., Fraser, K. A., Vezys, V. & Masopust, D. Sensing and alarm function of resident memory CD8(+) T cells. Nat. Immunol. 14, 509–513 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Park, S. L. et al. Local proliferation maintains a stable pool of tissue-resident memory T cells after antiviral recall responses. Nat. Immunol. 19, 183–191 (2018).

    Article  CAS  PubMed  Google Scholar 

  36. Bitirgen, G. et al. Corneal confocal microscopy identifies corneal nerve fibre loss and increased dendritic cells in patients with long covid. Br. J. Ophthalmol. 106, 1635–1641 (2022).

    Article  PubMed  Google Scholar 

  37. Li, W. et al. The miR-183/96/182 cluster is a checkpoint for resident immune cells and shapes the cellular landscape of the cornea. Ocul. Surf. 30, 17–41 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  38. DeMaio, A., Mehrotra, S., Sambamurti, K. & Husain, S. The role of the adaptive immune system and T cell dysfunction in neurodegenerative diseases. J. Neuroinflamm. 19, 251 (2022).

    Article  Google Scholar 

  39. Deliyanti, D. et al. CD8(+) T cells promote pathological angiogenesis in ocular neovascular disease. Arterioscler. Thromb. Vasc. Biol. 43, 522–536 (2023).

    Article  CAS  PubMed  Google Scholar 

  40. Deliyanti, D. et al. Foxp3(+) Tregs are recruited to the retina to repair pathological angiogenesis. Nat. Commun. 8, 748 (2017). This study shows that regulatory T cells are recruited to the retina and take an active role in protecting the eye from neovascularization in oxygen-induced retinopathy.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Luger, D. et al. Either a TH17 or a TH1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. J. Exp. Med. 205, 799–810 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chen, Y. H. et al. Functionally distinct IFN-gamma(+) IL-17a(+) TH cells in experimental autoimmune uveitis: T-cell heterogeneity, migration, and steroid response. Eur. J. Immunol. 50, 1941–1951 (2020).

    Article  CAS  PubMed  Google Scholar 

  43. Fan, N. W. et al. Long-lived autoreactive memory CD4(+) T cells mediate the sustained retinopathy in chronic autoimmune uveitis. FASEB J. 37, e22855 (2023).

    Article  CAS  PubMed  Google Scholar 

  44. Boldison, J. et al. Tissue-resident exhausted effector memory CD8+ T cells accumulate in the retina during chronic experimental autoimmune uveoretinitis. J. Immunol. 192, 4541–4550 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Paskeviciute, E. et al. Systemic virus infection results in CD8 T cell recruitment to the retina in the absence of local virus infection. Front. Immunol. 14, 1221511 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Voigt, V. et al. Cytomegalovirus establishes a latent reservoir and triggers long-lasting inflammation in the eye. PLoS Pathog. 14, e1007040 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Urban, S. L. et al. Peripherally induced brain tissue-resident memory CD8(+) T cells mediate protection against CNS infection. Nat. Immunol. 21, 938–949 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gate, D. et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature 577, 399–404 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Conedera, F. M. et al. Assessing the role of T cells in response to retinal injury to uncover new therapeutic targets for the treatment of retinal degeneration. J. Neuroinflamm. 20, 206 (2023).

    Article  CAS  Google Scholar 

  50. Groh, J. et al. Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline. Nat. Aging 1, 357–367 (2021).

    Article  PubMed  Google Scholar 

  51. Zhang, X. et al. Aged microglia promote peripheral T cell infiltration by reprogramming the microenvironment of neurogenic niches. Immun. Ageing 19, 34 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hu, P., Pollard, J. D. & Chan-Ling, T. Breakdown of the blood–retinal barrier induced by activated T cells of nonneural specificity. Am. J. Pathol. 156, 1139–1149 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bose, T., Lee, R., Hou, A., Tong, L. & Chandy, K. G. Tissue resident memory T cells in the human conjunctiva and immune signatures in human dry eye disease. Sci. Rep. 7, 45312 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Li, L. et al. Conjunctiva resident γδ T cells expressed high level of IL-17a and promoted the severity of dry eye. Invest. Ophthalmol. Vis. Sci. 63, 13 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhao, Z. et al. Choroidal γδ T cells in protection against retinal pigment epithelium and retinal injury. FASEB J. 31, 4903–4916 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Liu, J. et al. Local group 2 innate lymphoid cells promote corneal regeneration after epithelial abrasion. Am. J. Pathol. 187, 1313–1326 (2017).

    Article  PubMed  Google Scholar 

  57. Alam, J. et al. Single-cell transcriptional profiling of murine conjunctival immune cells reveals distinct populations expressing homeostatic and regulatory genes. Mucosal Immunol. 15, 620–628 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhang, X. et al. NK cells promote Th-17 mediated corneal barrier disruption in dry eye. PLoS ONE 7, e36822 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zarzuela, J. C., Reinoso, R., Armentia, A., Enriquez-de-Salamanca, A. & Corell, A. Conjunctival intraepithelial lymphocytes, lacrimal cytokines and ocular commensal microbiota: analysis of the three main players in allergic conjunctivitis. Front. Immunol. 13, 911022 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Knickelbein, J. E., Watkins, S. C., McMenamin, P. G. & Hendricks, R. L. Stratification of antigen-presenting cells within the normal cornea. Ophthalmol. Eye Dis. 1, 45–54 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chinnery, H. R. et al. The chemokine receptor CX3CR1 mediates homing of MHC class II-positive cells to the normal mouse corneal epithelium. Invest. Ophthalmol. Vis. Sci. 48, 1568–1574 (2007).

    Article  PubMed  Google Scholar 

  62. Hattori, T. et al. Characterization of langerin-expressing dendritic cell subsets in the normal cornea. Invest. Ophthalmol. Vis. Sci. 52, 4598–4604 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mass, E., Nimmerjahn, F., Kierdorf, K. & Schlitzer, A. Tissue-specific macrophages: how they develop and choreograph tissue biology. Nat. Rev. Immunol. 23, 563–579 (2023).

    Article  CAS  PubMed  Google Scholar 

  64. Ma, B. et al. Mapping resident immune cells in the murine ocular surface and lacrimal gland by flow cytometry. Ocul. Immunol. Inflamm. 31, 748–759 (2023).

    Article  CAS  PubMed  Google Scholar 

  65. Senthil, K., Jiao, H., Downie, L. E. & Chinnery, H. R. Altered corneal epithelial dendritic cell morphology and phenotype following acute exposure to hyperosmolar saline. Invest. Ophthalmol. Vis. Sci. 62, 38 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Liu, Y., Hamrah, P., Zhang, Q., Taylor, A. W. & Dana, M. R. Draining lymph nodes of corneal transplant hosts exhibit evidence for donor major histocompatibility complex (MHC) class II-positive dendritic cells derived from MHC class II-negative grafts. J. Exp. Med. 195, 259–268 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Buela, K. A. & Hendricks, R. L. Cornea-infiltrating and lymph node dendritic cells contribute to CD4+ T cell expansion after herpes simplex virus-1 ocular infection. J. Immunol. 194, 379–387 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. Knickelbein, J. E., Buela, K. A. & Hendricks, R. L. Antigen-presenting cells are stratified within normal human corneas and are rapidly mobilized during ex vivo viral infection. Invest. Ophthalmol. Vis. Sci. 55, 1118–1123 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Jamali, A. et al. Plasmacytoid dendritic cells in the eye. Prog. Retin. Eye Res. 80, 100877 (2021).

    Article  CAS  PubMed  Google Scholar 

  70. Colonna, M., Trinchieri, G. & Liu, Y. J. Plasmacytoid dendritic cells in immunity. Nat. Immunol. 5, 1219–1226 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Jamali, A. et al. Characterization of resident corneal plasmacytoid dendritic cells and their pivotal role in herpes simplex keratitis. Cell Rep. 32, 108099 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Luznik, Z. et al. Identification and characterization of dendritic cell subtypes in preserved and cultured cadaveric human corneolimbal tissue on amniotic membrane. Acta Ophthalmol. 97, e184–e193 (2019).

    Article  CAS  PubMed  Google Scholar 

  73. Chinnery, H. R., McMenamin, P. G. & Dando, S. J. Macrophage physiology in the eye. Pflug. Arch. 469, 501–515 (2017).

    Article  CAS  Google Scholar 

  74. Gulka, S. M. D., Gowen, B., Litke, A. M., Delaney, K. R. & Chow, R. L. Laser-induced microinjury of the corneal basal epithelium and imaging of resident macrophage responses in a live, whole-eye preparation. Front. Immunol. 14, 1050594 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhuang, X. et al. Time- and stimulus-dependent characteristics of innate immune cells in organ-cultured human corneal tissue. J. Innate Immun. 14, 98–111 (2022).

    Article  CAS  PubMed  Google Scholar 

  76. Orecchioni, M., Ghosheh, Y., Pramod, A. B. & Ley, K. Macrophage polarization: different gene signatures in M1(LPS+) vs. classically and M2(LPS−) vs. alternatively activated macrophages. Front. Immunol. 10, 1084 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Jaggi, U. et al. Increased phagocytosis in the presence of enhanced M2-like macrophage responses correlates with increased primary and latent HSV-1 infection. PLoS Pathog. 16, e1008971 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Jaggi, U. et al. Essential role of M1 macrophages in blocking cytokine storm and pathology associated with murine HSV-1 infection. PLoS Pathog. 17, e1009999 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Tian, H., Wu, J. & Ma, M. Implications of macrophage polarization in corneal transplantation rejection. Transpl. Immunol. 64, 101353 (2021).

    Article  PubMed  Google Scholar 

  80. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Benhar, I. et al. Temporal single-cell atlas of non-neuronal retinal cells reveals dynamic, coordinated multicellular responses to central nervous system injury. Nat. Immunol. 24, 700–713 (2023).

    Article  CAS  PubMed  Google Scholar 

  82. O’Koren, E. G., Mathew, R. & Saban, D. R. Fate mapping reveals that microglia and recruited monocyte-derived macrophages are definitively distinguishable by phenotype in the retina. Sci. Rep. 6, 20636 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Jordao, M. J. C. et al. Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science 363, eaat7554 (2019).

    Article  CAS  PubMed  Google Scholar 

  84. Kierdorf, K., Masuda, T., Jordao, M. J. C. & Prinz, M. Macrophages at CNS interfaces: ontogeny and function in health and disease. Nat. Rev. Neurosci. 20, 547–562 (2019).

    Article  CAS  PubMed  Google Scholar 

  85. Checchin, D., Sennlaub, F., Levavasseur, E., Leduc, M. & Chemtob, S. Potential role of microglia in retinal blood vessel formation. Invest. Ophthalmol. Vis. Sci. 47, 3595–3602 (2006).

    Article  PubMed  Google Scholar 

  86. Diaz-Araya, C. M., Provis, J. M., Penfold, P. L. & Billson, F. A. Development of microglial topography in human retina. J. Comp. Neurol. 363, 53–68 (1995).

    Article  CAS  PubMed  Google Scholar 

  87. Chen, L., Yang, P. & Kijlstra, A. Distribution, markers, and functions of retinal microglia. Ocul. Immunol. Inflamm. 10, 27–39 (2002).

    Article  PubMed  Google Scholar 

  88. Bodeutsch, N. & Thanos, S. Migration of phagocytotic cells and development of the murine intraretinal microglial network: an in vivo study using fluorescent dyes. Glia 32, 91–101 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Murenu, E., Gerhardt, M. J., Biel, M. & Michalakis, S. More than meets the eye: the role of microglia in healthy and diseased retina. Front. Immunol. 13, 1006897 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. O’Koren, E. G. et al. Microglial function is distinct in different anatomical locations during retinal homeostasis and degeneration. Immunity 50, 723–737.e7 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Xu, H., Chen, M., Mayer, E. J., Forrester, J. V. & Dick, A. D. Turnover of resident retinal microglia in the normal adult mouse. Glia 55, 1189–1198 (2007).

    Article  PubMed  Google Scholar 

  93. London, A. et al. Neuroprotection and progenitor cell renewal in the injured adult murine retina requires healing monocyte-derived macrophages. J. Exp. Med. 208, 23–39 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Guillonneau, X. et al. On phagocytes and macular degeneration. Prog. Retin. Eye Res. 61, 98–128 (2017).

    Article  CAS  PubMed  Google Scholar 

  95. Calippe, B. et al. Complement factor H inhibits CD47-mediated resolution of inflammation. Immunity 46, 261–272 (2017).

    Article  CAS  PubMed  Google Scholar 

  96. Beguier, F. et al. The 10q26 risk haplotype of age-related macular degeneration aggravates subretinal inflammation by impairing monocyte elimination. Immunity 53, 429–441.e8 (2020).

    Article  CAS  PubMed  Google Scholar 

  97. Yu, C. et al. Microglia at sites of atrophy restrict the progression of retinal degeneration via galectin-3 and Trem2. J. Exp. Med. 221, e20231011 (2024). This study shows that retinal microglia migrate into the subretinal space and undergo reprogramming by upregulating genes linked to neurodegeneration, playing a protective role for photoreceptors and retinal pigment epithelium.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Deczkowska, A. et al. Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell 173, 1073–1081 (2018).

    Article  CAS  PubMed  Google Scholar 

  99. Kuchroo, M. et al. Single-cell analysis reveals inflammatory interactions driving macular degeneration. Nat. Commun. 14, 2589 (2023). This study identifies a similar glial activation profile enriched in the early phase of age-related macular degeneration, Alzheimer disease and progressive multiple sclerosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Mun, Y., Hwang, J. S. & Shin, Y. J. Role of neutrophils on the ocular surface. Int. J. Mol. Sci. 22, 10386 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Mahajan, A. et al. Frontline science: aggregated neutrophil extracellular traps prevent inflammation on the neutrophil-rich ocular surface. J. Leukoc. Biol. 105, 1087–1098 (2019).

    Article  CAS  PubMed  Google Scholar 

  102. Postnikoff, C. K., Held, K., Viswanath, V. & Nichols, K. K. Enhanced closed eye neutrophil degranulation in dry eye disease. Ocul. Surf. 18, 841–851 (2020).

    Article  PubMed  Google Scholar 

  103. DeDreu, J. et al. An immune response to the avascular lens following wounding of the cornea involves ciliary zonule fibrils. FASEB J. 34, 9316–9336 (2020).

    Article  CAS  PubMed  Google Scholar 

  104. McHarg, S. et al. Mast cell infiltration of the choroid and protease release are early events in age-related macular degeneration associated with genetic risk at both chromosomes 1q32 and 10q26. Proc. Natl Acad. Sci. USA 119, e2118510119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Liu, J. et al. Mast cells participate in corneal development in mice. Sci. Rep. 5, 17569 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Xie, Y. et al. Mast cell activation protects cornea by promoting neutrophil infiltration via stimulating ICAM-1 and vascular dilation in fungal keratitis. Sci. Rep. 8, 8365 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Elieh Ali Komi, D., Rambasek, T. & Bielory, L. Clinical implications of mast cell involvement in allergic conjunctivitis. Allergy 73, 528–539 (2018).

    Article  CAS  PubMed  Google Scholar 

  108. McMenamin, P. G. The distribution of immune cells in the uveal tract of the normal eye. Eye 11, 183–193 (1997).

    Article  PubMed  Google Scholar 

  109. Bhutto, I. A. et al. Increased choroidal mast cells and their degranulation in age-related macular degeneration. Br. J. Ophthalmol. 100, 720–726 (2016).

    Article  PubMed  Google Scholar 

  110. McLeod, D. S. et al. Mast cell-derived tryptase in geographic atrophy. Invest. Ophthalmol. Vis. Sci. 58, 5887–5896 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Downie, L. E. et al. CLEAR — anatomy and physiology of the anterior eye. Cont. Lens Anterior Eye 44, 132–156 (2021).

    Article  PubMed  Google Scholar 

  112. Shetty, R. et al. Role of in vivo confocal microscopy in dry eye disease and eye pain. Indian J. Ophthalmol. 71, 1099–1104 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Lagali, N. S. et al. Dendritic cell maturation in the corneal epithelium with onset of type 2 diabetes is associated with tumor necrosis factor receptor superfamily member 9. Sci. Rep. 8, 14248 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Gao, N., Lee, P. & Yu, F. S. Intraepithelial dendritic cells and sensory nerves are structurally associated and functional interdependent in the cornea. Sci. Rep. 6, 36414 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Choi, E. Y. et al. Langerhans cells prevent subbasal nerve damage and upregulate neurotrophic factors in dry eye disease. PLoS ONE 12, e0176153 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Wu, M. et al. The neuroregenerative effects of topical decorin on the injured mouse cornea. J. Neuroinflamm. 17, 142 (2020).

    Article  CAS  Google Scholar 

  117. Doss, A. L. & Smith, P. G. Langerhans cells regulate cutaneous innervation density and mechanical sensitivity in mouse footpad. Neurosci. Lett. 578, 55–60 (2014).

    Article  CAS  PubMed  Google Scholar 

  118. Gao, N., Yan, C., Lee, P., Sun, H. & Yu, F. S. Dendritic cell dysfunction and diabetic sensory neuropathy in the cornea. J. Clin. Invest. 126, 1998–2011 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Parlanti, P. et al. Axonal debris accumulates in corneal epithelial cells after intraepithelial corneal nerves are damaged: a focused ion beam scanning electron microscopy (FIB-SEM) study. Exp. Eye Res. 194, 107998 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kovacs, I. et al. Substance P released from sensory nerve endings influences tear secretion and goblet cell function in the rat. Neuropeptides 39, 395–402 (2005).

    Article  CAS  PubMed  Google Scholar 

  121. Marriott, I. & Bost, K. L. Expression of authentic substance P receptors in murine and human dendritic cells. J. Neuroimmunol. 114, 131–141 (2001).

    Article  CAS  PubMed  Google Scholar 

  122. Lai, J. P., Douglas, S. D. & Ho, W. Z. Human lymphocytes express substance P and its receptor. J. Neuroimmunol. 86, 80–86 (1998).

    Article  CAS  PubMed  Google Scholar 

  123. Twardy, B. S., Channappanavar, R. & Suvas, S. Substance P in the corneal stroma regulates the severity of herpetic stromal keratitis lesions. Invest. Ophthalmol. Vis. Sci. 52, 8604–8613 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Foldenauer, M. E., McClellan, S. A., Berger, E. A. & Hazlett, L. D. Mammalian target of rapamycin regulates IL-10 and resistance to Pseudomonas aeruginosa corneal infection. J. Immunol. 190, 5649–5658 (2013).

    Article  CAS  PubMed  Google Scholar 

  125. Lasagni Vitar, R. M. et al. Modulating ocular surface pain through neurokinin-1 receptor blockade. Invest. Ophthalmol. Vis. Sci. 62, 26 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Hazlett, L. D. et al. Spantide I decreases type I cytokines, enhances IL-10, and reduces corneal perforation in susceptible mice after Pseudomonas aeruginosa infection. Invest. Ophthalmol. Vis. Sci. 48, 797–807 (2007).

    Article  PubMed  Google Scholar 

  127. Yun, H., Lathrop, K. L. & Hendricks, R. L. A central role for sympathetic nerves in herpes stromal keratitis in mice. Invest. Ophthalmol. Vis. Sci. 57, 1749–1756 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Yun, H., Yin, X. T., Stuart, P. M. & St Leger, A. J. Sensory nerve retraction and sympathetic nerve innervation contribute to immunopathology of murine recurrent herpes stromal keratitis. Invest. Ophthalmol. Vis. Sci. 63, 4 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Gaddipati, S. et al. Loss of neurokinin-1 receptor alters ocular surface homeostasis and promotes an early development of herpes stromal keratitis. J. Immunol. 197, 4021–4033 (2016).

    Article  CAS  PubMed  Google Scholar 

  130. Paunicka, K. J. et al. Severing corneal nerves in one eye induces sympathetic loss of immune privilege and promotes rejection of future corneal allografts placed in either eye. Am. J. Transpl. 15, 1490–1501 (2015).

    Article  CAS  Google Scholar 

  131. Taketani, Y. et al. Restoration of regulatory T-cell function in dry eye disease by antagonizing substance P/neurokinin-1 receptor. Am. J. Pathol. 190, 1859–1866 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Datta, A. et al. TRPA1 and TPRV1 ion channels are required for contact lens-induced corneal parainflammation and can modulate levels of resident corneal immune cells. Invest. Ophthalmol. Vis. Sci. 64, 21 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Werneburg, S. et al. Targeted complement inhibition at synapses prevents microglial synaptic engulfment and synapse loss in demyelinating disease. Immunity 52, 167–182.e7 (2020).

    Article  CAS  PubMed  Google Scholar 

  135. Lall, D. et al. C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation. Neuron 109, 2275–2291.e8 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Lehrman, E. K. et al. CD47 protects synapses from excess microglia-mediated pruning during development. Neuron 100, 120–134.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Jiang, D. et al. Neuronal signal-regulatory protein alpha drives microglial phagocytosis by limiting microglial interaction with CD47 in the retina. Immunity 55, 2318–2335.e7 (2022). This study shows that neuronal SIRPα regulates microglial phagocytosis by limiting microglial SIRPα access to neuronal CD47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Wang, H. et al. CD47 antibody blockade suppresses microglia-dependent phagocytosis and monocyte transition to macrophages, impairing recovery in EAE. JCI Insight 6, e148719 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Wolf, Y., Yona, S., Kim, K. W. & Jung, S. Microglia, seen from the CX3CR1 angle. Front. Cell Neurosci. 7, 26 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Zieger, M., Ahnelt, P. K. & Uhrin, P. CX3CL1 (fractalkine) protein expression in normal and degenerating mouse retina: in vivo studies. PLoS ONE 9, e106562 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Jobling, A. I. et al. The role of the microglial CX3CR1 pathway in the postnatal maturation of retinal photoreceptors. J. Neurosci. 38, 4708–4723 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Wang, X. et al. Requirement for microglia for the maintenance of synaptic function and integrity in the mature retina. J. Neurosci. 36, 2827–2842 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Combadiere, C. et al. CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration. J. Clin. Invest. 117, 2920–2928 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Biesecker, K. R. et al. Glial cell calcium signaling mediates capillary regulation of blood flow in the retina. J. Neurosci. 36, 9435–9445 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Mills, S. A. et al. Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic retinopathy. Proc. Natl Acad. Sci. USA 118, e2112561118 (2021). This study shows the role of microglia in regulating retinal capillary diameter that is defective early in diabetes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Bisht, K. et al. Capillary-associated microglia regulate vascular structure and function through PANX1–P2RY12 coupling in mice. Nat. Commun. 12, 5289 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Csaszar, E. et al. Microglia modulate blood flow, neurovascular coupling, and hypoperfusion via purinergic actions. J. Exp. Med. 219, e20211071 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Zabel, M. K. et al. Microglial phagocytosis and activation underlying photoreceptor degeneration is regulated by CX3CL1–CX3CR1 signaling in a mouse model of retinitis pigmentosa. Glia 64, 1479–1491 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Pfeifer, C. W. et al. Dysregulated CD200–CD200R signaling in early diabetes modulates microglia-mediated retinopathy. Proc. Natl Acad. Sci. USA 120, e2308214120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. D’Onofrio, L. et al. Small nerve fiber damage and Langerhans cells in type 1 and type 2 diabetes and LADA measured by corneal confocal microscopy. Invest. Ophthalmol. Vis. Sci. 62, 5 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  151. O’Brien, J. A. et al. T lymphocyte and monocyte subsets are dysregulated in type 1 diabetes patients with peripheral neuropathic pain. Brain Behav. Immun. Health 15, 100283 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  152. So, W. Z. et al. Diabetic corneal neuropathy as a surrogate marker for diabetic peripheral neuropathy. Neural Regen. Res. 17, 2172–2178 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Koronyo, Y. et al. Retinal pathological features and proteome signatures of Alzheimer’s disease. Acta Neuropathol. 145, 409–438 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Hayden, E. Y. & Teplow, D. B. Amyloid beta-protein oligomers and Alzheimer’s disease. Alzheimers Res. Ther. 5, 60 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45, 1452–1458 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. van der Poel, M. et al. Transcriptional profiling of human microglia reveals grey-white matter heterogeneity and multiple sclerosis-associated changes. Nat. Commun. 10, 1139 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Biessels, G. J. & Reijmer, Y. D. Brain changes underlying cognitive dysfunction in diabetes: what can we learn from MRI? Diabetes 63, 2244–2252 (2014).

    Article  PubMed  Google Scholar 

  158. Chai, Y. H. et al. Association between diabetic retinopathy, brain structural abnormalities, and cognitive impairment for accumulated evidence in observational studies. Am. J. Ophthalmol. 239, 37–53 (2022).

    Article  CAS  PubMed  Google Scholar 

  159. Xie, H. et al. Erythropoietin protects the inner blood–retinal barrier by inhibiting microglia phagocytosis via SRC/AKT/cofilin signalling in experimental diabetic retinopathy. Diabetologia 64, 211–225 (2021).

    Article  CAS  PubMed  Google Scholar 

  160. Chang, K. C., Shieh, B. & Petrash, J. M. Role of aldose reductase in diabetes-induced retinal microglia activation. Chem. Biol. Interact. 302, 46–52 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Huang, Z. et al. RIP3-mediated microglial necroptosis promotes neuroinflammation and neurodegeneration in the early stages of diabetic retinopathy. Cell Death Dis. 14, 227 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Jiang, M. et al. Enhancing fractalkine/CX3CR1 signalling pathway can reduce neuroinflammation by attenuating microglia activation in experimental diabetic retinopathy. J. Cell Mol. Med. 26, 1229–1244 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Kugadas, A., Wright, Q., Geddes-McAlister, J. & Gadjeva, M. Role of microbiota in strengthening ocular mucosal barrier function through secretory IgA. Invest. Ophthalmol. Vis. Sci. 58, 4593–4600 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Horai, R. et al. Microbiota-dependent activation of an autoreactive T cell receptor provokes autoimmunity in an immunologically privileged site. Immunity 43, 343–353 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Wu, M., Hill, L. J., Downie, L. E. & Chinnery, H. R. Neuroimmune crosstalk in the cornea: the role of immune cells in corneal nerve maintenance during homeostasis and inflammation. Prog. Retin. Eye Res. 91, 101105 (2022).

    Article  CAS  PubMed  Google Scholar 

  166. de Paiva, C. S., St Leger, A. J. & Caspi, R. R. Mucosal immunology of the ocular surface. Mucosal Immunol. 15, 1143–1157 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Reekie, I. R. et al. The cellular composition of the uveal immune environment. Front. Med. 8, 721953 (2021).

    Article  Google Scholar 

  168. McPherson, S. W., Heuss, N. D., Pierson, M. J. & Gregerson, D. S. Retinal antigen-specific regulatory T cells protect against spontaneous and induced autoimmunity and require local dendritic cells. J. Neuroinflamm. 11, 205 (2014).

    Article  Google Scholar 

  169. Menko, A. S. et al. Resident immune cells of the avascular lens: mediators of the injury and fibrotic response of the lens. FASEB J. 35, e21341 (2021).

    Article  CAS  PubMed  Google Scholar 

  170. Boneva, S. K. et al. Transcriptional profiling uncovers human hyalocytes as a unique innate immune cell population. Front. Immunol. 11, 567274 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Stachs, O., Guthoff, R. F. & Aumann, S. in High Resolution Imaging in Microscopy and Ophthalmology: New Frontiers in Biomedical Optics (ed. Bille, J. F.) 263–284 (Springer, 2019).

  172. Chiang, J. C. B., Roy, M., Kim, J., Markoulli, M. & Krishnan, A. V. In-vivo corneal confocal microscopy: imaging analysis, biological insights and future directions. Commun. Biol. 6, 652 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Stepp, M. A. et al. Corneal epithelial ‘neuromas’: a case of mistaken identity? Cornea 39, 930–934 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Chinnery, H. R. et al. Identification of presumed corneal neuromas and microneuromas using laser-scanning in vivo confocal microscopy: a systematic review. Br. J. Ophthalmol. 106, 765–771 (2022).

    Article  PubMed  Google Scholar 

  175. Wu, M., Chinnery, H. R., De Silva, M. E. H. & Downie, L. E. Characterisation and clustering of corneal stromal-epithelial nerve penetration sites in healthy adults: a laser-scanning in vivo confocal microscopy study. Clin. Exp. Ophthalmol. 51, 746–749 (2023).

    Article  PubMed  Google Scholar 

  176. Chinnery, H. R., Zhang, X. Y., Wu, C. Y. & Downie, L. E. Corneal immune cell morphometry as an indicator of local and systemic pathology: a review. Clin. Exp. Ophthalmol. 49, 729–740 (2021).

    Article  PubMed  Google Scholar 

  177. Liu, Z., Kurokawa, K., Zhang, F., Lee, J. J. & Miller, D. T. Imaging and quantifying ganglion cells and other transparent neurons in the living human retina. Proc. Natl Acad. Sci. USA 114, 12803–12808 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Liu, Z., Tam, J., Saeedi, O. & Hammer, D. X. Trans-retinal cellular imaging with multimodal adaptive optics. Biomed. Opt. Express 9, 4246–4262 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Migacz, J. V. et al. Imaging of vitreous cortex hyalocyte dynamics using non-confocal quadrant-detection adaptive optics scanning light ophthalmoscopy in human subjects. Biomed. Opt. Express 13, 1755–1773 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Hammer, D. X. et al. Cellular-level visualization of retinal pathology in multiple sclerosis with adaptive optics. Invest. Ophthalmol. Vis. Sci. 64, 21 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Castanos, M. V. et al. Imaging of macrophage-like cells in living human retina using clinical OCT. Invest. Ophthalmol. Vis. Sci. 61, 48 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Joseph, A., Chu, C. J., Feng, G., Dholakia, K. & Schallek, J. Label-free imaging of immune cell dynamics in the living retina using adaptive optics. eLife 9, e60547 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Joseph, A., Power, D. & Schallek, J. Imaging the dynamics of individual processes of microglia in the living retina in vivo. Biomed. Opt. Express 12, 6157–6183 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank H. Horsnell, L. Alarcon-Martinez and K. Senthil for critical input. This work was supported by the Australian Research Council (DP230102105 to H.R.C., L.E.D. and S.N.M.). S.N.M. is a recipient of a National Health and Medical Research Council Investigator Fellowship (2017220).

Author information

Author notes

  1. These authors contributed equally: Holly R. Chinnery, Laura E. Downie, Scott N. Mueller.

Authors and Affiliations

  1. Department of Optometry and Vision Sciences, The University of Melbourne, Carlton, Victoria, Australia

    Mengliang Wu, Holly R. Chinnery & Laura E. Downie

  2. Department of Microbiology and Immunology, The University of Melbourne, at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia

    Mengliang Wu & Scott N. Mueller

  3. Department of Anatomy and Physiology, The University of Melbourne, Carlton, Victoria, Australia

    Erica L. Fletcher

  4. Lions Eye Institute, Nedlands, Western Australia, Australia

    Holly R. Chinnery

  5. Optometry, The University of Western Australia, Crawley, Western Australia, Australia

    Holly R. Chinnery

Authors
  1. Mengliang Wu
    View author publications

    Search author on:PubMed Google Scholar

  2. Erica L. Fletcher
    View author publications

    Search author on:PubMed Google Scholar

  3. Holly R. Chinnery
    View author publications

    Search author on:PubMed Google Scholar

  4. Laura E. Downie
    View author publications

    Search author on:PubMed Google Scholar

  5. Scott N. Mueller
    View author publications

    Search author on:PubMed Google Scholar

Contributions

H.R.C., L.E.D. and S.N.M. conceived the article. M.W., H.R.C., L.E.D. and S.N.M. wrote the first draft of the manuscript. All authors contributed to additional writing and editing of the article. M.W. prepared display items under supervision from E.L.F., H.R.C., L.E.D. and S.N.M. All authors approved the submitted version of the article.

Corresponding authors

Correspondence to Holly R. Chinnery, Laura E. Downie or Scott N. Mueller.

Ethics declarations

Competing interests

M.W., H.R.C, L.E.D and S.N.M have submitted an Australian Provisional Patent Application (2023901150) relating to the imaging method described in this article (intellectual property owned by institution). E.L.F. declares no competing interests.

Peer review

Peer review information

Nature Reviews Immunology thanks John Forrester and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Age-related macular degeneration

(AMD). A degenerative condition of the central retina (macula) that is the leading cause of irreversible vision loss in those over 65 years of age. AMD is clinically classified into three main stages, based on severity: early, intermediate and late. Late AMD has two forms: neovascular and geographic atrophy.

Experimental autoimmune uveoretinitis

A T cell-mediated autoimmune disease induced in preclinical (animal) models to affect the uvea and retina, which serves as a model for the intraocular inflammation evident in human autoimmune (non-infectious) uveitis.

Ischaemic retinopathy

A retinal pathological state caused by lack of sufficient blood flow to match the metabolic needs of the retina. Common examples include experimental oxygen-induced retinopathy, human retinopathy of prematurity and diabetic retinopathy.

Retinal degeneration

A group of heterogeneous conditions defined by the progressive death of retinal neural cells.

Uveitis

An umbrella term for a group of conditions caused by inflammation of the uvea, comprising the iris, ciliary body and choroid. Causes of uveitis are heterogeneous, including infectious and non-infectious aetiologies.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, M., Fletcher, E.L., Chinnery, H.R. et al. Redefining our vision: an updated guide to the ocular immune system. Nat Rev Immunol 24, 896–911 (2024). https://doi.org/10.1038/s41577-024-01064-y

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41577-024-01064-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing