Basics of Ocular Immunology: Comparison
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Please note this is a comparison between Version 2 by Camila Xu and Version 1 by Christopher D. D Conrady.

Ocular infectious diseases are an important cause of potentially preventable vision loss and blindness. Bacteria and viruses represent the more common causes of ocular infections worldwide and can affect nearly any anatomical part of the eye.

  • acute retinal necrosis
  • innate immunity
  • ocular immunology
  • immune privilege

1. Introduction

The eye is a complex sensory organ directly exposed to the environment and responsible for converting light into electrical signals and eventually images interpreted by the brain. Local tissue changes associated with inflammation and infection can reduce eye function and visual acuity. In fact, an inflammatory event in one eye can affect the function of the clinically “normal” contralateral eye [1]. Complications from ocular infectious diseases are a significant cause of visual impairment, most notably with rates worldwide of 1.4% of total cases of blindness due to corneal opacification from Chlamydia trachomatis alone [2]. This results in estimates as high as 5.5 million people who are bilaterally blind from the disease [3]. Within the developed world, herpes simplex viruses are a common pathogen and the leading cause of corneal blindness [4]. As such, infectious diseases of the eye are a significant global burden, whether they be from corneal opacification from trachoma or herpetic keratitis or damage to other structures of the eye such as the retina from Toxoplasmosis gondii. Blindness from any cause is more common than previously thought and is estimated to cause a loss in productivity of over USD 400 billion worldwide [5,6][5][6] The socioeconomic and psychosocial burden of blindness to a patient, family, and community are substantial with underlying infectious etiologies being potentially treatable, if not completely preventable, common causes of severe vision loss.
Bacteria and viruses represent the more common causes of ocular infections worldwide and can affect nearly any anatomical part of the eye (Table 1 and Table 2). The overall geographic distribution and common bacterial isolates from ocular infections have been extensively reviewed elsewhere, but Staphylococcus aureus, Coagulase negative Staphylococci, Streptococcus pneumoniae, and Pseudomonas aeruginosa are the leading isolates of bacterial infections of the eye and adnexa (Table 1) [7]. While not specifically evaluated in a large meta-analysis, adenoviruses and herpesviruses are the most routinely encountered viruses within the eye (Table 2) [8]. However, there can be geographic variation in the most common ocular pathogens and rare ocular presentations from unlikely organisms [9,10,11,12,13][9][10][11][12][13]. This is most clearly seen with the geographic distribution of the three clades of Toxoplasmosis gondii worldwide and the very rare occurrence of Trypanosome cruzii-associated retinitis [9,14,15,16][9][14][15][16].
Table 1.
Ocular infections and their common causative bacteria.
Sites of Ocular Infections and Associated Bacterial Microbes
  Site of Infection   Associated Bacteria
Site of Infection
Infection Category Associated Pathogens
Ocular Surface Keratitis Gram-Positive Staphylococcus spp., Enterococcus faecalis, Corynebacterium spp., and Bacillus spp.
Ocular Surface Keratitis Viruses HSV, VSV, and adenovirus
Gram-Negative
FungiPseudomonas aeruginosa, Candida spp., and Aspergillus spp.
Protozoa Acanthamoeba spp.
Conjunctivitis Viruses HSV, and adenoviruses
Episcleritis/Scleritis Viruses VZV
Intraocular Anterior Uveitis Viruses HSV, VZV, and CMV
Posterior Uveitis Viruses HSV, VZV, and CMV
Endophthalmitis Protozoa Toxoplasma gondii
Viruses
Ocular Adnexa Dacryocystis Gram-Positive Staphylococcus spp., Streptococcus spp., and Corynebacterium spp.
Gram-Negative Pseudomonas spp., Enterobacter spp., Klebsella. pneumoniae, Haemophilus influenzae, Escherichia coli, * Acinetobacter iwoifi, * Haemophilus parainfluenzae, and * Haemophilus aegypticus
Blepharitis Gram-Positive Staphylococcus aureus, Staphylococcus spp., Enterococcus faecalis, and Corynebacterium spp.
Gram-Negative Haemophilus influenzae
Rarely Observed *.
Table 2.
Ocular infections and their common causative viruses, fungi, arthropods, and protozoan species.
Sites of Ocular Infections and Associated Microbes
 
Escherichia coli
, K. pneumoniae, Acinetobacter, Serratia marcescens, Serratia liquefaciens, Aeromonas spp., Fusobacterium spp., Enterobacter spp., Proteus mirabilis, P Pasteurella multocida, Morexella catarrhalis, and Haemophilus influenzae
Conjunctivitis Gram-Positive Staphylococcus spp., Streptoccus spp., E. faecalis, Corynebacterium spp., and Bacillus spp.
Gram-Negative Neisseria gonorrhoeae, Chlamydia trachomatis, Escherichia coli, P. aeruginosa, Enterobacter spp. (i.e., E. cloacae and E. aerogenes), Citrobacter koseri, Proteus spp., Moraxella spp., Morexella catarrhalis, and Haemophilus influenzae
Episcleritis/Scleritis Gram-Positive Staphylococcus spp., Streptococcus spp., Nocardia
Gram-Negative Pseudomonas aeruginosa, Klebsiella spp., and Mycobacterium tuberculosis
Intraocular Uveitis Gram-Positive * Nocardia brasiliensis
Gram-Negative Mycobaterium tuberculosis, * Rickettsia spp., * Francisella tularensis, * Bartonella henselae, * Yersinia enterocolitica, * Pasteurella multocida, and * Chlamydia trachomatis
Endophthalmitis Gram-Positive  Staphylococcus spp., Streptoccus spp., Corynebacterium spp., Bacillus spp., and * Clostridium spp.
Gram-Negative Pseudomonas aeruginosa, Escherichia coli,
FungiPropiolactone spp., Serratia spp., Klebsiella pneumoniae, Enterobacter spp., CandidaAcinetobacter spp., Morexella catarrhailis, and Haemophilus spp. spp., Aspergillus spp., and Fusarium spp.
Ocular Adnexa Blepharitis Mites Demodex folliculorum

2. Basics of Ocular Immunology

The eye is directly exposed to the surrounding environment with this interface providing an external surface for the establishment of a local microbiome. As such, the host response to infection of the eye is complex as the organ must rid itself of invading environmental pathogens while minimizing immunologically driven pathology from the self or the nonpathogenic microbiota. The combination of the tear film contents (e.g., IgA, Lactoferrin, defensins, and growth factors) and the continuous washing by tears produced by the lacrimal gland serve to remove infectious agents, limit uncontrolled and unregulated inflammatory damage, provide a physical barrier to the surrounding environment, and promote the healing of the ocular surface to reduce the risk of ocular infection [17]. These antimicrobial compounds and barriers alone, however, are insufficient to protect the eye from pathogen invasion. Relatively similar barriers can be found within the retina and posterior segment [18].
Once physical barriers are breached on or within the eye, innate immune mechanisms serve to rapidly identify the pathogen. While the overall immunological response of the eye may slightly differ compared to that of other sites, innate immune sensors are expressed throughout the eye [19,20,21,22,23][19][20][21][22][23]. Much like those found in other tissues, Toll-like receptors (TLRs) and other innate sensors recognize conserved pathogen-associated molecular patterns and activate Myeloid differentiation primary response protein (MyD)88-dependent and -independent pathways following complex interactions with other inflammatory receptors [24,25][24][25]. NF-κB-related pathways and/or type I interferon (IFN) pathways are preferentially activated by these innate immune sensors [22,26][22][26]. Activation of these pathways leads to local innate immune responses including the production of chemokines to facilitate leukocyte trafficking and priming of the more pathogen-specific adaptive immune response [26]. The interplay between many of these pathways will be further highlighted below regarding specific pathogens within distinct areas of the eye.
To further complicate matters, certain parts of the eye are considered “immune privileged” and respond immunologically in ways not seen in other tissues and organs. This is due in part to blood–aqueous and blood–retinal barriers that prohibit the egress of macromolecules into the eye, limiting the exposure of ocular tissue, including local innate immune cells, to circulating pathogens and toxins [27]. Retinal pigment epithelial cells also upregulate T regulatory responses and suppress effector T cell activation [28,29][28][29]. This ocular anti-inflammatory milieu with an atypical response known as anterior chamber-associated immune deviation (ACAID) is a phenomenon within the eye in which antigens injected into the anterior chamber induce tolerance whereas the host develops a muted or abolished systemic response to the antigen. While the process is not completely understood, the generation of antigen-specific, antigen-presenting B cells within the spleen following antigen exposure intracamerally results in the development of T regulatory cells and interleukin (IL)-10 production in a relatively immunosuppressive microenvironment within the anterior chamber [30,31,32,33][30][31][32][33]. γδ T cells and IFN-γ production also appear to be important in this response as their loss does not allow ACAID to develop [34,35][34][35]. Subretinal exposure to antigens has been shown to induce a similar response to that induced by ACAID [36]. While different cells, cytokines, and chemokines have all been implicated, ACAID is still not completely understood and it is unclear if this is simply a mouse phenomenon or if it is seen in humans.
The hallmark of immune privilege and immune deviation within the eye is epitomized by the exceptionally high rates of success of corneal transplantation compared to those of other tissues and organs despite the lack of preoperative HLA typing [37]. The success of corneal transplantation appears to be related to the unique nature of the eye in which physical and cellular barriers of the cornea, ACAID-induced by T regulatory cells, and the immunosuppressive microenvironment of the anterior chamber reduce inflammatory reactions, promote immune privilege, and thereby reduce graft failure [37,38,39,40][37][38][39][40]. However, immune privilege and corneal transplant rejection can be overridden by severing corneal nerves and this rejection process appears to be driven by minor H alloantigens and the loss of regulatory T cells [41,42,43][41][42][43]. Ocular immune privilege is tightly controlled and can be overcome with relatively innocuous changes to eye anatomy.

References

  1. Azarmina, M.; Soheilian, M.; Ahmadieh, H.; Azarmina, H. Electroretinogram changes in the sound eye of subjects with unilateral necrotizing herpetic retinitis. J. Ophthalmic Vis. Res. 2014, 9, 195–203.
  2. Burton, M.J.; Mabey, D.C.W. The Global Burden of Trachoma: A Review. PLoS Neglected Trop. Dis. 2009, 3, e460.
  3. Wang, E.; Kong, X.; Wolle, M.; Gasquet, N.; Ssekasanvu, J.; Mariotti, S.P.; Bourne, R.; Taylor, H.; Resnikoff, S.; West, S. Global trends in blindness and vision impairment due to corneal opacity 1984–2020: A meta-analysis. Ophthalmology 2023, 2022, 8828358.
  4. Liesegang, T.J.; Melton, L.J., III; Daly, P.J.; Ilstrup, D.M. Epidemiology of Ocular Herpes Simplex: Incidence in Rochester, Minn, 1950 Through 1982. Arch. Ophthalmol. 1989, 107, 1155–1159.
  5. Marques, A.P.; Ramke, J.; Cairns, J.; Butt, T.; Zhang, J.H.; Muirhead, D.; Jones, I.; Tong, B.A.M.A.; Swenor, B.K.; Faal, H.; et al. Global economic productivity losses from vision impairment and blindness. eClinicalMedicine 2021, 35, 100852.
  6. Flaxman, A.D.; Wittenborn, J.S.; Robalik, T.; Gulia, R.; Gerzoff, R.B.; Lundeen, E.A.; Saaddine, J.; Rein, D.B. Vision and Eye Health Surveillance System study group Prevalence of Visual Acuity Loss or Blindness in the US: A Bayesian Meta-analysis. JAMA Ophthalmol. 2021, 139, 717–723.
  7. Teweldemedhin, M.; Gebreyesus, H.; Atsbaha, A.H.; Asgedom, S.W.; Saravanan, M. Bacterial profile of ocular infections: A systematic review. BMC Ophthalmol. 2017, 17, 212.
  8. Petrillo, F.; Petrillo, A.; Sasso, F.P.; Schettino, A.; Maione, A.; Galdiero, M. Viral Infection and Antiviral Treatments in Ocular Pathologies. Microorganisms 2022, 10, 2224.
  9. Conrady, C.D.; Hanson, K.E.; Mehra, S.; Carey, A.; Larochelle, M.; Shakoor, A. The First Case of Trypanosoma cruzi-Associated Retinitis in an Immunocompromised Host Diagnosed With Pan-Organism Polymerase Chain Reaction. Clin. Infect. Dis. 2018, 67, 141–143.
  10. Fashina, T.; Huang, Y.; Thomas, J.; Conrady, C.D.; Yeh, S. Ophthalmic Features and Implications of Poxviruses: Lessons from Clinical and Basic Research. Microorganisms 2022, 10, 2487.
  11. Conrady, C.D.; Faia, L.J.; Gregg, K.S.; Rao, R.C. Coronavirus-19-Associated Retinopathy. Ocul. Immunol. Inflamm. 2021, 29, 675–676.
  12. Conrady, C.D.; Demirci, H.; Wubben, T.J. Retinal Whitening After Lung Transplant for Cystic Fibrosis. JAMA Ophthalmol. 2020, 138, 994–995.
  13. Conrady, C.D.; Feist, R.M.; Crum, A. Shingles as the underlying cause of orbital myositis in an adolescent: A case report. Am. J. Ophthalmol. Case Rep. 2017, 5, 111–113.
  14. Pappas, G.; Roussos, N.; Falagas, M.E. Toxoplasmosis snapshots: Global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis. Int. J. Parasitol. 2009, 39, 1385–1394.
  15. Desai, R.J.; Solomon, D.H.; Shadick, N.; Iannaccone, C.; Kim, S.C. Identification of smoking using Medicare data--A validation study of claims-based algorithms. Pharmacoepidemiol. Drug Saf. 2016, 25, 472–475.
  16. Khan, A.; Jordan, C.; Muccioli, C.; Vallochi, A.L.; Rizzo, L.V.; Belfort, R., Jr.; Vitor, R.W.A.; Silveira, C.; Sibley, L.D. Genetic divergence of Toxoplasma gondii strains associated with ocular toxoplasmosis, Brazil. Emerg. Infect. Dis. 2006, 12, 942–949.
  17. Conrady, C.D.; Joos, Z.P.; Patel, B.C.K. Review: The Lacrimal Gland and Its Role in Dry Eye. J. Ophthalmol. 2016, 2016, 7542929.
  18. Du, Y.; Yan, B. Ocular immune privilege and retinal pigment epithelial cells. J. Leukoc. Biol. 2023, 113, 288–304.
  19. Jin, X.; Qin, Q.; Chen, W.; Qu, J. Expression of Toll-Like Receptors in the Healthy and Herpes Simplex Virus-Infected Cornea. Cornea 2007, 26, 847–852.
  20. Kumar, M.V.; Nagineni, C.N.; Chin, M.S.; Hooks, J.J.; Detrick, B. Innate immunity in the retina: Toll-like receptor (TLR) signaling in human retinal pigment epithelial cells. J. Neuroimmunol. 2004, 153, 7–15.
  21. Singh, P.K.; Kumar, A. Retinal Photoreceptor Expresses Toll-like Receptors (TLRs) and Elicits Innate Responses Following TLR Ligand and Bacterial Challenge. PLoS ONE 2015, 10, e0119541.
  22. Bryant-Hudson, K.; Conrady, C.D.; Carr, D.J.J. Type I interferon and lymphangiogenesis in the HSV-1 infected cornea—Are they beneficial to the host? Prog. Retin. Eye Res. 2013, 36, 281–291.
  23. Song, P.I.; Abraham, T.A.; Park, Y.; Zivony, A.S.; Harten, B.; Edelhauser, H.F.; Ward, S.L.; Armstrong, C.A.; Ansel, J.C. The Expression of Functional LPS Receptor Proteins CD14 And Toll-like Receptor 4 in Human Corneal Cells. Investig. Ophthalmol. Vis. Sci. 2001, 42, 2867–2877.
  24. Huang, X.; Hazlett, L.D. Analysis of Pseudomonas aeruginosa Corneal Infection Using an Oligonucleotide Microarray. Investig. Ophthalmol. Vis. Sci. 2003, 44, 3409–3416.
  25. Yu, F.-S.X.; Hazlett, L.D. Toll-like Receptors and the Eye. Investig. Ophthalmol. Vis. Sci. 2006, 47, 1255–1263.
  26. Conrady, C.D.; Drevets, D.A.; Carr, D.J.J. Herpes simplex type I (HSV-1) infection of the nervous system: Is an immune response a good thing? J. Neuroimmunol. 2010, 220, 1–9.
  27. Enzmann, V.; Row, B.W.; Yamauchi, Y.; Kheirandish, L.; Gozal, D.; Kaplan, H.J.; McCall, M.A. Behavioral and anatomical abnormalities in a sodium iodate-induced model of retinal pigment epithelium degeneration. Exp. Eye Res. 2006, 82, 441–448.
  28. Horie, S.; Sugita, S.; Futagami, Y.; Yamada, Y.; Mochizuki, M. Human retinal pigment epithelium-induced CD4+CD25+ regulatory T cells suppress activation of intraocular effector T cells. Clin. Immunol. 2010, 136, 83–95.
  29. Sugita, S.; Horie, S.; Nakamura, O.; Futagami, Y.; Takase, H.; Keino, H.; Aburatani, H.; Katunuma, N.; Ishidoh, K.; Yamamoto, Y.; et al. Retinal Pigment Epithelium-Derived CTLA-2α Induces TGFβ-Producing T Regulatory Cells12. J. Immunol. 2008, 181, 7525–7536.
  30. Ashour, H.M.; Niederkorn, J.Y. Peripheral Tolerance Via the Anterior Chamber of the Eye: Role of B Cells in MHC Class I and II Antigen Presentation1. J. Immunol. 2006, 176, 5950–5957.
  31. Skelsey, M.E.; Mayhew, E.; Niederkorn, J.Y. Splenic B Cells Act as Antigen Presenting Cells for the Induction of Anterior Chamber-Associated Immune Deviation. Investig. Ophthalmol. Vis. Sci. 2003, 44, 5242–5251.
  32. Skelsey, M.E.; Mayhew, E.; Niederkorn, J.Y. CD25+, interleukin-10-producing CD4+ T cells are required for suppressor cell production and immune privilege in the anterior chamber of the eye. Immunology 2003, 110, 18–29.
  33. Streilein, J.W. Ocular immune privilege: Therapeutic opportunities from an experiment of nature. Nat. Rev. Immunol. 2003, 3, 879–889.
  34. Skelsey, M.E.; Mellon, J.; Niederkorn, J.Y. γδ T Cells Are Needed for Ocular Immune Privilege and Corneal Graft Survival1. J. Immunol. 2001, 166, 4327–4333.
  35. Paunicka, K.; Chen, P.W.; Niederkorn, J.Y. Role of IFN-γ in the establishment of anterior chamber-associated immune deviation (ACAID)-induced CD8+ T regulatory cells. J. Leukoc. Biol. 2012, 91, 475–483.
  36. Wenkel, H.; Streilein, J.W. Analysis of immune deviation elicited by antigens injected into the subretinal space. Investig. Ophthalmol. Vis. Sci. 1998, 39, 1823–1834.
  37. Hori, J.; Yamaguchi, T.; Keino, H.; Hamrah, P.; Maruyama, K. Immune privilege in corneal transplantation. Prog. Retin. Eye Res. 2019, 72, 100758.
  38. Niederkorn, J.Y. Corneal Transplantation and Immune Privilege. Int. Rev. Immunol. 2013, 32, 57–67.
  39. Cunnusamy, K.; Chen, P.W.; Niederkorn, J.Y. IL-17A–Dependent CD4+CD25+ Regulatory T Cells Promote Immune Privilege of Corneal Allografts. J. Immunol. 2011, 186, 6737–6745.
  40. Toda, M.; Ueno, M.; Yamada, J.; Hiraga, A.; Asada, K.; Hamuro, J.; Sotozono, C.; Kinoshita, S. Quiescent innate and adaptive immune responses maintain the long-term integrity of corneal endothelium reconstituted through allogeneic cell injection therapy. Sci. Rep. 2022, 12, 18072.
  41. Neelam, S.; Niederkorn, J.Y. Corneal Nerve Ablation Abolishes Ocular Immune Privilege by Downregulating CD103 on T Regulatory Cells. Investig. Ophthalmol. Vis. Sci. 2020, 61, 25.
  42. Paunicka, K.J.; Mellon, J.; Robertson, D.; Petroll, M.; Brown, J.R.; Niederkorn, J.Y. 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. Transplant. 2015, 15, 1490–1501.
  43. Haskova, Z.; Sproule, T.J.; Roopenian, D.C.; Ksander, B.R. An immunodominant minor histocompatibility alloantigen that initiates corneal allograft rejection1. Transplantation 2003, 75, 1368–1374.
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