{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T06:47:09Z","timestamp":1782715629374,"version":"3.54.5"},"reference-count":102,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Vernal keratoconjunctivitis (VKC) is a chronic condition that causes remodeling of the cornea and conjunctiva through recurring episodes of allergic inflammation of the ocular surface. This can lead to corneal scarring, keratoconus, and chronic conjunctival papillae. However, the details of the immunopathological processes behind these remodeling changes are not completely understood. Despite involving IgE-modulated mechanisms, about half of patients with VKC test negative on systemic allergy tests. This calls for the need to understand the common and novel inflammatory mediators involved in the pathogenesis of VKC development and severity levels. Eye rubbing stimulates the release of inflammatory cytokines TNF-alpha, IL-4, IL-5, and IL-13 and remodeling enzymes MMP-1, MMP-3, MMP-9, and MMP-10, which drive a dysregulated cycle of stromal tissue remodeling that leads to progressive ectasia. Eosinophilic activity is driven by CCL11 and ICAM-1 and eye rubbing, which leads to degranulation and the release of EMBP, ECP, and MMP-9. These inflammatory mediators drive the remodeling changes that lead to corneal scarring and ectasia. The purpose of this comprehensive review paper is to shed light on common and novel immunological mediators that help us further understand VKC and eventually lead to the discovery of more effective and targeted treatment options.<\/jats:p>","DOI":"10.3390\/life16071087","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T05:49:33Z","timestamp":1782712173000},"page":"1087","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inflammatory Mediators Involved in Conjunctival and Corneal Remodeling of Vernal Keratoconjunctivitis"],"prefix":"10.3390","volume":"16","author":[{"given":"Nicholas J.","family":"Karbach","sequence":"first","affiliation":[{"name":"Pennsylvania College of Optometry, Drexel University, Elkins Park, PA 19027, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiza","family":"Tariq","sequence":"additional","affiliation":[{"name":"Pennsylvania College of Optometry, Drexel University, Elkins Park, PA 19027, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109301","DOI":"10.1016\/j.exer.2022.109301","article-title":"Tissue remodeling in adult vernal keratoconjunctivitis","volume":"225","author":"Micera","year":"2022","journal-title":"Exp. Eye Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1016\/S0161-6420(00)00092-0","article-title":"Vernal keratoconjunctivitis revisited: A case series of 195 patients with long-term followup","volume":"107","author":"Bonini","year":"2000","journal-title":"Ophthalmology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s12016-023-08970-4","article-title":"Vernal Keratoconjunctivitis: A Systematic Review","volume":"65","author":"Bruschi","year":"2023","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_4","unstructured":"Yanoff, M., and Duker, J.S. (2019). Ophthalmology, Elsevier. [6th ed.]."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.survophthal.2018.12.001","article-title":"Vernal Keratoconjunctivitis","volume":"64","author":"Singhal","year":"2019","journal-title":"Surv. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"59","DOI":"10.4103\/ijo.IJO_1179_21","article-title":"Clinical, histological and immunohistochemistry characteristics of cornea in the sequelae stage of chronic vernal keratoconjunctivitis","volume":"70","author":"Jaffet","year":"2022","journal-title":"Indian J. Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Fukuda, K., Ishida, W., Kishimoto, T., Nakajima, I., Miura, Y., Sumi, T., and Yamashiro, K. (2022). Role of Damage-Associated Molecular Patterns (DAMPs\/Alarmins) in Severe Ocular Allergic Diseases. Cells, 11.","DOI":"10.3390\/cells11061051"},{"key":"ref_8","first-page":"370","article-title":"Effects of vernal and allergic conjunctivitis on severity of keratoconus","volume":"6","author":"Cingu","year":"2013","journal-title":"Int. J. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1136\/bjophthalmol-2015-308251","article-title":"Case-control study of risk factors for acute corneal hydrops in keratoconus","volume":"101","author":"Barsam","year":"2017","journal-title":"Br. J. Ophthalmol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.ajo.2016.09.009","article-title":"Very Low Prevalence of Keratoconus in a Large Series of Vernal Keratoconjunctivitis Patients","volume":"172","author":"Caputo","year":"2016","journal-title":"Am. J. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1097\/00130832-200310000-00011","article-title":"Allergic chronic inflammation of the ocular surface in vernal keratoconjunctivitis","volume":"3","author":"Bonini","year":"2003","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1097\/ACI.0000000000000765","article-title":"Vernal keratoconjunctivitis and keratoconus","volume":"21","author":"Wajnsztajn","year":"2021","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Di Zazzo, A., Zhu, A.Y., Nischal, K., and Fung, S.S.M. (2024). Vernal keratoconjunctivitis in adults: A narrative review of prevalence, pathogenesis, and management. Front. Ophthalmol., 4.","DOI":"10.3389\/fopht.2024.1328953"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Alemayehu, A.M., Yibekal, B.T., and Fekadu, S.A. (2019). Prevalence of vernal keratoconjunctivitis and its associated factors among children in Gambella town, southwest Ethiopia, June 2018. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0215528"},{"key":"ref_15","unstructured":"Justiz Vaillant, A.A., Modi, P., Syed, H.A., and Jan, A. (2025). Atopy. StatPearls, StatPearls Publishing."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1097\/ACI.0000000000000204","article-title":"Epidemiology of allergic conjunctivitis: Clinical appearance and treatment patterns in a population-based study","volume":"15","author":"Leonardi","year":"2015","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1111\/cea.12536","article-title":"Allergic conjunctivitis: A cross-sectional study","volume":"45","author":"Leonardi","year":"2015","journal-title":"Clin. Exp. Allergy"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.alit.2020.03.005","article-title":"Japanese guidelines for allergic conjunctival diseases 2020","volume":"69","author":"Miyazaki","year":"2020","journal-title":"Allergol. Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1016\/j.ophtha.2012.03.041","article-title":"Vernal keratoconjunctivitis in school children in Rwanda: Clinical presentation, impact on school attendance, and access to medical care","volume":"119","author":"Nkurikiye","year":"2012","journal-title":"Ophthalmology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1136\/bjo.2007.117812","article-title":"Prevalence of vernal keratoconjunctivitis: A rare disease?","volume":"92","author":"Donadieu","year":"2008","journal-title":"Br. J. Ophthalmol."},{"key":"ref_21","first-page":"237","article-title":"Allergic conjunctivitis","volume":"19","author":"Kosrirukvongs","year":"2001","journal-title":"Asian Pac. J. Allergy Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1001\/jamaophthalmol.2021.1708","article-title":"Association of Allergic Conjunctivitis with Health-Related Quality of Life in Children and Their Parents","volume":"139","author":"Zhang","year":"2021","journal-title":"JAMA Ophthalmol."},{"key":"ref_23","first-page":"e89972","article-title":"Risk Factors Associated with Steroid-Induced Ocular Hypertension and Glaucoma in Patients with Vernal Keratoconjunctivitis in a North Indian Population: A Multicenter Study","volume":"17","author":"Dubey","year":"2025","journal-title":"Cureus"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"AlHuthail, R. (2025). The impact of tacrolimus therapy on the outcomes of vernal keratoconjunctivitis: A systematic review and meta-analysis. Front. Med., 12.","DOI":"10.3389\/fmed.2025.1542440"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Chigbu, D.I., Karbach, N.J., Abu, S.L., and Hehar, N.K. (2024). Cytokines in Allergic Conjunctivitis: Unraveling Their Pathophysiological Roles. Life, 14.","DOI":"10.3390\/life14030350"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Chigbu, D.I., and Labib, B.A. (2021). Immunopharmacology in Vernal Keratoconjunctivitis: Current and Future Perspectives. Pharmaceuticals, 14.","DOI":"10.3390\/ph14070658"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4512","DOI":"10.1167\/iovs.04-1494","article-title":"The implications of the upregulation of ICAM-1\/VCAM-1 expression of corneal fibroblasts on the pathogenesis of allergic keratopathy","volume":"46","author":"Okada","year":"2005","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"121","DOI":"10.2332\/allergolint.55.121","article-title":"Fibroblasts as local immune modulators in ocular allergic disease","volume":"55","author":"Fukuda","year":"2006","journal-title":"Allergol. Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1177\/2040622315612745","article-title":"Ocular itch associated with allergic conjunctivitis: Latest evidence and clinical management","volume":"7","author":"Ackerman","year":"2016","journal-title":"Ther. Adv. Chronic Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5372","DOI":"10.1167\/iovs.16-19677","article-title":"Differential Molecular Expression of Extracellular Matrix and Inflammatory Genes at the Corneal Cone Apex Drives Focal Weakening in Keratoconus","volume":"57","author":"Pahuja","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.1167\/iovs.02-0766","article-title":"Tear levels and activity of matrix metalloproteinase (MMP)-1 and MMP-9 in vernal keratoconjunctivitis","volume":"44","author":"Leonardi","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1097\/01.ico.0000121710.58571.c4","article-title":"Surgical management of corneal plaques in vernal keratoconjunctivitis: A clinicopathologic study","volume":"23","author":"Solomon","year":"2004","journal-title":"Cornea"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.coi.2005.06.002","article-title":"Alarmins: Chemotactic activators of immune responses","volume":"17","author":"Oppenheim","year":"2005","journal-title":"Curr. Opin. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1038\/sj.embor.7400759","article-title":"Alarmin(g) news about danger: Workshop on Innate Danger Signals and HMGB1","volume":"7","author":"Harris","year":"2006","journal-title":"EMBO Rep."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Labib, B.A., and Chigbu, D.I. (2022). Therapeutic Targets in Allergic Conjunctivitis. Pharmaceuticals, 15.","DOI":"10.3390\/ph15050547"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Hehar, N.K., and Chigbu, D.I. (2024). Vernal Keratoconjunctivitis: Immunopathological Insights and Therapeutic Applications of Immunomodulators. Life, 14.","DOI":"10.3390\/life14030361"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Nemmer, J.M., Kuchner, M., Datsi, A., Ol\u00e1h, P., Julia, V., Raap, U., and Homey, B. (2021). Interleukin-31 Signaling Bridges the Gap Between Immune Cells, the Nervous System and Epithelial Tissues. Front. Med., 8.","DOI":"10.3389\/fmed.2021.639097"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"13229","DOI":"10.1038\/s41598-018-31408-3","article-title":"Histamine causes endothelial barrier disruption via Ca2+-mediated RhoA activation and tension at adherens junctions","volume":"8","author":"Kugelmann","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"S423","DOI":"10.1194\/jlr.R800094-JLR200","article-title":"Prostanoids in health and disease","volume":"50","author":"Smyth","year":"2009","journal-title":"J. Lipid Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Skaria, T., Burgener, J., Bachli, E., and Schoedon, G. (2016). IL-4 Causes Hyperpermeability of Vascular Endothelial Cells through Wnt5A Signaling. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0156002"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4186","DOI":"10.1167\/iovs.14-15496","article-title":"IL-13 Stimulates Proliferation and Expression of Mucin and Immunomodulatory Genes in Cultured Conjunctival Goblet Cells","volume":"56","author":"Coursey","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_42","first-page":"172","article-title":"The ocular surface: From physiology to the ocular allergic diseases","volume":"60","author":"Santacruz","year":"2013","journal-title":"Rev. Alerg. Mex."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.preteyeres.2005.09.002","article-title":"Role of structural cells of the cornea and conjunctiva in the pathogenesis of vernal keratoconjunctivitis","volume":"25","author":"Kumagai","year":"2006","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.clae.2010.09.002","article-title":"Ocular surface disease: A case of vernal keratoconjunctivitis","volume":"34","author":"Chigbu","year":"2011","journal-title":"Contact Lens Anterior Eye"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1111\/j.1749-6632.2011.06351.x","article-title":"From interleukin-9 to T helper 9 cells","volume":"1247","author":"Stassen","year":"2012","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"S47","DOI":"10.1097\/01.ico.0000247213.24133.26","article-title":"Mechanisms of giant papillary formation in vernal keratoconjunctivitis","volume":"25","author":"Kato","year":"2006","journal-title":"Cornea"},{"key":"ref_47","first-page":"e74268","article-title":"Efficacy of Epinastine Eyelid Cream in Pediatric Vernal Keratoconjunctivitis: A Case Report","volume":"16","author":"Hashida","year":"2024","journal-title":"Cureus"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1097\/ACI.0000000000000915","article-title":"Diagnostic criteria of chronic conjunctivitis: Atopic keratoconjunctivitis and vernal keratoconjunctivitis","volume":"23","author":"Leonardi","year":"2023","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1097\/ICL.0000000000001181","article-title":"Vernal Keratoconjunctivitis: Impact on Children","volume":"51","author":"Gu","year":"2025","journal-title":"Eye Contact Lens"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.jtos.2020.10.005","article-title":"Management of corneal complications in vernal keratoconjunctivitis: A review","volume":"19","author":"Feizi","year":"2021","journal-title":"Ocul. Surf."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1097\/ACI.0000000000000202","article-title":"Corneal complications of vernal keratoconjunctivitis","volume":"15","author":"Solomon","year":"2015","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1038\/s41385-020-0288-4","article-title":"IL-33\/ST2\/IL-9\/IL-9R signaling disrupts ocular surface barrier in allergic inflammation","volume":"13","author":"Hu","year":"2020","journal-title":"Mucosal Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/j.ajo.2012.09.014","article-title":"Management, clinical outcomes, and complications of shield ulcers in vernal keratoconjunctivitis","volume":"155","author":"Reddy","year":"2013","journal-title":"Am. J. Ophthalmol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1136\/bjo.73.10.816","article-title":"Association between keratoconus and atopy","volume":"73","author":"Harrison","year":"1989","journal-title":"Br. J. Ophthalmol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1111\/cxo.12038","article-title":"Effects of eye rubbing on the levels of protease, protease activity and cytokines in tears: Relevance in keratoconus","volume":"96","author":"Balasubramanian","year":"2013","journal-title":"Clin. Exp. Optom."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"S48","DOI":"10.1097\/ICL.0000000000000432","article-title":"Keratoconus Progression in Patients with Allergy and Elevated Surface Matrix Metalloproteinase 9 Point-of-Care Test","volume":"44","author":"Mazzotta","year":"2018","journal-title":"Eye Contact Lens"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1080\/09273948.2023.2190804","article-title":"Characteristics of Vernal Keratoconjunctivitis in Lhasa: A Single-Center, Observational Study","volume":"32","author":"Yang","year":"2024","journal-title":"Ocul. Immunol. Inflamm."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1007\/s10792-022-02608-8","article-title":"Corneal biomechanical properties in vernal keratoconjunctivitis and its subtypes: A preliminary study","volume":"43","author":"Zhang","year":"2023","journal-title":"Int. Ophthalmol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s40662-021-00241-7","article-title":"Corneal biomechanical changes in allergic conjunctivitis","volume":"8","author":"Wang","year":"2021","journal-title":"Eye Vis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1167\/iovs.64.2.22","article-title":"The Impaired Wound Healing Process Is a Major Factor in Remodeling of the Corneal Epithelium in Adult and Adolescent Patients with Keratoconus","volume":"64","author":"Jaskiewicz","year":"2023","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1136\/bjo.2008.144253","article-title":"Subclinical keratoconus and inflammatory molecules from tears","volume":"93","author":"Lema","year":"2009","journal-title":"Br. J. Ophthalmol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.ophtha.2004.11.050","article-title":"Inflammatory molecules in the tears of patients with keratoconus","volume":"112","author":"Lema","year":"2005","journal-title":"Ophthalmology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"101559","DOI":"10.1016\/j.clae.2021.101559","article-title":"Keratoconus: An updated review","volume":"45","author":"Carracedo","year":"2022","journal-title":"Contact Lens Anterior Eye"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1177\/11206721221125013","article-title":"Investigating the role of inflammation in keratoconus: A retrospective analysis of 551 eyes","volume":"33","author":"Nichani","year":"2023","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"S50","DOI":"10.1097\/ICO.0b013e318269ccd0","article-title":"Metalloproteinases in corneal diseases: Degradation and processing","volume":"31","author":"Sakimoto","year":"2012","journal-title":"Cornea"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/S1542-0124(12)70308-7","article-title":"Matrix Revolution: Molecular Mechanism for Inflammatory Corneal Neovascularization and Restoration of Corneal Avascularity by Epithelial stem Cell Transplantation","volume":"7","author":"Jesse","year":"2009","journal-title":"Ocul. Surf."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/j.1749-6632.1999.tb07675.x","article-title":"Insights into MMP-TIMP interactions","volume":"878","author":"Bode","year":"1999","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3293","DOI":"10.1167\/iovs.05-1382","article-title":"Desiccating stress stimulates expression of matrix metalloproteinases by the corneal epithelium","volume":"47","author":"Corrales","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Zhao, Z., Liang, M., He, H., Wang, X., Zhu, C., Li, L., Liu, B., Zong, R., Jin, Q., and Wu, H. (2022). Ovalbumin-Induced Allergic Inflammation Diminishes Cross-Linked Collagen Structures in an Experimental Rabbit Model of Corneal Cross-Linking. Front. Med., 9.","DOI":"10.3389\/fmed.2022.762730"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Unni, P., and Lee, H.J. (2023). Systemic Associations with Keratoconus. Life, 13.","DOI":"10.3390\/life13061363"},{"key":"ref_71","first-page":"12","article-title":"Attenuation of lysyl oxidase and collagen gene expression in keratoconus patient corneal epithelium corresponds to disease severity","volume":"21","author":"Shetty","year":"2015","journal-title":"Mol. Vis."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1167\/iovs.14-14831","article-title":"Elevated expression of matrix metalloproteinase-9 and inflammatory cytokines in keratoconus patients is inhibited by cyclosporine A","volume":"56","author":"Shetty","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1038\/35036374","article-title":"Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis","volume":"2","author":"Bergers","year":"2000","journal-title":"Nat. Cell Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"S62","DOI":"10.1097\/ICO.0b013e3181ea9b2b","article-title":"Ocular allergic inflammation: Interaction between the cornea and conjunctiva","volume":"29","author":"Fukuda","year":"2010","journal-title":"Cornea"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.exer.2013.05.015","article-title":"Involvement of chymase in allergic conjunctivitis of guinea pigs","volume":"113","author":"Nabe","year":"2013","journal-title":"Exp. Eye Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1165\/ajrcmb\/5.3.206","article-title":"Properties and function of lysyl oxidase","volume":"5","author":"Kagan","year":"1991","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1097\/ICL.0b013e3181ee8971","article-title":"Ocular surface inflammation mediated by innate immunity","volume":"36","author":"Ueta","year":"2010","journal-title":"Eye Contact Lens"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1159\/000099252","article-title":"Anatomy and immunology of the ocular surface","volume":"92","author":"Knop","year":"2007","journal-title":"Chem. Immunol. Allergy"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1042\/CS20100425","article-title":"Toll-like receptors in ocular surface diseases: Overview and new findings","volume":"120","author":"Lambiase","year":"2011","journal-title":"Clin. Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.survophthal.2023.10.008","article-title":"Management of vernal keratoconjunctivitis: Navigating a changing treatment landscape","volume":"69","author":"Ali","year":"2024","journal-title":"Surv. Ophthalmol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1097\/ACI.0b013e32830e6b04","article-title":"Functions of ocular surface mucins in health and disease","volume":"8","author":"Mantelli","year":"2008","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1097\/00004397-200343010-00006","article-title":"Role of chemokines in vernal keratoconjunctivitis","volume":"43","author":"Struyf","year":"2003","journal-title":"Int. Ophthalmol. Clin."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1136\/bjo.81.12.1099","article-title":"Adhesion molecules in vernal keratoconjunctivitis","volume":"81","author":"Geboes","year":"1997","journal-title":"Br. J. Ophthalmol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.1084\/jem.20101111","article-title":"CD14 is a coreceptor of Toll-like receptors 7 and 9","volume":"207","author":"Baumann","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/S1542-0124(12)70279-3","article-title":"Toll-like receptors at the ocular surface","volume":"6","author":"Pearlman","year":"2008","journal-title":"Ocul. Surf."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/90609","article-title":"Toll-like receptors: Critical proteins linking innate and acquired immunity","volume":"2","author":"Akira","year":"2001","journal-title":"Nat. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.imbio.2007.03.011","article-title":"Immunobiology of toll-like receptors in allergic disease","volume":"212","author":"Bauer","year":"2007","journal-title":"Immunobiology"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1528; discussion 1548","DOI":"10.1016\/j.ophtha.2005.04.009","article-title":"Expression of Toll-like receptors in healthy and allergic conjunctiva","volume":"112","author":"Bonini","year":"2005","journal-title":"Ophthalmology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.exer.2010.03.012","article-title":"Toll-like receptors in ocular surface disease","volume":"90","author":"Redfern","year":"2010","journal-title":"Exp. Eye Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"36150","DOI":"10.1038\/srep36150","article-title":"Pollen\/TLR4 Innate Immunity Signaling Initiates IL-33\/ST2\/Th2 Pathways in Allergic Inflammation","volume":"6","author":"Li","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2274","DOI":"10.1177\/11206721211048814","article-title":"Vernal keratoconjunctivitis activity induces decrease of ocular surface CD14, TLR-4 and TLR-9 expression","volume":"32","author":"Sacchetti","year":"2022","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_92","first-page":"2037","article-title":"Nerve growth factor modulates toll-like receptor (TLR) 4 and 9 expression in cultured primary VKC conjunctival epithelial cells","volume":"15","author":"Micera","year":"2009","journal-title":"Mol. Vis."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.jtos.2020.09.009","article-title":"Conjunctival transcriptome analysis reveals the overexpression of multiple pattern recognition receptors in vernal keratoconjunctivitis","volume":"19","author":"Leonardi","year":"2021","journal-title":"Ocul. Surf."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Kang, C., Li, X., Liu, P., Liu, Y., Niu, Y., Zeng, X., Zhao, H., Liu, J., and Qiu, S. (2023). Tolerogenic dendritic cells and TLR4\/IRAK4\/NF-\u03baB signaling pathway in allergic rhinitis. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1276512"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"4235","DOI":"10.1167\/iovs.05-0543","article-title":"LBP and CD14 Secreted in Tears by the Lacrimal Glands Modulate the LPS Response of Corneal Epithelial Cells","volume":"46","author":"Blais","year":"2005","journal-title":"Investig. Opthalmology Vis. Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"7151","DOI":"10.1128\/IAI.73.11.7151-7160.2005","article-title":"Human airway epithelial cells sense Pseudomonas aeruginosa infection via recognition of flagellin by Toll-like receptor 5","volume":"73","author":"Zhang","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.cyto.2011.07.004","article-title":"Effect of Toll-like receptor 2 and 4 of corneal fibroblasts on cytokine expression with co-cultured antigen presenting cells","volume":"56","author":"Choi","year":"2011","journal-title":"Cytokine"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.jaci.2022.09.022","article-title":"Human natural killer cells: Form, function, and development","volume":"151","author":"Mace","year":"2023","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1182\/blood-2009-08-238469","article-title":"Regulation of human NK-cell cytokine and chemokine production by target cell recognition","volume":"115","author":"Fauriat","year":"2010","journal-title":"Blood"},{"key":"ref_100","first-page":"1562","article-title":"Natural killer cells in vernal keratoconjunctivitis","volume":"13","author":"Lambiase","year":"2007","journal-title":"Mol. Vis."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/ni1582","article-title":"Functions of natural killer cells","volume":"9","author":"Vivier","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"445","DOI":"10.2353\/ajpath.2006.050676","article-title":"Matrix metalloproteinase-1 produced by human CXCL12-stimulated natural killer cells","volume":"169","author":"Goda","year":"2006","journal-title":"Am. J. Pathol."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/7\/1087\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T06:23:45Z","timestamp":1782714225000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/7\/1087"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,29]]},"references-count":102,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["life16071087"],"URL":"https:\/\/doi.org\/10.3390\/life16071087","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,29]]}}}