{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T05:44:23Z","timestamp":1794375863680,"version":"4.9.0"},"reference-count":102,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,9,26]],"date-time":"2021-09-26T00:00:00Z","timestamp":1632614400000},"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, recurrent, inflammatory disease of the cornea and conjunctiva mostly affecting boys in prepubertal age. VKC recurrence is characterized by intense symptoms of itching, redness, and photophobia associated with corneal damage, impairment of visual function, and quality of life. The pathogenesis of VKC has not yet been completely understood, and it is still controversial. In fact, VKC is considered an ocular allergic disease due to the involvement of immunoglobulin E, eosinophils, and mast cells, and of a lymphocyte T-helper type 2 reaction. However, approximately half of VKC patients have negative allergological history and testing, suggesting that other pathogenic mechanisms participate in VKC development and severity. Specifically, evidence suggests that genetic, endocrine, neuronal factors and an imbalance of innate immunity are involved in the pathogenesis of VKC. The purpose of this review is to summarize evidence on the pathogenic role of innate immunity, neuroimmune reaction, and hormonal changes in VKC. Increasing understanding of the pathogenic mechanisms behind VKC may lead to the identification of novel biomarkers for diagnosis and\/or potential therapeutic targets in order to improve the management of this challenging condition.<\/jats:p>","DOI":"10.3390\/life11101012","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T04:55:33Z","timestamp":1632718533000},"page":"1012","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Understanding Vernal Keratoconjunctivitis: Beyond Allergic Mechanisms"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5569-778X","authenticated-orcid":false,"given":"Marta","family":"Sacchetti","sequence":"first","affiliation":[{"name":"Department of Sense Organs, University Sapienza of Rome, Viale del Policlinico, 155, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocco","family":"Plateroti","sequence":"additional","affiliation":[{"name":"Department of Sense Organs, University Sapienza of Rome, Viale del Policlinico, 155, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1627-5493","authenticated-orcid":false,"given":"Alice","family":"Bruscolini","sequence":"additional","affiliation":[{"name":"Department of Sense Organs, University Sapienza of Rome, Viale del Policlinico, 155, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalia","family":"Giustolisi","sequence":"additional","affiliation":[{"name":"Department of Sense Organs, University Sapienza of Rome, Viale del Policlinico, 155, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6978-3790","authenticated-orcid":false,"given":"Marco","family":"Marenco","sequence":"additional","affiliation":[{"name":"Department of Sense Organs, University Sapienza of Rome, Viale del Policlinico, 155, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/sj.eye.6700675","article-title":"Vernal keratoconjunctivitis","volume":"18","author":"Bonini","year":"2004","journal-title":"Eye"},{"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":"406","DOI":"10.1111\/j.1600-0420.2005.00622.x","article-title":"Case series of 406 vernal keratoconjunctivitis patients: A demographic and epidemiological study","volume":"84","author":"Leonardi","year":"2006","journal-title":"Acta Ophthalmol. Scand."},{"key":"ref_4","first-page":"49","article-title":"Allergic conjunctivitis: Current concepts on pathogenesis and management","volume":"32","author":"Sacchetti","year":"2018","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1136\/bjophthalmol-2011-301376","article-title":"Vernal keratoconjunctivitis: An update","volume":"97","author":"Wildner","year":"2013","journal-title":"Br. J. Ophthalmol."},{"key":"ref_6","first-page":"1562","article-title":"Natural killer cells in vernal keratoconjunctivitis","volume":"13","author":"Lambiase","year":"2007","journal-title":"Mol. Vis."},{"key":"ref_7","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_8","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_9","doi-asserted-by":"crossref","first-page":"1528","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_10","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.ajo.2012.11.018","article-title":"Vernal keratoconjunctivitis-like disease in adults","volume":"155","author":"Leonardi","year":"2013","journal-title":"Am. J. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1097\/ACI.0000000000000672","article-title":"Adult vernal keratoconjunctivitis","volume":"20","author":"Bonini","year":"2020","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_12","first-page":"25","article-title":"Vernal keratoconjunctivitis in Thailand","volume":"21","author":"Kosrirukvongs","year":"2003","journal-title":"Asian Pac. J. Allergy Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1080\/09286580802573177","article-title":"Prospective, multicenter demographic and epidemiological study on vernal keratoconjunctivitis: A glimpse of ocular surface in Italian population","volume":"16","author":"Lambiase","year":"2009","journal-title":"Ophthalmic Epidemiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1111\/pai.12197","article-title":"Vernal keratoconjunctivitis: A severe allergic eye disease with remodeling changes","volume":"25","author":"Vichyanond","year":"2014","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S1350-9462(02)00006-X","article-title":"Vernal keratoconjunctivitis: Pathogenesis and treatment","volume":"21","author":"Leonardi","year":"2002","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1097\/ACI.0b013e3282efb726","article-title":"Clinical grading of vernal keratoconjunctivitis","volume":"7","author":"Bonini","year":"2007","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_17","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_18","doi-asserted-by":"crossref","first-page":"211","DOI":"10.5935\/0004-2749.20170052","article-title":"Topical tacrolimus for the treatment of severe allergic keratoconjunctivitis in children","volume":"80","author":"Liendo","year":"2017","journal-title":"Arq. Bras. Oftalmol."},{"key":"ref_19","first-page":"58","article-title":"Corneal Complications and Visual Impairment in Vernal Keratoconjunctivitis Patients","volume":"29","author":"Arif","year":"2017","journal-title":"J. Ayub Med. Coll. Abbottabad JAMC"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3109\/08820538.2013.821508","article-title":"Assessment of corneal alterations by confocal microscopy in vernal keratoconjunctivitis","volume":"30","author":"Nebbioso","year":"2015","journal-title":"Semin. Ophthalmol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.ophtha.2011.09.018","article-title":"Corneal confocal microscopy in patients with vernal keratoconjunctivitis","volume":"119","author":"Leonardi","year":"2012","journal-title":"Ophthalmology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.4103\/1673-5374.213534","article-title":"Neurotrophic factors and corneal nerve regeneration","volume":"12","author":"Sacchetti","year":"2017","journal-title":"Neural Regen. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1111\/pai.13520","article-title":"Health-related quality of life in children at the diagnosis of Vernal Keratoconjunctivitis","volume":"32","author":"Artesani","year":"2021","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/j.ajo.2007.06.028","article-title":"Development and testing of the quality of life in children with vernal keratoconjunctivitis questionnaire","volume":"144","author":"Sacchetti","year":"2007","journal-title":"Am. J. Ophthalmol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s13052-019-0656-4","article-title":"Vernal Keratoconjunctivitis: An update focused on clinical grading system","volume":"45","author":"Zicari","year":"2019","journal-title":"Ital. J. Pediatr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1080\/21678707.2017.1300524","article-title":"Current and emerging treatment options for vernal keratoconjunctivitis","volume":"5","author":"Sacchetti","year":"2017","journal-title":"Expert Opin. Orphan Drugs"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1136\/bjophthalmol-2019-313988","article-title":"Steroid-induced glaucoma and blindness in vernal keratoconjunctivitis","volume":"104","author":"Senthil","year":"2020","journal-title":"Br. J. Ophthalmol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.jaci.2011.07.004","article-title":"Topical cyclosporine prevents seasonal recurrences of vernal keratoconjunctivitis in a randomized, double-masked, controlled 2-year study","volume":"128","author":"Lambiase","year":"2011","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/j.jaci.2021.03.026","article-title":"Efficacy of medical treatments for vernal keratoconjunctivitis: A systematic review and meta-analysis","volume":"148","author":"Roumeau","year":"2021","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"507","DOI":"10.11622\/smedj.2015161","article-title":"Efficacy and safety of topical cyclosporine A 0.05% in vernal keratoconjunctivitis","volume":"57","author":"Yucel","year":"2016","journal-title":"Singap. Med. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1016\/j.ophtha.2009.11.043","article-title":"Tailored approach to the treatment of vernal keratoconjunctivitis","volume":"117","author":"Sacchetti","year":"2010","journal-title":"Ophthalmology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1136\/bjophthalmol-2017-311171","article-title":"Corneal staining patterns in vernal keratoconjunctivitis: The new VKC-CLEK scoring scale","volume":"102","author":"Leonardi","year":"2018","journal-title":"Br. J. Ophthalmol."},{"key":"ref_33","first-page":"296","article-title":"IgE and non-IgE mechanisms in ocular allergy","volume":"71","author":"Bonini","year":"1993","journal-title":"Ann. Allergy"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/S0161-6420(80)35158-0","article-title":"Tear histamine levels in vernal conjunctivitis and other ocular inflammations","volume":"87","author":"Abelson","year":"1980","journal-title":"Ophthalmology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1097\/00003226-199407000-00010","article-title":"Histamine and tryptase levels in allergic conjunctivitis and vernal keratoconjunctivitis","volume":"13","author":"Fukagawa","year":"1994","journal-title":"Cornea"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1111\/j.1398-9995.2011.02612.x","article-title":"Histamine H4 receptors in normal conjunctiva and in vernal keratoconjunctivitis","volume":"66","author":"Leonardi","year":"2011","journal-title":"Allergy"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S0091-6749(05)80046-6","article-title":"Conjunctival hyperresponsiveness to ocular histamine challenge in patients with vernal conjunctivitis","volume":"89","author":"Bonini","year":"1992","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/0002-9394(76)90310-X","article-title":"Tissue, tear, and serum IgE concentrations in vernal conjunctivitis","volume":"81","author":"Allansmith","year":"1976","journal-title":"Am. J. Ophthalmol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1111\/pai.12450","article-title":"Microarray-based IgE detection in tears of patients with vernal keratoconjunctivitis","volume":"26","author":"Leonardi","year":"2015","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/0091-6749(80)90057-3","article-title":"Specific immunoglobulin E antibodies in tear secretions of patients with vernal conjunctivitis","volume":"66","author":"Ballow","year":"1980","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1159\/000233640","article-title":"Allergen-specific immunoglobulin E antibodies in tears and serum of vernal conjunctivitis patients","volume":"75","author":"Sompolinsky","year":"1984","journal-title":"Int. Arch. Allergy Appl. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/eye.2001.65","article-title":"Expression of CD23\/CD21 and CD40\/CD40 ligand in vernal keratoconjunctivitis","volume":"15","author":"Fatani","year":"2001","journal-title":"Eye"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1038\/eye.1990.109","article-title":"Correlation between conjunctival provocation test (CPT) and systemic allergometric tests in allergic conjunctivitis","volume":"4","author":"Leonardi","year":"1990","journal-title":"Eye"},{"key":"ref_44","first-page":"3036","article-title":"Identification of local Th2 and Th0 lymphocytes in vernal conjunctivitis by cytokine flow cytometry","volume":"40","author":"Leonardi","year":"1999","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/S0091-6749(97)70279-3","article-title":"T-cell cytokines in chronic allergic eye disease","volume":"100","author":"Metz","year":"1997","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1046\/j.1365-2222.1999.00585.x","article-title":"Cytokine production and mRNA expression by conjunctival T-cell lines in chronic allergic eye disease","volume":"29","author":"Calder","year":"1999","journal-title":"Clin. Exp. Allergy"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1007\/s00417-006-0285-7","article-title":"Th1- and Th2-type cytokines in chronic ocular allergy","volume":"244","author":"Leonardi","year":"2006","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1034\/j.1600-0420.2000.078s230041.x","article-title":"The early and late phase of the ocular allergic reaction","volume":"230","author":"Bonini","year":"2000","journal-title":"Acta Ophthalmol. Scand."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"S41","DOI":"10.1097\/ICO.0b013e3181ea9958","article-title":"The epithelium takes center stage in allergic keratoconjunctivitis","volume":"29","author":"Ebihara","year":"2010","journal-title":"Cornea"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1097\/ICO.0000000000001832","article-title":"Thymic Stromal Lymphopoietin-Related Allergic Pathway in Patients with Vernal Keratoconjunctivitis","volume":"38","author":"Zhang","year":"2019","journal-title":"Cornea"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Iype, J., and Fux, M. (2021). Basophils Orchestrating Eosinophils\u2019 Chemotaxis and Function in Allergic Inflammation. Cells, 10.","DOI":"10.3390\/cells10040895"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/j.1398-9995.1997.tb04810.x","article-title":"The eosinophil and the eye","volume":"52","author":"Bonini","year":"1997","journal-title":"Allergy"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1111\/j.1398-9995.1995.tb01209.x","article-title":"Eosinophil cationic protein in tears of normal subjects and patients affected by vernal keratoconjunctivitis","volume":"50","author":"Leonardi","year":"1995","journal-title":"Allergy"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/iid3.278","article-title":"Role of ocular cytology in vernal keratoconjunctivitis","volume":"8","author":"Bruschi","year":"2020","journal-title":"Immun. Inflamm. Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/S0161-6420(97)30223-1","article-title":"Efficacy of lodoxamide eye drops on mast cells and eosinophils after allergen challenge in allergic conjunctivitis","volume":"104","author":"Bonini","year":"1997","journal-title":"Ophthalmology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/S0161-6420(02)01767-0","article-title":"Tear and mucus eotaxin-1 and eotaxin-2 in allergic keratoconjunctivitis","volume":"110","author":"Leonardi","year":"2003","journal-title":"Ophthalmology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1136\/bjo.84.12.1360","article-title":"Chemokines in the limbal form of vernal keratoconjunctivitis","volume":"84","author":"Struyf","year":"2000","journal-title":"Br. J. Ophthalmol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"23","DOI":"10.3109\/09273949509057807","article-title":"The role of eosinophil cationic protein (ECP) and histamine in vernal keratoconjunctivitis","volume":"3","author":"Secchi","year":"1995","journal-title":"Ocul. Immunol. Inflamm."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1076\/ceyr.26.5.319.15437","article-title":"Neutrophil and eosinophil participation in atopic and vernal keratoconjunctivitis","volume":"26","author":"Trocme","year":"2003","journal-title":"Curr. Eye Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1016\/S0091-6749(96)70204-X","article-title":"Serum levels of eosinophil cationic protein in allergic diseases and natural allergen exposure","volume":"97","author":"Tomassini","year":"1996","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_61","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_62","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_63","first-page":"15","article-title":"Immunopathogenesis of vernal keratoconjunctivitis","volume":"261","author":"Geboes","year":"1996","journal-title":"Bull. Soc. Belg. D\u2019ophtalmol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1111\/all.12814","article-title":"Chaperone patterns in vernal keratoconjunctivitis are distinctive of cell and Hsp type and are modified by inflammatory stimuli","volume":"71","author":"Leonardi","year":"2016","journal-title":"Allergy"},{"key":"ref_65","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_66","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_67","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1177\/09680519010070010701","article-title":"CD14: A bridge between innate immunity and adaptive IgE responses","volume":"7","author":"Vercelli","year":"2001","journal-title":"J. Endotoxin Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1034\/j.1398-9995.2002.1r152.x","article-title":"CD14: An example of gene by environment interaction in allergic disease","volume":"57","author":"Baldini","year":"2002","journal-title":"Allergy"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"169","DOI":"10.2174\/1568010053586336","article-title":"CD14 and toll-like receptors: Potential contribution of genetic factors and mechanisms to inflammation and allergy","volume":"4","author":"Leung","year":"2005","journal-title":"Curr. Drug Targets Inflamm. Allergy"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1007\/s00417-007-0682-6","article-title":"Preliminary evidence of the efficacy of probiotic eye-drop treatment in patients with vernal keratoconjunctivitis","volume":"246","author":"Iovieno","year":"2008","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_71","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_72","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/pai.12142","article-title":"High-mobility group box-1 (HMGB-1) and serum soluble receptor for advanced glycation end products (sRAGE) in children affected by vernal keratoconjunctivitis","volume":"25","author":"Zicari","year":"2014","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1080\/09273948.2018.1467465","article-title":"Increased Lacrimal Fluid Level of HMGB1 in Vernal Keratoconjunctivitis","volume":"27","author":"Caputo","year":"2019","journal-title":"Ocul. Immunol. Inflamm."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1258\/0007142001903580","article-title":"Genetics of allergic disease","volume":"56","author":"Feijen","year":"2000","journal-title":"Br. Med Bull."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1159\/000053709","article-title":"Genetics of allergic disease: Evidence for organ-specific susceptibility genes","volume":"124","author":"Nishimura","year":"2001","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1111\/j.1399-3038.2012.01281.x","article-title":"New insights into childhood Vernal keratoconjunctivitis-associated factors","volume":"23","author":"Tesse","year":"2012","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1159\/000236942","article-title":"Vernal keratoconjunctivitis: A model of 5q cytokine gene cluster disease","volume":"107","author":"Bonini","year":"1995","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1111\/pai.12231","article-title":"Immunogenetic investigation in vernal keratoconjunctivitis","volume":"25","author":"Zicari","year":"2014","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1097\/00003226-198404000-00012","article-title":"Vernal keratoconjunctivitis: New corneal findings in fraternal twins","volume":"3","author":"Rosenthal","year":"1984","journal-title":"Cornea"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/s13052-021-01073-w","article-title":"Vernal keratoconjunctivitis in twins: Case report and literature review","volume":"47","author":"Artesani","year":"2021","journal-title":"Ital. J. Pediatr."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1001\/archopht.124.4.462","article-title":"Altered expression of neurotransmitter receptors and neuromediators in vernal keratoconjunctivitis","volume":"124","author":"Motterle","year":"2006","journal-title":"Arch. Ophthalmol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1097\/ACI.0000000000000555","article-title":"Neurotrophic factors and nerve growth factor in ocular allergy","volume":"19","author":"Sacchetti","year":"2019","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1084\/jem.20010897","article-title":"The neurotrophins nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 are survival and activation factors for eosinophils in patients with allergic bronchial asthma","volume":"198","author":"Nassenstein","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1097\/ACI.0b013e32833e16cc","article-title":"Neurogenic inflammation of the ocular surface","volume":"10","author":"Mantelli","year":"2010","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1111\/j.1398-9995.2007.01382.x","article-title":"Nonspecific provocation of target organs in allergic diseases: EAACI-GA(2)LEN consensus report","volume":"62","author":"Bonini","year":"2007","journal-title":"Allergy"},{"key":"ref_86","first-page":"47","article-title":"Tear levels of neuropeptides increase after specific allergen challenge in allergic conjunctivitis","volume":"17","author":"Sacchetti","year":"2011","journal-title":"Mol. Vis."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1111\/j.1365-2222.1997.tb00721.x","article-title":"Elevated levels of substance P in tears of patients with allergic conjunctivitis and vernal keratoconjunctivitis","volume":"27","author":"Fujishima","year":"1997","journal-title":"Clin. Exp. Allergy J. Br. Soc. Allergy Clin. Immunol."},{"key":"ref_88","first-page":"2161","article-title":"Increased plasma levels of substance P in vernal keratoconjunctivitis","volume":"38","author":"Lambiase","year":"1997","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1111\/all.13641","article-title":"Changes of NGF pathway in allergic rhinoconjunctivitis: A conjunctival allergen challenge study","volume":"74","author":"Sacchetti","year":"2019","journal-title":"Allergy"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"10955","DOI":"10.1073\/pnas.93.20.10955","article-title":"Circulating nerve growth factor levels are increased in humans with allergic diseases and asthma","volume":"93","author":"Bonini","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_91","first-page":"1272","article-title":"Expression of nerve growth factor receptors on the ocular surface in healthy subjects and during manifestation of inflammatory diseases","volume":"39","author":"Lambiase","year":"1998","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_92","first-page":"2127","article-title":"Increased plasma levels of nerve growth factor in vernal keratoconjunctivitis and relationship to conjunctival mast cells","volume":"36","author":"Lambiase","year":"1995","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1159\/000024054","article-title":"Neural hyperresponsiveness and nerve growth factor in allergic rhinitis","volume":"118","author":"Sanico","year":"1999","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_94","first-page":"981","article-title":"Nerve growth factor has a modulatory role on human primary fibroblast cultures derived from vernal keratoconjunctivitis-affected conjunctiva","volume":"13","author":"Micera","year":"2007","journal-title":"Mol. Vis."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"340","DOI":"10.3109\/08820538.2013.874483","article-title":"Pathogenesis of Vernal Keratoconjunctivitis and Associated Factors","volume":"30","author":"Nebbioso","year":"2015","journal-title":"Semin. Ophthalmol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1111\/j.1398-9995.2008.01880.x","article-title":"Gender difference, sex hormones, and immediate type hypersensitivity reactions","volume":"63","author":"Chen","year":"2008","journal-title":"Allergy"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"945317","DOI":"10.1155\/2015\/945317","article-title":"Sex hormones in allergic conjunctivitis: Altered levels of circulating androgens and estrogens in children and adolescents with vernal keratoconjunctivitis","volume":"2015","author":"Sacchetti","year":"2015","journal-title":"J. Immunol. Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.jtos.2019.07.004","article-title":"Adult Vernal Keratoconjunctivitis: Clinical and biochemical profile of a rare disease","volume":"17","author":"Micera","year":"2019","journal-title":"Ocul. Surf."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/j.1749-6632.2002.tb04210.x","article-title":"Androgens and estrogens modulate the immune and inflammatory responses in rheumatoid arthritis","volume":"966","author":"Cutolo","year":"2002","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1016\/S0161-6420(95)30861-5","article-title":"Estrogen and progesterone receptors in vernal keratoconjunctivitis","volume":"102","author":"Bonini","year":"1995","journal-title":"Ophthalmology"},{"key":"ref_101","first-page":"1419","article-title":"Vernal keratoconjunctivitis: Atopy and autoimmunity","volume":"17","author":"Zicari","year":"2013","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"804870","DOI":"10.1155\/2014\/804870","article-title":"Increased incidence of thyroid dysfunction and autoimmunity in patients with vernal keratoconjunctivitis","volume":"2014","author":"Stagi","year":"2014","journal-title":"Int. J. Endocrinol."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/11\/10\/1012\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:05:10Z","timestamp":1760166310000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/11\/10\/1012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,26]]},"references-count":102,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["life11101012"],"URL":"https:\/\/doi.org\/10.3390\/life11101012","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,26]]}}}