{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T13:36:53Z","timestamp":1792762613911,"version":"4.5.0"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,6]],"date-time":"2022-07-06T00:00:00Z","timestamp":1657065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>The ocular surface inflammatory disorders (OSID) are caused by systemic disorders that conduct a persistent inflammatory reaction in the ocular adnexal connective tissues, such as the conjunctiva, lacrimal gland (LG) and meibomian glands (MGs), which cause an inflammatory dry eye. The etiologies of OSID are a subset of systemic pathologies such as graft versus host disease, Sj\u00f6gren\u2019s syndrome, allergies, cicatrizing conjunctivitis, and more. These cause a purely inflammatory dry eye syndrome as a consequence of the persistent surrounding inflammation in the adnexal tissues, which is distinct from the age-related dry eye disease. A limitation toward management of these conditions is the lack of available biomarkers that can detect presence of inflammation and quantify damage on the conjunctiva and LG, even though these are considered to be drivers of the inflammatory milieu. The OSID and dry eye syndrome are caused by different immune cells which are not exclusively limited to T cell lymphocytes, but rather derive from an orchestrated multicellular immunologic response. Recognition of this syndrome is crucial to direct research in a direction that clarifies the potential role of inflammation and its associated immune phenotype on the conjunctiva and adnexal ocular tissues in OSID and dry eye syndrome. On this paper, we review the basic and clinical research evidence for the existence of OSID with focus on the different immune cells involved, the target tissues and potential consequences and OSIDs diagnostic and therapeutic implications.<\/jats:p>","DOI":"10.3389\/fmed.2022.949202","type":"journal-article","created":{"date-parts":[[2022,7,6]],"date-time":"2022-07-06T16:53:52Z","timestamp":1657126432000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":25,"title":["Ocular Surface Inflammatory Disorders (OSID): A Collective of Systemic Etiologies Which Cause or Amplify Dry Eye Syndrome"],"prefix":"10.3389","volume":"9","author":[{"given":"Matias","family":"Soifer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadim S.","family":"Azar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hazem M.","family":"Mousa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor L.","family":"Perez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1016\/j.jtos.2017.05.003","article-title":"TFOS DEWS II epidemiology report.","volume":"15","author":"Stapleton","year":"2017","journal-title":"Ocul Surf."},{"key":"B2","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1097\/IIO.0000000000000170","article-title":"Effects of aging in dry eye.","volume":"57","author":"De Paiva","year":"2017","journal-title":"Int Ophthalmol Clin."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/J.EXER.2020.108294","article-title":"Inflammatory basis for dry eye disease flares.","volume":"201","author":"Perez","year":"2020","journal-title":"Exp Eye Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/J.OPHTHA.2013.06.049","article-title":"Neutrophil collagenase, gelatinase, and myeloperoxidase in tears of patients with stevens-johnson syndrome and ocular cicatricial pemphigoid.","volume":"121","author":"Arafat","year":"2014","journal-title":"Ophthalmology."},{"key":"B5","doi-asserted-by":"publisher","first-page":"6111","DOI":"10.1167\/IOVS.18-25571","article-title":"Clinically relevant immune-cellular metrics of inflammation in meibomian gland dysfunction.","volume":"59","author":"Qazi","year":"2018","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1016\/J.AJO.2009.09.013","article-title":"A simplified quantitative method for assessing keratoconjunctivitis sicca from the Sj\u00f6gren\u2019s syndrome international registry.","volume":"149","author":"Whitcher","year":"2010","journal-title":"Am J Ophthalmol."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2021.702755\/BIBTEX","article-title":"Differentially expressed gene pathways in the conjunctiva of Sj\u00f6gren syndrome keratoconjunctivitis sicca.","volume":"12","author":"de Paiva","year":"2021","journal-title":"Front Immunol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/J.JTOS.2021.06.001","article-title":"Relationships between activated dendritic cells and dry eye symptoms and signs.","volume":"21","author":"Levine","year":"2021","journal-title":"Ocul Surf."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e290","DOI":"10.1097\/OPX.0000000000000600","article-title":"Corneal confocal microscopy in dry eye treated with corticosteroids.","volume":"92","author":"Villani","year":"2015","journal-title":"Optom Vis Sci Off Publ Am Acad Optom."},{"key":"B10","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1167\/IOVS.09-3629","article-title":"Changes in corneal epithelial layer inflammatory cells in aqueous tear-deficient dry eye.","volume":"51","author":"Lin","year":"2010","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1016\/j.jtos.2017.05.011","article-title":"TFOS DEWS II pathophysiology report.","volume":"15","author":"Bron","year":"2017","journal-title":"Ocul Surf."},{"key":"B12","doi-asserted-by":"crossref","first-page":"3950","DOI":"10.4049\/jimmunol.176.7.3950","article-title":"Desiccating stress induces T cell-mediated Sj\u00f6gren\u2019s Syndrome-like lacrimal keratoconjunctivitis.","volume":"176","author":"Jy","year":"2006","journal-title":"J Immunol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1097\/01.ICO.0000133994.22392.47","article-title":"Topical cyclosporine inhibits conjunctival epithelial apoptosis in experimental murine keratoconjunctivitis sicca.","volume":"24","author":"Strong","year":"2005","journal-title":"Cornea."},{"key":"B14","article-title":"A method to extract cytokines and matrix metalloproteinases from Schirmer strips and analyze using Luminex.","volume":"17","author":"VanDerMeid","year":"2011","journal-title":"Mol Vis."},{"key":"B15","doi-asserted-by":"publisher","first-page":"198.","DOI":"10.1016\/J.AJO.2008.08.032","article-title":"Tear cytokine profiles in dysfunctional tear syndrome.","volume":"147","author":"Lam","year":"2009","journal-title":"Am J Ophthalmol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2079","DOI":"10.1016\/J.BBMT.2015.08.020","article-title":"Tear cytokines as biomarkers for chronic graft-versus-host disease.","volume":"21","author":"Jung","year":"2015","journal-title":"Biol Blood Marrow Transplant."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-021-97575-y","article-title":"Differential expression of tear film cytokines in Stevens\u2013Johnson syndrome patients and comparative review of literature.","volume":"11","author":"Koduri","year":"2021","journal-title":"Sci Rep."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1097\/OPX.0B013E31821DDC6C","article-title":"Membrane array analysis of tear proteins in ocular cicatricial pemphigoid.","volume":"88","author":"Chan","year":"2011","journal-title":"Optom Vis Sci."},{"key":"B19","first-page":"28","article-title":"Regulation of human leukocyte antigen expression in human conjunctival epithelium.","volume":"40","author":"Tsubota","year":"2021","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1167\/IOVS.08-2722","article-title":"Conjunctival in vivo confocal scanning laser microscopy in patients with Sj\u00f6gren syndrome.","volume":"51","author":"Wakamatsu","year":"2010","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1007\/s40135-020-00226-0","article-title":"Ocular cicatricial pemphigoid.","volume":"8","author":"Mousa","year":"2020","journal-title":"Curr Ophthalmol Rep."},{"key":"B22","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1007\/S40135-020-00227-Z","article-title":"Ocular graft-versus-host disease topic review.","volume":"8","author":"Mousa","year":"2020","journal-title":"Curr Ophthalmol Rep."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.656998","article-title":"Understanding immune responses to surgical transplant procedures in Stevens Johnsons syndrome patients.","volume":"8","author":"Soifer","year":"2021","journal-title":"Front Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1007\/s00005-015-0335-0","article-title":"Macrophage phenotype in the ocular surface of experimental murine dry eye disease HHS public access.","volume":"63","author":"You","year":"2015","journal-title":"Arch Immunol Ther Exp Warsz."},{"key":"B25","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1016\/J.JTOS.2020.08.011","article-title":"Enhanced closed eye neutrophil degranulation in dry eye disease.","volume":"18","author":"Postnikoff","year":"2020","journal-title":"Ocul Surf."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1126\/SCITRANSLMED.AAS9164","article-title":"Neutrophils cause obstruction of eyelid sebaceous glands in inflammatory eye disease in mice.","volume":"10","author":"Reyes","year":"2018","journal-title":"Sci Transl Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/J.JTOS.2020.12.005","article-title":"Aggregated neutrophil extracellular traps occlude meibomian glands during ocular surface inflammation.","volume":"20","author":"Mahajan","year":"2021","journal-title":"Ocul Surf."},{"key":"B28","doi-asserted-by":"publisher","first-page":"8253","DOI":"10.1167\/IOVS.12-10430","article-title":"Ocular surface extracellular DNA and nuclease activity imbalance: a new paradigm for inflammation in dry eye disease.","volume":"53","author":"Sonawane","year":"2012","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1097\/OPX.0000000000001303","article-title":"Impact of dry eye on prolonged reading.","volume":"95","author":"Karakus","year":"2018","journal-title":"Optom Vis Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1016\/J.EXER.2006.02.004","article-title":"Corticosteroid and doxycycline suppress MMP-9 and inflammatory cytokine expression, MAPK activation in the corneal epithelium in experimental dry eye.","volume":"83","author":"De Paiva","year":"2006","journal-title":"Exp Eye Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1097\/ICO.0B013E31803DCDA2","article-title":"Interleukin-6 and tumor necrosis factor-\u03b1 levels in tears of patients with dry eye syndrome.","volume":"26","author":"Yoon","year":"2007","journal-title":"Cornea."},{"key":"B32","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.jtos.2020.10.003","article-title":"Matrix metalloproteinase 9 positivity predicts long term decreased tear production: MMP-9 positivity predicts decreased tear production.","volume":"19","author":"Soifer","year":"2020","journal-title":"Ocul Surf."},{"key":"B33","doi-asserted-by":"publisher","first-page":"4293","DOI":"10.1167\/IOVS.03-1145","article-title":"Experimental dry eye stimulates production of inflammatory cytokines and MMP-9 and activates MAPK signaling pathways on the ocular surface.","volume":"45","author":"Luo","year":"2004","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/J.PRETEYERES.2020.100877","article-title":"Plasmacytoid dendritic cells in the eye.","volume":"80","author":"Jamali","year":"2021","journal-title":"Prog Retin Eye Res."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1097\/IIO.0000000000000169","article-title":"What we have learned from animal models of dry eye.","volume":"57","author":"Stern","year":"2017","journal-title":"Int Ophthalmol Clin."},{"key":"B36","doi-asserted-by":"publisher","first-page":"3653","DOI":"10.4049\/JIMMUNOL.1101442","article-title":"Ocular surface APCs are necessary for autoreactive T cell-mediated experimental autoimmune lacrimal keratoconjunctivitis.","volume":"187","author":"Schaumburg","year":"2011","journal-title":"J Immunol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"S4","DOI":"10.1016\/J.OPHTHA.2017.07.010","article-title":"The pathophysiology of dry eye disease: what we know and future directions for research.","volume":"124","author":"Pflugfelder","year":"2017","journal-title":"Ophthalmology."},{"key":"B38","doi-asserted-by":"publisher","first-page":"3950","DOI":"10.4049\/JIMMUNOL.176.7.3950","article-title":"Desiccating stress induces T cell-mediated Sj\u00f6gren\u2019s syndrome-like lacrimal keratoconjunctivitis.","volume":"176","author":"Niederkorn","year":"2006","journal-title":"J Immunol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.4049\/JIMMUNOL.182.3.1247","article-title":"Autoimmunity in dry eye is due to resistance of Th17 to Treg suppression.","volume":"182","author":"Chauhan","year":"2009","journal-title":"J Immunol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"317","DOI":"10.3109\/02713683.2012.747617","article-title":"New twists to an old story: novel concepts in the pathogenesis of allergic eye disease.","volume":"38","author":"Saban","year":"2013","journal-title":"Curr Eye Res."},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3390\/JCM8122110","article-title":"The innate immune cell profile of the cornea predicts the onset of ocular surface inflammatory disorders.","volume":"8","author":"Del Palomar","year":"2019","journal-title":"J Clin Med."},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3390\/IJMS21020650","article-title":"Mechanisms of disease in Sj\u00f6gren syndrome-new developments and directions.","volume":"21","author":"de Paiva","year":"2020","journal-title":"Int J Mol Sci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/J.JTOS.2019.12.005","article-title":"Tear cytokine levels in the diagnosis and severity assessment of ocular chronic graft-versus-host disease(GVHD).","volume":"18","author":"Hu","year":"2020","journal-title":"Ocul Surf."},{"key":"B44","doi-asserted-by":"publisher","first-page":"4423","DOI":"10.1167\/IOVS.04-0816","article-title":"Aquaporin-dependent water permeation at the mouse ocular surface: in vivo microfluorimetric measurements in cornea and conjunctiva.","volume":"45","author":"Levin","year":"2004","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1016\/S1350-9462(02)00038-1","article-title":"Regulation of mucin and fluid secretion by conjunctival epithelial cells.","volume":"21","author":"Dartt","year":"2002","journal-title":"Prog Retin Eye Res."},{"key":"B46","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1001\/JAMAOPHTHALMOL.2013.2385","article-title":"Transcription, translation, and function of lubricin, a boundary lubricant, at the ocular surface.","volume":"131","author":"Schmidt","year":"2013","journal-title":"JAMA Ophthalmol."},{"key":"B47","first-page":"2609","article-title":"Conjunctival T-cell subpopulations in Sj\u00f6gren\u2019s and non-Sj\u00f6gren\u2019s patients with dry eye.","volume":"43","author":"Stern","year":"2002","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1016\/S0161-6420(90)32478-8","article-title":"Conjunctival cytologiec features of primary Sj\u00f6gren\u2019s syndrome.","volume":"97","author":"Pflugfelder","year":"1990","journal-title":"Ophthalmology."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1485","DOI":"10.1016\/S0161-6420(98)98033-2","article-title":"Meibomian gland dysfunction in patients with Sj\u00f6gren syndrome.","volume":"105","author":"Shimazaki","year":"1998","journal-title":"Ophthalmology."},{"key":"B50","doi-asserted-by":"publisher","first-page":"e173","DOI":"10.1111\/AOS.14240","article-title":"Evaluation of IL8 pathway on the ocular surface: new insights in patients with ocular mucous membrane pemphigoid.","volume":"98","author":"Bruscolini","year":"2020","journal-title":"Acta Ophthalmol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1111\/J.1398-9995.2007.01414.X","article-title":"The differences of tear function and ocular surface findings in patients with atopic keratoconjunctivitis and vernal keratoconjunctivitis.","volume":"62","author":"Hu","year":"2007","journal-title":"Allergy."},{"key":"B52","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1007\/S10384-008-0577-Z","article-title":"Efficacy of topical cyclosporin A 0.05% in conjunctival impression cytology specimens and clinical findings of severe vernal keratoconjunctivitis in children.","volume":"52","author":"Keklikci","year":"2008","journal-title":"Jpn J Ophthalmol."},{"key":"B53","article-title":"Morphologic evaluation of meibomian glands in chronic graft-versus-host disease using in vivo laser confocal microscopy.","volume":"17","author":"Ban","year":"2011","journal-title":"Mol Vis."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1969","DOI":"10.1172\/JCI118629","article-title":"Common T cell receptor clonotype in lacrimal glands and labial salivary glands from patients with Sj\u00f6gren\u2019s syndrome.","volume":"97","author":"Matsumoto","year":"1996","journal-title":"J Clin Invest."},{"key":"B55","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1002\/JCLA.1860070309","article-title":"Expression of cell adhesion molecules in the salivary and lacrimal glands of sjogren\u2019s syndrome.","volume":"7","author":"Saito","year":"1993","journal-title":"J Clin Lab Anal."},{"key":"B56","doi-asserted-by":"publisher","first-page":"2348","DOI":"10.1167\/iovs.14-15630","article-title":"Recruitment of donor t cells to the eyes during ocular GVHD in recipients of MHC-matched allogeneic hematopoietic stem cell transplants.","volume":"56","author":"Herretes","year":"2015","journal-title":"Immunol Microbiol Invest Ophthalmol Vis Sci."},{"key":"B57","doi-asserted-by":"publisher","first-page":"2553","DOI":"10.1167\/IOVS.07-0069","article-title":"Dry eye-induced conjunctival epithelial squamous metaplasia is modulated by interferon-gamma.","volume":"48","author":"De Paiva","year":"2007","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B58","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1097\/ICO.0000000000000335","article-title":"Prospective study of ocular manifestations of pemphigus and bullous pemphigoid identifies a high prevalence of dry eye syndrome.","volume":"34","author":"Tan","year":"2015","journal-title":"Cornea."},{"key":"B59","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1136\/ARD.58.7.415","article-title":"Sicca symptoms, saliva and tear production, and disease variables in 636 patients with rheumatoid arthritis.","volume":"58","author":"Uhlig","year":"1999","journal-title":"Ann Rheum Dis."},{"key":"B60","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1097\/ICO.0000000000001902","article-title":"Evaluation of Dry eye disease in children with systemic lupus erythematosus and healthy controls.","volume":"38","author":"Ong Tone","year":"2019","journal-title":"Cornea."},{"key":"B61","doi-asserted-by":"publisher","first-page":"158","DOI":"10.6061\/CLINICS\/2014(03)02","article-title":"Sj\u00f6gren\u2019s syndrome: an underdiagnosed condition in mixed connective tissue disease.","volume":"69","author":"Usuba","year":"2014","journal-title":"Clin Sao Paulo Braz."},{"key":"B62","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1007\/S00296-018-4013-5\/FIGURES\/1","article-title":"Factors associated with severe dry eye in primary Sj\u00f6gren\u2019s syndrome diagnosed patients.","volume":"38","author":"Fernandez Castro","year":"2018","journal-title":"Rheumatol Int."},{"key":"B63","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/J.JTOS.2020.04.005","article-title":"Prevalence and risk factors of dry eye in 79,866 participants of the population-based lifelines cohort study in the Netherlands.","volume":"19","author":"Vehof","year":"2021","journal-title":"Ocul Surf."},{"key":"B64","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/J.AJO.2016.03.020","article-title":"Ocular manifestations of Stevens-Johnson syndrome and toxic epidermal necrolysis in children.","volume":"166","author":"Catt","year":"2016","journal-title":"Am J Ophthalmol."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.949202\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,6]],"date-time":"2022-07-06T16:54:01Z","timestamp":1657126441000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.949202\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,6]]},"references-count":64,"alternative-id":["10.3389\/fmed.2022.949202"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2022.949202","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,6]]},"article-number":"949202"}}