{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T00:34:01Z","timestamp":1793666041373,"version":"4.5.1"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T00:00:00Z","timestamp":1631750400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T00:00:00Z","timestamp":1631750400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100005809","name":"Hyderabad Eye Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>To investigate the differential expression of tear cytokine levels among chronic Stevens\u2013Johnson syndrome (SJS) patients to better understand the role of significantly altered cytokines in disease development. Tear samples were collected using Schirmer strips in 24 eyes of chronic SJS, 24 eyes of age and gender-matched controls, and 14 eyes of aqueous deficiency dry eye disease (DED) patients. The cytokine analysis was performed among 18 analytes which include pro-inflammatory, anti-inflammatory factors, and ELR-negative CXC chemokines. String analysis was performed for the significantly altered cytokines to understand their co-expression and role in the disease development. Additionally, a literature review was conducted to identify the signature cytokines present in chronic SJS tears. The differential expression of IL-6 (p\u2009\u2264\u20090.029), CXCL8\/IL-8 (p\u2009\u2264\u20090.009), IL-1\u03b2 (p\u2009\u2264\u20090.041), IL-2 (p\u2009\u2264\u20090.025), IL-10 (p\u2009\u2264\u20090.053), and CXCL-10 (p\u2009\u2264\u20090.044) were observed in chronic SJS patients and healthy controls. Whereas, IL-6 (p\u2009\u2264\u20090.029), CXCL8\/IL-8 (p\u2009\u2264\u20090.058), CCL4 (p\u2009\u2264\u20090.056), GM-CSF (p\u2009\u2264\u20090.0001) IL-10 (p\u2009\u2264\u20090.025), and CXCL-10 (p\u2009\u2264\u20090.010), were differentially expressed in SJS as compared to severe DED patients. String analysis of the significantly altered cytokines revealed the involvement of several biological processes including the chronic inflammatory response, nitric oxide synthesis, angiogenesis, and cellular response to drugs. Among all the cytokines evaluated, the expression of CXCL8\/IL-8 and CXCL10 levels were consistently reported in the literature. There was a differential expression of tear cytokines in SJS when compared to DED and healthy controls. The differential expression of CXCL8\/IL-8 and CXCL10 was in line with existing literature and their role in chronic SJS pathogenesis merits further evaluation.<\/jats:p>","DOI":"10.1038\/s41598-021-97575-y","type":"journal-article","created":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T10:03:34Z","timestamp":1631786614000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Differential expression of tear film cytokines in Stevens\u2013Johnson syndrome patients and comparative review of literature"],"prefix":"10.1038","volume":"11","author":[{"given":"Madhuri Amulya","family":"Koduri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deeksha","family":"Prasad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shriya","family":"Upadhyaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jilu","family":"Jaffet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swapna S.","family":"Shanbhag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayan","family":"Basu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,16]]},"reference":[{"key":"97575_CR1","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1111\/bjd.14530","volume":"174","author":"D Creamer","year":"2016","unstructured":"Creamer, D. et al. U.K. guidelines for the management of Stevens-Johnson syndrome\/toxic epidermal necrolysis in adults 2016. Br. J. Dermatol. 174, 1194\u20131227. https:\/\/doi.org\/10.1111\/bjd.14530 (2016).","journal-title":"Br. J. Dermatol."},{"key":"97575_CR2","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1001\/archderm.1990.01670320127028","volume":"126","author":"L Naldi","year":"1990","unstructured":"Naldi, L., Locati, F., Marchesi, L. & Cainelli, T. Incidence of toxic epidermal necrolysis in Italy. Arch. Dermatol. 126, 1103\u20131104. https:\/\/doi.org\/10.1001\/archderm.1990.01670320127028 (1990).","journal-title":"Arch. Dermatol."},{"key":"97575_CR3","doi-asserted-by":"publisher","first-page":"389","DOI":"10.4103\/0378-6323.110749","volume":"79","author":"TK Patel","year":"2013","unstructured":"Patel, T. K., Barvaliya, M. J., Sharma, D. & Tripathi, C. A systematic review of the drug-induced Stevens\u2013Johnson syndrome and toxic epidermal necrolysis in Indian population. Indian J. Dermatol. Venereol. Leprol. 79, 389\u2013398. https:\/\/doi.org\/10.4103\/0378-6323.110749 (2013).","journal-title":"Indian J. Dermatol. Venereol. Leprol."},{"key":"97575_CR4","doi-asserted-by":"publisher","first-page":"607532","DOI":"10.3389\/fgene.2020.607532","volume":"11","author":"SS Shanbhag","year":"2020","unstructured":"Shanbhag, S. S. et al. Genetic markers for Stevens\u2013Johnson syndrome\/toxic epidermal necrolysis in the Asian Indian population: Implications on prevention. Front. Genet. 11, 607532. https:\/\/doi.org\/10.3389\/fgene.2020.607532 (2020).","journal-title":"Front. Genet."},{"key":"97575_CR5","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1080\/07853890701753664","volume":"40","author":"R Hazin","year":"2008","unstructured":"Hazin, R., Ibrahimi, O. A., Hazin, M. I. & Kimyai-Asadi, A. Stevens\u2013Johnson syndrome: Pathogenesis, diagnosis, and management. Ann. Med. 40, 129\u2013138. https:\/\/doi.org\/10.1080\/07853890701753664 (2008).","journal-title":"Ann. Med."},{"key":"97575_CR6","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/1750-1172-5-39","volume":"5","author":"T Harr","year":"2010","unstructured":"Harr, T. & French, L. E. Toxic epidermal necrolysis and Stevens\u2013Johnson syndrome. Orphanet J. Rare Dis. 5, 39. https:\/\/doi.org\/10.1186\/1750-1172-5-39 (2010).","journal-title":"Orphanet J. Rare Dis."},{"key":"97575_CR7","doi-asserted-by":"publisher","first-page":"204062231989446","DOI":"10.1177\/2040622319894469","volume":"11","author":"SS Shanbhag","year":"2020","unstructured":"Shanbhag, S. S. et al. Multidisciplinary care in Stevens\u2013Johnson syndrome. Ther. Adv. Chronic Dis. 11, 2040622319894469. https:\/\/doi.org\/10.1177\/2040622319894469 (2020).","journal-title":"Ther. Adv. Chronic Dis."},{"key":"97575_CR8","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1167\/iovs.18-24019","volume":"59","author":"C Sotozono","year":"2018","unstructured":"Sotozono, C., Ueta, M. & Yokoi, N. Severe dry eye with combined mechanisms is involved in the ocular sequelae of SJS\/TEN at the chronic stage. Investig. Ophthalmol. Vis. Sci. 59, 80\u201386. https:\/\/doi.org\/10.1167\/iovs.18-24019 (2018).","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"97575_CR9","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1016\/j.ophtha.2020.08.016","volume":"128","author":"S Singh","year":"2021","unstructured":"Singh, S. et al. Lacrimal gland involvement in severe dry eyes after Stevens\u2013Johnson syndrome. Ophthalmology 128, 621\u2013624. https:\/\/doi.org\/10.1016\/j.ophtha.2020.08.016 (2021).","journal-title":"Ophthalmology"},{"key":"97575_CR10","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1111\/1346-8138.12674","volume":"42","author":"R Abe","year":"2015","unstructured":"Abe, R. Immunological response in Stevens\u2013Johnson syndrome and toxic epidermal necrolysis. J. Dermatol. 42, 42\u201348. https:\/\/doi.org\/10.1111\/1346-8138.12674 (2015).","journal-title":"J. Dermatol."},{"key":"97575_CR11","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1097\/00130832-200410000-00018","volume":"4","author":"EB Cook","year":"2004","unstructured":"Cook, E. B. Tear cytokines in acute and chronic ocular allergic inflammation. Curr. Opin. Allergy Clin. Immunol. 4, 441\u2013445. https:\/\/doi.org\/10.1097\/00130832-200410000-00018 (2004).","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"97575_CR12","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1136\/bjophthalmol-2017-310373","volume":"102","author":"S Gurumurthy","year":"2018","unstructured":"Gurumurthy, S., Iyer, G., Srinivasan, B., Agarwal, S. & Angayarkanni, N. Ocular surface cytokine profile in chronic Stevens\u2013Johnson syndrome and its response to mucous membrane grafting for lid margin keratinisation. Br. J. Ophthalmol. 102, 169\u2013176. https:\/\/doi.org\/10.1136\/bjophthalmol-2017-310373 (2018).","journal-title":"Br. J. Ophthalmol."},{"key":"97575_CR13","doi-asserted-by":"publisher","first-page":"e000073","DOI":"10.1136\/bmjophth-2017-000073","volume":"1","author":"M Ueta","year":"2017","unstructured":"Ueta, M., Nishigaki, H., Sotozono, C. & Kinoshita, S. Downregulation of interferon-gamma-induced protein 10 in the tears of patients with Stevens\u2013Johnson syndrome with severe ocular complications in the chronic stage. BMJ Open Ophthalmol. 1, e000073. https:\/\/doi.org\/10.1136\/bmjophth-2017-000073 (2017).","journal-title":"BMJ Open Ophthalmol."},{"key":"97575_CR14","doi-asserted-by":"publisher","first-page":"18922","DOI":"10.1038\/s41598-020-76064-8","volume":"10","author":"Y Yoshikawa","year":"2020","unstructured":"Yoshikawa, Y. et al. Predictive biomarkers for the progression of ocular complications in chronic Stevens\u2013Johnson syndrome and toxic eeidermal necrolysis. Sci. Rep. 10, 18922. https:\/\/doi.org\/10.1038\/s41598-020-76064-8 (2020).","journal-title":"Sci. Rep."},{"key":"97575_CR15","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.ajo.2018.01.028","volume":"189","author":"S Basu","year":"2018","unstructured":"Basu, S. et al. Chronic ocular sequelae of Stevens\u2013Johnson syndrome in children: Long-term impact of appropriate therapy on natural history of disease. Am. J. Ophthalmol. 189, 17\u201328. https:\/\/doi.org\/10.1016\/j.ajo.2018.01.028 (2018).","journal-title":"Am. J. Ophthalmol."},{"key":"97575_CR16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtos.2021.03.011","author":"S Singh","year":"2021","unstructured":"Singh, S. et al. Lid margin keratinization in Stevens\u2013Johnson syndrome: Review of pathophysiology and histopathology. Ocul. Surf. https:\/\/doi.org\/10.1016\/j.jtos.2021.03.011 (2021).","journal-title":"Ocul. Surf."},{"key":"97575_CR17","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.ctrv.2017.11.007","volume":"63","author":"R Tokunaga","year":"2018","unstructured":"Tokunaga, R. et al. CXCL9, CXCL10, CXCL11\/CXCR3 axis for immune activation\u2014A target for novel cancer therapy. Cancer Treat. Rev. 63, 40\u201347. https:\/\/doi.org\/10.1016\/j.ctrv.2017.11.007 (2018).","journal-title":"Cancer Treat. Rev."},{"key":"97575_CR18","doi-asserted-by":"publisher","first-page":"1900","DOI":"10.36740\/WLek202009202","volume":"73","author":"NV Ivanyushko-Nazarko","year":"2020","unstructured":"Ivanyushko-Nazarko, N. V., Syzon, \u041e\u041e, Volbyn, S. V., Rudnyk, T. I. & Dashko, M. O. Examining the role of the nitric oxide system as the essential pathogenetic link in Stevens-Johnson syndrome. Wiad. Lek. 73, 1900\u20131903 (2020).","journal-title":"Wiad. Lek."},{"key":"97575_CR19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1189\/jlb.68.1.1","volume":"68","author":"JA Belperio","year":"2000","unstructured":"Belperio, J. A. et al. CXC chemokines in angiogenesis. J. Leukoc. Biol. 68, 1\u20138 (2000).","journal-title":"J. Leukoc. Biol."},{"key":"97575_CR20","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.4049\/jimmunol.159.3.1437","volume":"159","author":"MP Keane","year":"1997","unstructured":"Keane, M. P. et al. The CXC chemokines, IL-8 and IP-10, regulate angiogenic activity in idiopathic pulmonary fibrosis. J. Immunol. 159, 1437\u20131443 (1997).","journal-title":"J. Immunol."},{"key":"97575_CR21","doi-asserted-by":"crossref","first-page":"5686","DOI":"10.4049\/jimmunol.163.10.5686","volume":"163","author":"MP Keane","year":"1999","unstructured":"Keane, M. P. et al. IFN-gamma-inducible protein-10 attenuates bleomycin-induced pulmonary fibrosis via inhibition of angiogenesis. J. Immunol. 163, 5686\u20135692 (1999).","journal-title":"J. Immunol."},{"key":"97575_CR22","doi-asserted-by":"publisher","first-page":"3195","DOI":"10.4049\/jimmunol.168.7.3195","volume":"168","author":"JH Dufour","year":"2002","unstructured":"Dufour, J. H. et al. IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking. J. Immunol. 168, 3195\u20133204. https:\/\/doi.org\/10.4049\/jimmunol.168.7.3195 (2002).","journal-title":"J. Immunol."},{"key":"97575_CR23","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1136\/bjophthalmol-2019-314928","volume":"104","author":"SS Shanbhag","year":"2020","unstructured":"Shanbhag, S. S. et al. Clinical clues predictive of Stevens\u2013Johnson syndrome as the cause of chronic cicatrising conjunctivitis. Br. J. Ophthalmol. 104, 1005\u20131009. https:\/\/doi.org\/10.1136\/bjophthalmol-2019-314928 (2020).","journal-title":"Br. J. Ophthalmol."},{"key":"97575_CR24","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2020-318159","author":"S Singh","year":"2021","unstructured":"Singh, S., Shanbhag, S. S. & Basu, S. Tear secretion from the lacrimal gland: Variations in normal versus dry eyes. Br. J. Ophthalmol. https:\/\/doi.org\/10.1136\/bjophthalmol-2020-318159 (2021).","journal-title":"Br. J. Ophthalmol."},{"key":"97575_CR25","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.aanat.2012.10.001","volume":"195","author":"A Posa","year":"2013","unstructured":"Posa, A. et al. Schirmer strip vs capillary tube method: Non-invasive methods of obtaining proteins from tear fluid. Ann. Anat. 195, 137\u2013142. https:\/\/doi.org\/10.1016\/j.aanat.2012.10.001 (2013).","journal-title":"Ann. Anat."},{"key":"97575_CR26","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1016\/j.ophtha.2006.10.029","volume":"114","author":"C Sotozono","year":"2007","unstructured":"Sotozono, C. et al. New grading system for the evaluation of chronic ocular manifestations in patients with Stevens\u2013Johnson syndrome. Ophthalmology 114, 1294\u20131302 (2007).","journal-title":"Ophthalmology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-97575-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-97575-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-97575-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T11:08:22Z","timestamp":1673262502000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-97575-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,16]]},"references-count":26,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["97575"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-97575-y","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,16]]},"assertion":[{"value":"28 May 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 September 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"18433"}}