{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:38:20Z","timestamp":1776818300610,"version":"3.51.2"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,8,6]],"date-time":"2015-08-06T00:00:00Z","timestamp":1438819200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,8,6]],"date-time":"2015-08-06T00:00:00Z","timestamp":1438819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>IL-17 has a putative role in the pathophysiology of Sjogren\u2019s syndrome (SS) and has been shown to be upregulated in the salivary glands of affected individuals. Sequestration of IL-17 with Adenoviral-mediated gene therapy has previously shown a benefit upon the SS-like phenotype in the Aec1\/Aec2 mouse model. We sought to understand the proteomic consequences of IL-17 sequestration in the salivary gland of this mouse model as a means of illuminating the role of IL-17 in SS-like disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Ultrasound-assisted gene transfer (UAGT) was utilized to express a fusion protein composed of the extracellular portion of the IL-17 receptor fused to fragment of crystallization (Fc) in the submandibular glands of Aec1\/Aec2 mice at 8 weeks of age. After confirming expression of the fusion protein and local and systemic sequestration of IL-17, proteomic profiling was performed on submandibular glands of a treated cohort of Aec1\/Aec2 animals relative to the background strain and sham-treated animals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The most notable proteomic signatures of IL-17 sequestration on SS-like disease-related proteins were Kallikrein-related peptidases, including the putative autoantigen Klk1b22. IL-17 sequestration also notably led to an isoelectric shift, but not a molecular weight shift, of Kallikrein-1, attributed to phosphorylation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Non-viral IL-17 sequestration gene therapy in the salivary gland is feasible and downregulates expression of a putative SS autoantigen in the Aec1\/Aec2 mouse.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13075-015-0714-2","type":"journal-article","created":{"date-parts":[[2015,8,5]],"date-time":"2015-08-05T06:32:33Z","timestamp":1438756353000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["IL-17 sequestration via salivary gland gene therapy in a mouse model of Sjogren\u2019s syndrome suppresses disease-associated expression of the putative autoantigen Klk1b22"],"prefix":"10.1186","volume":"17","author":[{"given":"Changgong","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhimin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lee","family":"Zourelias","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiteshi","family":"Thakker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Passineau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,8,6]]},"reference":[{"key":"714_CR1","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1002\/acr.21591","volume":"64","author":"SC Shiboski","year":"2012","unstructured":"Shiboski SC, Shiboski CH, Criswell L, Baer A, Challacombe S, Lanfranchi H, et al. American College of Rheumatology classification criteria for Sjogren\u2019s syndrome: a data-driven, expert consensus approach in the Sjogren\u2019s International Collaborative Clinical Alliance cohort. Arthritis Care Res. 2012;64:475\u201387.","journal-title":"Arthritis Care Res."},{"key":"714_CR2","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1016\/j.autrev.2014.02.002","volume":"13","author":"PD Burbelo","year":"2014","unstructured":"Burbelo PD, Ambatipudi K, Alevizos I. Genome-wide association studies in Sjogren\u2019s syndrome: What do the genes tell us about disease pathogenesis? Autoimmun Rev. 2014;13:756\u201361.","journal-title":"Autoimmun Rev."},{"key":"714_CR3","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1136\/ard.2005.038232","volume":"65","author":"BM Lodde","year":"2006","unstructured":"Lodde BM, Mineshiba F, Wang J, Cotrim AP, Afione S, Tak PP, et al. Effect of human vasoactive intestinal peptide gene transfer in a murine model of Sjogren\u2019s syndrome. Ann Rheum Dis. 2006;65:195\u2013200.","journal-title":"Ann Rheum Dis."},{"key":"714_CR4","doi-asserted-by":"publisher","first-page":"R172","DOI":"10.1186\/ar3925","volume":"14","author":"BH Lee","year":"2012","unstructured":"Lee BH, Carcamo WC, Chiorini JA, Peck AB, Nguyen CQ. Gene therapy using IL-27 ameliorates Sjogren\u2019s syndrome-like autoimmune exocrinopathy. Arthritis Res Ther. 2012;14:R172.","journal-title":"Arthritis Res Ther."},{"key":"714_CR5","doi-asserted-by":"publisher","first-page":"R40","DOI":"10.1186\/ar3753","volume":"14","author":"H Yin","year":"2012","unstructured":"Yin H, Nguyen CQ, Samuni Y, Uede T, Peck AB, Chiorini JA. Local delivery of AAV2-CTLA4IgG decreases sialadenitis and improves gland function in the C57BL\/6.NOD-Aec1Aec2 mouse model of Sjogren\u2019s syndrome. Arthritis Res Ther. 2012;14:R40.","journal-title":"Arthritis Res Ther."},{"key":"714_CR6","doi-asserted-by":"publisher","first-page":"3767","DOI":"10.4049\/jimmunol.1201216","volume":"189","author":"M Bombardieri","year":"2012","unstructured":"Bombardieri M, Barone F, Lucchesi D, Nayar S, van den Berg WB, Proctor G, et al. Inducible tertiary lymphoid structures, autoimmunity, and exocrine dysfunction in a novel model of salivary gland inflammation in C57BL\/6 mice. J Immunol. 2012;189:3767\u201376.","journal-title":"J Immunol."},{"key":"714_CR7","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1038\/labinvest.2010.164","volume":"91","author":"CQ Nguyen","year":"2011","unstructured":"Nguyen CQ, Yin H, Lee BH, Chiorini JA, Peck AB. IL17: potential therapeutic target in Sjogren\u2019s syndrome using adenovirus-mediated gene transfer. Lab Invest. 2011;91:54\u201362.","journal-title":"Lab Invest."},{"key":"714_CR8","doi-asserted-by":"publisher","first-page":"R220","DOI":"10.1186\/ar3207","volume":"12","author":"CQ Nguyen","year":"2010","unstructured":"Nguyen CQ, Yin H, Lee BH, Carcamo WC, Chiorini JA, Peck AB. Pathogenic effect of interleukin-17A in induction of Sjogren\u2019s syndrome-like disease using adenovirus-mediated gene transfer. Arthritis Res Ther. 2010;12:R220.","journal-title":"Arthritis Res Ther."},{"key":"714_CR9","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1111\/j.1365-3083.2006.01828.x","volume":"64","author":"C Nguyen","year":"2006","unstructured":"Nguyen C, Singson E, Kim JY, Cornelius JG, Attia R, Doyle ME, et al. Sjogren\u2019s syndrome-like disease of C57BL\/6.NOD-Aec1 Aec2 mice: gender differences in keratoconjunctivitis sicca defined by a cross-over in the chromosome 3 Aec1 locus. Scand J Immunol. 2006;64:295\u2013307.","journal-title":"Scand J Immunol"},{"key":"714_CR10","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1038\/gt.2010.86","volume":"17","author":"MJ Passineau","year":"2010","unstructured":"Passineau MJ, Zourelias L, Machen L, Edwards PC, Benza RL. Ultrasound-assisted non-viral gene transfer to the salivary glands. Gene Ther. 2010;17:1318\u201324.","journal-title":"Gene Ther."},{"key":"714_CR11","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1089\/hum.2010.069","volume":"22","author":"MJ Passineau","year":"2011","unstructured":"Passineau MJ, Fahrenholz T, Machen L, Zourelias L, Nega K, Paul R, et al. alpha-Galactosidase A expressed in the salivary glands partially corrects organ biochemical deficits in the fabry mouse through endocrine trafficking. Hum Gene Ther. 2011;22:293\u2013301.","journal-title":"Hum Gene Ther"},{"key":"714_CR12","doi-asserted-by":"publisher","first-page":"14007","DOI":"10.1038\/mtm.2014.7","volume":"1","author":"R Geguchadze","year":"2014","unstructured":"Geguchadze R, Wang Z, Zourelias L, Perez-Riveros P, Edwards P, Machen L, et al. Proteomic profiling of salivary gland after non-viral gene transfer mediated by conventional plasmids and minicircles. Mol Ther Methods Clin Dev. 2014;1:14007.","journal-title":"Mol Ther Methods Clin Dev."},{"key":"714_CR13","doi-asserted-by":"publisher","first-page":"2262","DOI":"10.1074\/mcp.M110.000034","volume":"9","author":"C Wu","year":"2010","unstructured":"Wu C, Liu T, Chen W, Oka S, Fu C, Jain MR, et al. Redox regulatory mechanism of transnitrosylation by thioredoxin. Mol Cell Proteomics. 2010;9:2262\u201375.","journal-title":"Mol Cell Proteomics."},{"key":"714_CR14","doi-asserted-by":"publisher","first-page":"2245","DOI":"10.1167\/iovs.08-1949","volume":"50","author":"G Jiang","year":"2009","unstructured":"Jiang G, Ke Y, Sun D, Li H, Ihnen M, Jumblatt MM, et al. A new model of experimental autoimmune keratoconjunctivitis sicca (KCS) induced in Lewis rat by the autoantigen Klk1b22. Invest Ophthalmol Vis Sci. 2009;50:2245\u201354.","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"714_CR15","doi-asserted-by":"publisher","first-page":"3982","DOI":"10.1074\/jbc.M410157200","volume":"280","author":"K Takada","year":"2005","unstructured":"Takada K, Takiguchi M, Konno A, Inaba M. Autoimmunity against a tissue kallikrein in IQI\/Jic Mice: a model for Sjogren\u2019s syndrome. J Biol Chem. 2005;280:3982\u20138.","journal-title":"J Biol Chem."},{"key":"714_CR16","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1136\/ard.48.9.753","volume":"48","author":"D Greaves","year":"1989","unstructured":"Greaves D, Whicher JT, Bhoola KD, Scully C, Flint S, Porter SR, et al. Anionic salivary proteins associated with connective tissue disorders: sialated tissue kallikreins. Ann Rheum Dis. 1989;48:753\u20139.","journal-title":"Ann Rheum Dis."},{"key":"714_CR17","doi-asserted-by":"publisher","first-page":"1652","DOI":"10.1002\/(SICI)1522-2683(19990601)20:7<1652::AID-ELPS1652>3.0.CO;2-R","volume":"20","author":"JA Beeley","year":"1999","unstructured":"Beeley JA, Khoo KS. Salivary proteins in rheumatoid arthritis and Sjogren\u2019s syndrome: one-dimensional and two-dimensional electrophoretic studies. Electrophoresis. 1999;20:1652\u201360.","journal-title":"Electrophoresis."},{"key":"714_CR18","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1136\/annrheumdis-2012-201511","volume":"72","author":"A Alunno","year":"2013","unstructured":"Alunno A, Bistoni O, Bartoloni E, Caterbi S, Bigerna B, Tabarrini A, et al. IL-17-producing CD4-CD8- T cells are expanded in the peripheral blood, infiltrate salivary glands and are resistant to corticosteroids in patients with primary Sjogren\u2019s syndrome. Ann Rheum Dis. 2013;72:286\u201392.","journal-title":"Ann Rheum Dis."},{"key":"714_CR19","doi-asserted-by":"publisher","first-page":"1302","DOI":"10.1136\/annrheumdis-2013-204584","volume":"74","author":"X Lin","year":"2014","unstructured":"Lin X, Rui K, Deng J, Tian J, Wang X, Wang S, et al. Th17 cells play a critical role in the development of experimental Sjogren\u2019s syndrome. Ann Rheum Dis. 2014;74:1302.","journal-title":"Ann Rheum Dis."},{"key":"714_CR20","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.jaut.2012.05.019","volume":"39","author":"N Singh","year":"2012","unstructured":"Singh N, Cohen PL. The T cell in Sjogren\u2019s syndrome: force majeure, not spectateur. J Autoimmun. 2012;39:229\u201333.","journal-title":"J Autoimmun."},{"key":"714_CR21","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.2353\/ajpath.2009.090319","volume":"175","author":"GE Katsifis","year":"2009","unstructured":"Katsifis GE, Rekka S, Moutsopoulos NM, Pillemer S, Wahl SM. Systemic and local interleukin-17 and linked cytokines associated with Sjogren\u2019s syndrome immunopathogenesis. Am J Pathol. 2009;175:1167\u201377.","journal-title":"Am J Pathol."},{"key":"714_CR22","doi-asserted-by":"publisher","first-page":"2898","DOI":"10.4049\/jimmunol.181.4.2898","volume":"181","author":"A Sakai","year":"2008","unstructured":"Sakai A, Sugawara Y, Kuroishi T, Sasano T, Sugawara S. Identification of IL-18 and Th17 cells in salivary glands of patients with Sjogren\u2019s syndrome, and amplification of IL-17-mediated secretion of inflammatory cytokines from salivary gland cells by IL-18. J Immunol. 2008;181:2898\u2013906.","journal-title":"J Immunol."},{"key":"714_CR23","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1016\/j.autrev.2014.08.022","volume":"13","author":"A Alunno","year":"2014","unstructured":"Alunno A, Carubbi F, Bartoloni E, Bistoni O, Caterbi S, Cipriani P, et al. Unmasking the pathogenic role of IL-17 axis in primary Sjogren\u2019s syndrome: A new era for therapeutic targeting? Autoimmun Rev. 2014;13:1167\u201373.","journal-title":"Autoimmun Rev."},{"key":"714_CR24","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2015.36","author":"Z Wang","year":"2015","unstructured":"Wang Z, Zourelias L, Wu C, Edwards PC, Trombetta M, Passineau MJ. Ultrasound-assisted nonviral gene transfer of AQP1 to the irradiated minipig parotid gland restores fluid secretion. Gene Ther. 2015. doi:10.1038\/gt.2015.36. Epub 2015 Apr 14.","journal-title":"Gene Ther"},{"key":"714_CR25","doi-asserted-by":"crossref","first-page":"7780","DOI":"10.1016\/S0021-9258(17)42861-4","volume":"259","author":"S Lundgren","year":"1984","unstructured":"Lundgren S, Ronne H, Rask L, Peterson PA. Sequence of an epidermal growth factor-binding protein. J Biol Chem. 1984;259:7780\u20134.","journal-title":"J Biol Chem."},{"key":"714_CR26","doi-asserted-by":"publisher","first-page":"6750","DOI":"10.1021\/bi00395a026","volume":"26","author":"CC Drinkwater","year":"1987","unstructured":"Drinkwater CC, Evans BA, Richards RI. Mouse glandular kallikrein genes: identification and characterization of the genes encoding the epidermal growth factor binding proteins. Biochemistry. 1987;26:6750\u20136.","journal-title":"Biochemistry."},{"key":"714_CR27","doi-asserted-by":"publisher","first-page":"3443","DOI":"10.1021\/bi00228a014","volume":"30","author":"M Fahnestock","year":"1991","unstructured":"Fahnestock M, Woo JE, Lopez GA, Snow J, Walz DA, Arici MJ, et al. beta-NGF-endopeptidase: structure and activity of a kallikrein encoded by the gene mGK-22. Biochemistry. 1991;30:3443\u201350.","journal-title":"Biochemistry"},{"key":"714_CR28","first-page":"471","volume":"75","author":"Y Hayashi","year":"1989","unstructured":"Hayashi Y, Hirokawa K. Immunopathology of experimental autoallergic sialadenitis in C3H\/He mice. Clin Exp Immunol. 1989;75:471\u20136.","journal-title":"Clin Exp Immunol."},{"key":"714_CR29","first-page":"270","volume":"28","author":"SH Liu","year":"1987","unstructured":"Liu SH, Prendergast RA, Silverstein AM. Experimental autoimmune dacryoadenitis. I. Lacrimal gland disease in the rat. Invest Ophthalmol Vis Sci. 1987;28:270\u20135.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"714_CR30","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1097\/ICO.0b013e31823f8e47","volume":"31","author":"RH Wei","year":"2012","unstructured":"Wei RH, Thomas PB, Samant DM, Schechter JE, Mircheff AK, Trousdale MD. Autoimmune dacryoadenitis and sialadenitis induced in rabbits by intravenous injection of autologous lymphocytes activated ex vivo against lacrimal antigens. Cornea. 2012;31:693\u2013701.","journal-title":"Cornea."},{"key":"714_CR31","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/j.exer.2008.10.006","volume":"88","author":"CQ Nguyen","year":"2009","unstructured":"Nguyen CQ, Sharma A, She JX, McIndoe RA, Peck AB. Differential gene expressions in the lacrimal gland during development and onset of keratoconjunctivitis sicca in Sjogren\u2019s syndrome (SJS)-like disease of the C57BL\/6.NOD-Aec1Aec2 mouse. Exp Eye Res. 2009;88:398\u2013409.","journal-title":"Exp Eye Res"},{"key":"714_CR32","doi-asserted-by":"publisher","first-page":"e90284","DOI":"10.1371\/journal.pone.0090284","volume":"9","author":"A Chiricozzi","year":"2014","unstructured":"Chiricozzi A, Nograles KE, Johnson-Huang LM, Fuentes-Duculan J, Cardinale I, Bonifacio KM, et al. IL-17 induces an expanded range of downstream genes in reconstituted human epidermis model. PLoS One. 2014;9:e90284.","journal-title":"PLoS One."}],"container-title":["Arthritis Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-015-0714-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13075-015-0714-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-015-0714-2","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-015-0714-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T12:08:50Z","timestamp":1728907730000},"score":1,"resource":{"primary":{"URL":"https:\/\/arthritis-research.biomedcentral.com\/articles\/10.1186\/s13075-015-0714-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8,6]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,12]]}},"alternative-id":["714"],"URL":"https:\/\/doi.org\/10.1186\/s13075-015-0714-2","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.725703368.793512522","asserted-by":"object"}]},"ISSN":["1478-6354"],"issn-type":[{"value":"1478-6354","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8,6]]},"assertion":[{"value":"14 April 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 July 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 August 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"198"}}