{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T18:09:06Z","timestamp":1776276546142,"version":"3.50.1"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T00:00:00Z","timestamp":1617667200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T00:00:00Z","timestamp":1617667200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DE026450"],"award-info":[{"award-number":["DE026450"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1S10 OD021676"],"award-info":[{"award-number":["1S10 OD021676"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Sj\u00f6gren\u2019s syndrome (SjS), one of the most common autoimmune diseases, impacts millions of people annually. SjS results from autoimmune attack on exocrine (salivary and lacrimal) glands, and women are nine times more likely to be affected than men. To date, no vaccine or therapeutic exists to treat SjS, and patients must rely on lifelong therapies to alleviate symptoms.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Oral treatment with the adhesin from enterotoxigenic <jats:italic>Escherichia coli<\/jats:italic> colonization factor antigen I (CFA\/I) fimbriae protects against several autoimmune diseases in an antigen (Ag)-independent manner. <jats:italic>Lactococcus lactis<\/jats:italic>, which was recently adapted to express CFA\/I fimbriae (LL-CFA\/I), effectively suppresses inflammation by the induction of infectious tolerance via Ag-specific regulatory T cells (Tregs), that produce IL-10 and TGF-\u03b2. To test the hypothesis that CFA\/I fimbriae can offset the development of inflammatory T cells via Treg induction, oral treatments with LL-CFA\/I were performed on the spontaneous, genetically defined model for SjS, C57BL\/6.NOD-<jats:italic>Aec1Aec2<\/jats:italic> mice to maintain salivary flow.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Six-week (wk)-old C57BL\/6.NOD-<jats:italic>Aec1Aec2<\/jats:italic> mice were orally dosed with LL-CFA\/I and treated every 3 wks; control groups were given <jats:italic>L. lactis<\/jats:italic> vector or PBS. LL-CFA\/I-treated mice retained salivary flow up to 28 wks of age and showed significantly reduced incidence of inflammatory infiltration into the submandibular and lacrimal glands relative to PBS-treated mice. A significant increase in Foxp3<jats:sup>+<\/jats:sup> and IL-10- and TGF-\u03b2-producing Tregs was observed. Moreover, LL-CFA\/I significantly reduced the expression of proinflammatory cytokines, IL-6, IL-17, GM-CSF, and IFN-\u03b3. Adoptive transfer of CD4<jats:sup>+<\/jats:sup> T cells from LL-CFA\/I-treated, not LL vector-treated mice, restored salivary flow in diseased SjS mice.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>These data demonstrate that oral LL-CFA\/I reduce or halts SjS progression, and these studies will provide the basis for future testing in SjS patients.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13075-021-02475-1","type":"journal-article","created":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T07:02:32Z","timestamp":1617692552000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Stimulation of regulatory T cells with Lactococcus lactis expressing enterotoxigenic E. coli colonization factor antigen 1 retains salivary flow in a genetic model of Sj\u00f6gren\u2019s syndrome"],"prefix":"10.1186","volume":"23","author":[{"given":"Ali","family":"Akgul","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimo","family":"Maddaloni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sang Mu","family":"Jun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew S.","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanessa Aguilera","family":"Odreman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol","family":"Hoffman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ella","family":"Bhagyaraj","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandria","family":"Voigt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey R.","family":"Abbott","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cuong Q.","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6572-6916","authenticated-orcid":false,"given":"David W.","family":"Pascual","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,4,6]]},"reference":[{"issue":"9482","key":"2475_CR1","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/S0140-6736(05)66990-5","volume":"366","author":"RI Fox","year":"2005","unstructured":"Fox RI. Sj\u00f6gren\u2019s syndrome. Lancet. 2005;366(9482):321\u201331. https:\/\/doi.org\/10.1016\/S0140-6736(05)66990-5.","journal-title":"Lancet"},{"issue":"3","key":"2475_CR2","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1007\/s40266-013-0050-7","volume":"30","author":"RV Moerman","year":"2013","unstructured":"Moerman RV, Bootsma H, Kroese FG, Vissink A. Sj\u00f6gren\u2019s syndrome in older patients: aetiology, diagnosis and management. Drug Aging. 2013;30(3):137\u201353. https:\/\/doi.org\/10.1007\/s40266-013-0050-7.","journal-title":"Drug Aging"},{"issue":"1","key":"2475_CR3","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/S1542-0124(12)70289-6","volume":"7","author":"CQ Nguyen","year":"2009","unstructured":"Nguyen CQ, Peck AB. Unraveling the pathophysiology of Sj\u00f6gren syndrome-associated dry eye disease. Ocul Surf. 2009;7(1):11\u201327. https:\/\/doi.org\/10.1016\/S1542-0124(12)70289-6.","journal-title":"Ocul Surf"},{"key":"2475_CR4","doi-asserted-by":"publisher","unstructured":"Voigt, Alexandria et al. \u201cBeyond the Glands: An in-Depth Perspective of Neurological Manifestations in Sj\u00f6gren's Syndrome.\u201d Rheumatology (Sunnyvale, Calif.) vol. 2014;2014: S4-010. doi:https:\/\/doi.org\/10.4172\/2161-1149.S4-010.","DOI":"10.4172\/2161-1149.S4-010"},{"key":"2475_CR5","first-page":"3","volume":"116","author":"RI Fox","year":"2002","unstructured":"Fox RI, Stern M. Sj\u00f6gren\u2019s syndrome: mechanisms of pathogenesis involve interaction of immune and neurosecretory systems. Scand J Rheumatol Supp. 2002;116:3\u201313.","journal-title":"Scand J Rheumatol Supp"},{"issue":"4","key":"2475_CR6","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.jaut.2009.10.004","volume":"34","author":"MI Christodoulou","year":"2010","unstructured":"Christodoulou MI, Kapsogeorgou EK, Moutsopoulos HM. Characteristics of the minor salivary gland infiltrates in Sj\u00f6gren\u2019s syndrome. J Autoimmun. 2010;34(4):400\u20137. https:\/\/doi.org\/10.1016\/j.jaut.2009.10.004.","journal-title":"J Autoimmun"},{"issue":"4","key":"2475_CR7","doi-asserted-by":"publisher","first-page":"E607","DOI":"10.1152\/ajpendo.1992.263.4.E607","volume":"263","author":"Y Hu","year":"1992","unstructured":"Hu Y, Nakagawa Y, Purushotham KR, Humphreys-Beher MG. Functional changes in salivary glands of autoimmune disease-prone NOD mice. Am J Physiol Endocrinol Metab. 1992;263(4):E607\u2013E14. https:\/\/doi.org\/10.1152\/ajpendo.1992.263.4.E607.","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2475_CR8","first-page":"73","volume":"10","author":"MG Humphreys-Beher","year":"1996","unstructured":"Humphreys-Beher MG. Animal models for autoimmune disease-associated xerostomia and xerophthalmia. Dent Res J. 1996;10:73\u20135.","journal-title":"Dent Res J"},{"key":"2475_CR9","doi-asserted-by":"publisher","unstructured":"Ridgway WM, Peterson LB, Todd JA, Rainbow DB, Healy B, Burren OS, et al. Chapter 6 gene\u2013gene interactions in the NOD mouse model of type 1 diabetes. Adv Immunol. 2008:151\u201375. https:\/\/doi.org\/10.1016\/S0065-2776(08)00806-7.","DOI":"10.1016\/S0065-2776(08)00806-7"},{"issue":"5","key":"2475_CR10","doi-asserted-by":"publisher","first-page":"1390","DOI":"10.1002\/art.10258","volume":"46","author":"S Cha","year":"2002","unstructured":"Cha S, Nagashima H, Brown VB, Peck AB, Humphreys-Beher MG. Two NOD Idd-associated intervals contribute synergistically to the development of autoimmune exocrinopathy (Sj\u00f6gren\u2019s syndrome) on a healthy murine background. Arthritis Rheum. 2002;46(5):1390\u20138. https:\/\/doi.org\/10.1002\/art.10258.","journal-title":"Arthritis Rheum"},{"issue":"3","key":"2475_CR11","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1002\/art.23214","volume":"58","author":"CQ Nguyen","year":"2008","unstructured":"Nguyen CQ, Hu MH, Li Y, Stewart C, Peck AB. Salivary gland tissue expression of interleukin-23 and interleukin-17 in Sj\u00f6gren\u2019s syndrome: findings in humans and mice. Arthritis Rheum. 2008;58(3):734\u201343. https:\/\/doi.org\/10.1002\/art.23214.","journal-title":"Arthritis Rheum"},{"key":"2475_CR12","first-page":"67","volume":"192","author":"A Voigt","year":"2018","unstructured":"Voigt A, Bohn K, Sukumaran S, Stewart CM, Bhattacharya I, Nguyen CQ. Unique glandular ex-vivo Th1 and Th17 receptor motifs in Sj\u00f6gren\u2019s syndrome patients using single-cell analysis. J. Clin. Immunol. 2018;192:67.","journal-title":"J. Clin. Immunol"},{"issue":"6367","key":"2475_CR13","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1038\/356314a0","volume":"356","author":"R Watanabe-Fukunaga","year":"1992","unstructured":"Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992;356(6367):314\u20137. https:\/\/doi.org\/10.1038\/356314a0.","journal-title":"Nature"},{"issue":"5","key":"2475_CR14","doi-asserted-by":"publisher","first-page":"1198","DOI":"10.1084\/jem.148.5.1198","volume":"148","author":"BS Andrews","year":"1978","unstructured":"Andrews BS, Eisenberg RA, Theofilopoulos AN, Izui S, Wilson CB, McConahey PJ, et al. Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med. 1978;148(5):1198\u2013215. https:\/\/doi.org\/10.1084\/jem.148.5.1198.","journal-title":"J Exp Med"},{"issue":"6","key":"2475_CR15","doi-asserted-by":"publisher","first-page":"1690","DOI":"10.1084\/jem.155.6.1690","volume":"155","author":"L Hang","year":"1982","unstructured":"Hang L, Theofilopoulos AN, Dixon FJ. A spontaneous rheumatoid arthritis-like disease in MRL\/l mice. J Exp Med. 1982;155(6):1690\u2013701. https:\/\/doi.org\/10.1084\/jem.155.6.1690.","journal-title":"J Exp Med"},{"issue":"4","key":"2475_CR16","first-page":"611","volume":"60","author":"R Jonsson","year":"1987","unstructured":"Jonsson R, Tarkowski A, B\u00e4ckman K, Holmdahl R, Klareskog L. Sialadenitis in the MRL-l mouse: morphological and immunohistochemical characterization of resident and infiltrating cells. Immunology. 1987;60(4):611\u20136.","journal-title":"Immunology"},{"issue":"1","key":"2475_CR17","first-page":"9","volume":"83","author":"M Wahren","year":"1994","unstructured":"Wahren M, Skarstein K, Blange I, Pettersson I, Jonsson R. MRL\/lpr mice produce anti-Ro 52,000 MW antibodies: detection, analysis of specificity and site of production. Immunology. 1994;83(1):9\u201315.","journal-title":"Immunology"},{"issue":"18","key":"2475_CR18","doi-asserted-by":"publisher","first-page":"2350","DOI":"10.2174\/1381612821666150316120024","volume":"21","author":"Y-S Park","year":"2015","unstructured":"Park Y-S, Gauna AE, Cha S. Mouse models of primary Sjogren\u2019s syndrome. Curr Pharm Des. 2015;21(18):2350\u201364. https:\/\/doi.org\/10.2174\/1381612821666150316120024.","journal-title":"Curr Pharm Des"},{"issue":"11","key":"2475_CR19","doi-asserted-by":"publisher","first-page":"1410","DOI":"10.1242\/bio.013771","volume":"4","author":"A Voigt","year":"2015","unstructured":"Voigt A, Esfandiary L, Nguyen CQ. Sexual dimorphism in an animal model of Sj\u00f6gren\u2019s syndrome: a potential role for Th17 cells. Biol Open. 2015;4(11):1410\u20139. https:\/\/doi.org\/10.1242\/bio.013771.","journal-title":"Biol Open"},{"issue":"4","key":"2475_CR20","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 Sj\u00f6gren\u2019s syndrome, and amplification of IL-17-mediated secretion of inflammatory cytokines from salivary gland cells by IL-18. J Immunol. 2008;181(4):2898\u2013906. https:\/\/doi.org\/10.4049\/jimmunol.181.4.2898.","journal-title":"J Immunol"},{"issue":"3","key":"2475_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 Sj\u00f6gren\u2019s syndrome immunopathogenesis. Am J Path. 2009;175(3):1167\u201377. https:\/\/doi.org\/10.2353\/ajpath.2009.090319.","journal-title":"Am J Path"},{"key":"2475_CR22","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.jaut.2013.11.001","volume":"51","author":"NC Kyriakidis","year":"2014","unstructured":"Kyriakidis NC, Kapsogeorgou EK, Tzioufas AG. A comprehensive review of autoantibodies in primary Sj\u00f6gren\u2019s syndrome: clinical phenotypes and regulatory mechanisms. J Autoimmun. 2014;51:67\u201374. https:\/\/doi.org\/10.1016\/j.jaut.2013.11.001.","journal-title":"J Autoimmun"},{"issue":"6","key":"2475_CR23","doi-asserted-by":"publisher","first-page":"1302","DOI":"10.1136\/annrheumdis-2013-204584","volume":"74","author":"X Lin","year":"2015","unstructured":"Lin X, Rui K, Deng J, Tian J, Wang X, Wang S, Ko KH, Jiao Z, Chan VSF, Lau CS, Cao X, Lu L. Th17 cells play a critical role in the development of experimental Sj\u00f6gren\u2019s syndrome. Ann Rheum Dis. 2015;74(6):1302\u201310. https:\/\/doi.org\/10.1136\/annrheumdis-2013-204584.","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"2475_CR24","doi-asserted-by":"publisher","first-page":"12512","DOI":"10.1038\/s41598-017-12627-6","volume":"7","author":"A Wanchoo","year":"2017","unstructured":"Wanchoo A, Voigt A, Sukumaran S, Stewart CM, Bhattacharya I, Nguyen CQ. Single-cell analysis reveals sexually dimorphic repertoires of interferon-\u03b3 and IL-17A producing T cells in salivary glands of Sj\u00f6gren\u2019s syndrome mice. Sci Rep. 2017;7(1):12512. https:\/\/doi.org\/10.1038\/s41598-017-12627-6.","journal-title":"Sci Rep"},{"issue":"6","key":"2475_CR25","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 Sj\u00f6gren\u2019s syndrome-like disease using adenovirus-mediated gene transfer. Arthritis Res Ther. 2010;12(6):R220. https:\/\/doi.org\/10.1186\/ar3207.","journal-title":"Arthritis Res Ther"},{"issue":"5","key":"2475_CR26","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1097\/BOR.0b013e328363eaa5","volume":"25","author":"CP Mavragani","year":"2013","unstructured":"Mavragani CP, Nezos A, Moutsopoulos HM. New advances in the classification, pathogenesis and treatment of Sj\u00f6gren\u2019s syndrome. Curr Opin Rheumatol. 2013;25(5):623\u20139. https:\/\/doi.org\/10.1097\/BOR.0b013e328363eaa5.","journal-title":"Curr Opin Rheumatol"},{"issue":"7","key":"2475_CR27","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/nrrheum.2012.53","volume":"8","author":"M Ramos-Casals","year":"2012","unstructured":"Ramos-Casals M, Brito-Zeron P, Siso-Almirall A, Bosch X, Tzioufas AG. Topical and systemic medications for the treatment of primary Sj\u00f6gren\u2019s syndrome. Nat Rev Rheumatol. 2012;8(7):399\u2013411. https:\/\/doi.org\/10.1038\/nrrheum.2012.53.","journal-title":"Nat Rev Rheumatol"},{"issue":"3","key":"2475_CR28","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.jaut.2012.05.014","volume":"39","author":"D Cornec","year":"2012","unstructured":"Cornec D, Devauchelle-Pensec V, Tobon GJ, Pers JO, Jousse-Joulin S, Saraux A. B cells in Sj\u00f6gren\u2019s syndrome: from pathophysiology to diagnosis and treatment. J Autoimmun. 2012;39(3):161\u20137. https:\/\/doi.org\/10.1016\/j.jaut.2012.05.014.","journal-title":"J Autoimmun"},{"key":"2475_CR29","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1517\/14712598.2011.605352","volume":"11","author":"PM Meiners","year":"2011","unstructured":"Meiners PM, Vissink A, Kallenberg CG, Kroese FG, Bootsma H. Treatment of primary Sj\u00f6gren\u2019s syndrome with anti-CD20 therapy (rituximab). A feasible approach or just a starting point? Expert. Opin. Biol. Ther. 2011;11:1381\u201394.","journal-title":"Expert. Opin. Biol. Ther"},{"issue":"3","key":"2475_CR30","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1111\/j.1365-2796.2009.02207.x","volume":"267","author":"F Perosa","year":"2010","unstructured":"Perosa F, Prete M, Racanelli V, Dammacco F. CD20-depleting therapy in autoimmune diseases: from basic research to the clinic. J Intern Med. 2010;267(3):260\u201377. https:\/\/doi.org\/10.1111\/j.1365-2796.2009.02207.x.","journal-title":"J Intern Med"},{"key":"2475_CR31","doi-asserted-by":"publisher","first-page":"R172-R","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 Sj\u00f6gren\u2019s syndrome-like autoimmune exocrinopathy. Arthritis Res. Ther. 2012;14:R172-R.","journal-title":"Arthritis Res. Ther"},{"issue":"3","key":"2475_CR32","doi-asserted-by":"publisher","first-page":"1791","DOI":"10.4049\/jimmunol.178.3.1791","volume":"178","author":"J Ochoa-Rep\u00e1raz","year":"2007","unstructured":"Ochoa-Rep\u00e1raz J, Riccardi C, Rynda A, Jun S, Callis G, Pascual DW. Regulatory T cell vaccination without autoantigen protects against experimental autoimmune encephalomyelitis. J Immunol. 2007;178(3):1791\u20139. https:\/\/doi.org\/10.4049\/jimmunol.178.3.1791.","journal-title":"J Immunol"},{"issue":"4","key":"2475_CR33","doi-asserted-by":"publisher","first-page":"2741","DOI":"10.4049\/jimmunol.181.4.2741","volume":"181","author":"I Kochetkova","year":"2008","unstructured":"Kochetkova I, Trunkle T, Callis G, Pascual DW. Vaccination without autoantigen protects against collagen II-induced arthritis via immune deviation and regulatory T cells. J Immunol. 2008;181(4):2741\u201352. https:\/\/doi.org\/10.4049\/jimmunol.181.4.2741.","journal-title":"J Immunol"},{"issue":"1","key":"2475_CR34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0117825","volume":"10","author":"M Maddaloni","year":"2015","unstructured":"Maddaloni M, Kochetkova I, Jun S, Callis G, Thornburg T, Pascual DW. Milk-based nutraceutical for treating autoimmune arthritis via the stimulation of IL-10- and TGF-\u03b2-producing CD39+ regulatory T cells. PLoS One. 2015;10(1):e0117825. https:\/\/doi.org\/10.1371\/journal.pone.0117825.","journal-title":"PLoS One"},{"issue":"1","key":"2475_CR35","doi-asserted-by":"publisher","first-page":"6156","DOI":"10.1038\/s41598-020-62881-4","volume":"10","author":"AS Nelson","year":"2020","unstructured":"Nelson AS, Maddaloni M, Abbott JR, Hoffman C, Akgul A, Ohland C, Gharaibeh RZ, Jobin C, Brusko TM, Pascual DW. Oral therapy with colonization factor antigen I prevents development of type 1 diabetes in non-obese diabetic mice. Sci Rep. 2020;10(1):6156. https:\/\/doi.org\/10.1038\/s41598-020-62881-4.","journal-title":"Sci Rep"},{"issue":"9","key":"2475_CR36","doi-asserted-by":"publisher","first-page":"4654","DOI":"10.4049\/jimmunol.1100530","volume":"187","author":"I Kochetkova","year":"2011","unstructured":"Kochetkova I, Thornburg T, Callis G, Pascual DW. Segregated regulatory CD39+CD4+ T cell function: TGF-\u03b2-producing Foxp3\u2212 and IL-10-producing Foxp3+ cells are interdependent for protection against collagen-induced arthritis. J Immunol. 2011;187(9):4654\u201366. https:\/\/doi.org\/10.4049\/jimmunol.1100530.","journal-title":"J Immunol"},{"issue":"2","key":"2475_CR37","doi-asserted-by":"publisher","first-page":"804","DOI":"10.4049\/jimmunol.1302018","volume":"192","author":"I Kochetkova","year":"2014","unstructured":"Kochetkova I, Thornburg T, Callis G, Holderness K, Maddaloni M, Pascual DW. Oral Escherichia coli colonization factor antigen I fimbriae ameliorate arthritis via IL-35, not IL-27. J Immunol. 2014;192(2):804\u201316. https:\/\/doi.org\/10.4049\/jimmunol.1302018.","journal-title":"J Immunol"},{"key":"2475_CR38","doi-asserted-by":"publisher","first-page":"2596","DOI":"10.3389\/fmicb.2017.02596","volume":"8","author":"M Yamashita","year":"2017","unstructured":"Yamashita M, Ukibe K, Matsubara Y, Hosoya T, Sakai F, Kon S, et al. Lactobacillus helveticus SBT2171 attenuates experimental autoimmune encephalomyelitis in mice. Front Microbiol. 2017;8:2596.","journal-title":"Front Microbiol"},{"issue":"11","key":"2475_CR39","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1007\/s11926-017-0696-y","volume":"19","author":"A Schorpion","year":"2017","unstructured":"Schorpion A, Kolasinski SL. Can probiotic supplements improve outcomes in rheumatoid arthritis? Curr Rheumatol Rep. 2017;19(11):73. https:\/\/doi.org\/10.1007\/s11926-017-0696-y.","journal-title":"Curr Rheumatol Rep"},{"key":"2475_CR40","doi-asserted-by":"publisher","first-page":"e82","DOI":"10.1038\/cti.2016.29","volume":"5","author":"JL Richards","year":"2016","unstructured":"Richards JL, Yap YA, McLeod KH, Mackay CR, Marino E. Dietary metabolites and the gut microbiota: an alternative approach to control inflammatory and autoimmune diseases. Clin. Transl. Immunol. 2016;5:e82.","journal-title":"Clin. Transl. Immunol"},{"issue":"4","key":"2475_CR41","doi-asserted-by":"publisher","first-page":"1780","DOI":"10.4049\/jimmunol.1501705","volume":"196","author":"S Kandasamy","year":"2016","unstructured":"Kandasamy S, Vlasova AN, Fischer D, Kumar A, Chattha KS, Rauf A, Shao L, Langel SN, Rajashekara G, Saif LJ. Differential effects of Escherichia coli Nissle and Lactobacillus rhamnosus strain GG on human rotavirus binding, infection, and B cell immunity. J Immunol. 2016;196(4):1780\u20139. https:\/\/doi.org\/10.4049\/jimmunol.1501705.","journal-title":"J Immunol"},{"key":"2475_CR42","doi-asserted-by":"publisher","unstructured":"Sonnenborn U. Escherichia coli strain Nissle 1917-from bench to bedside and back: history of a special Escherichia coli strain with probiotic properties. FEMS Microbiol Lett. 2016;363(19). https:\/\/doi.org\/10.1093\/femsle\/fnw212.","DOI":"10.1093\/femsle\/fnw212"},{"issue":"20","key":"2475_CR43","doi-asserted-by":"publisher","first-page":"8693","DOI":"10.1007\/s00253-016-7829-5","volume":"100","author":"B Ou","year":"2016","unstructured":"Ou B, Yang Y, Tham WL, Chen L, Guo J, Zhu G. Genetic engineering of probiotic Escherichia coli Nissle 1917 for clinical application. Appl Microbiol Biot. 2016;100(20):8693\u20139. https:\/\/doi.org\/10.1007\/s00253-016-7829-5.","journal-title":"Appl Microbiol Biot"},{"issue":"35","key":"2475_CR44","doi-asserted-by":"publisher","first-page":"4376","DOI":"10.1016\/j.vaccine.2013.12.026","volume":"32","author":"JE Galen","year":"2014","unstructured":"Galen JE, Curtiss R 3rd. The delicate balance in genetically engineering live vaccines. Vaccine. 2014;32(35):4376\u201385. https:\/\/doi.org\/10.1016\/j.vaccine.2013.12.026.","journal-title":"Vaccine"},{"issue":"1","key":"2475_CR45","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1146\/annurev-food-030216-030207","volume":"9","author":"N Kirmiz","year":"2018","unstructured":"Kirmiz N, Robinson RC, Shah IM, Barile D, Mills DA. Milk glycans and their interaction with the infant-gut microbiota. Annu Rev Food Sci Technol. 2018;9(1):429\u201350. https:\/\/doi.org\/10.1146\/annurev-food-030216-030207.","journal-title":"Annu Rev Food Sci Technol"},{"key":"2475_CR46","doi-asserted-by":"publisher","first-page":"117955221775267","DOI":"10.1177\/1179552217752679","volume":"11","author":"MI More","year":"2018","unstructured":"More MI, Vandenplas Y. Saccharomyces boulardii CNCM I-745 improves intestinal enzyme function: a trophic effects review. Clin Med Insights Gastroenterol. 2018;11:1179552217752679.","journal-title":"Clin Med Insights Gastroenterol"},{"issue":"8","key":"2475_CR47","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1111\/1348-0421.12397","volume":"60","author":"NM Mansour","year":"2016","unstructured":"Mansour NM, Abdelaziz SA. Oral immunization of mice with engineered Lactobacillus gasseri NM713 strain expressing Streptococcus pyogenes M6 antigen. Microbiol Immunol. 2016;60(8):527\u201332. https:\/\/doi.org\/10.1111\/1348-0421.12397.","journal-title":"Microbiol Immunol"},{"issue":"20","key":"2475_CR48","doi-asserted-by":"publisher","first-page":"6091","DOI":"10.1128\/AEM.01533-16","volume":"82","author":"S O'Flaherty","year":"2016","unstructured":"O'Flaherty S, Klaenhammer TR. Multivalent chromosomal expression of the Clostridium botulinum serotype a neurotoxin heavy-chain antigen and the Bacillus anthracis protective antigen in Lactobacillus acidophilus. Appl Environ Microbiol. 2016;82(20):6091\u2013101. https:\/\/doi.org\/10.1128\/AEM.01533-16.","journal-title":"Appl Environ Microbiol"},{"issue":"2","key":"2475_CR49","doi-asserted-by":"publisher","first-page":"576","DOI":"10.3892\/ol.2013.1743","volume":"7","author":"Y Li","year":"2014","unstructured":"Li Y, Li X, Liu H, Zhuang S, Yang J, Zhang F. Intranasal immunization with recombinant lactococci carrying human papillomavirus E7 protein and mouse interleukin-12 DNA induces E7-specific antitumor effects in C57BL\/6 mice. Oncol Let. 2014;7(2):576\u201382. https:\/\/doi.org\/10.3892\/ol.2013.1743.","journal-title":"Oncol Let"},{"key":"2475_CR50","doi-asserted-by":"publisher","first-page":"1352","DOI":"10.1126\/science.289.5483.1352","volume":"289","author":"L Steidler","year":"2000","unstructured":"Steidler L, Hans W, Schotte L, Neirynck S, Obermeier F, Falk W, et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science (New York, NY). 2000;289:1352\u20135.","journal-title":"Science (New York, NY)"},{"key":"2475_CR51","unstructured":"R. D. O. Carvalho, F. L. R. do Carmo, A. de Oliveira Junior, P. Langella, J. M. Chatel, L. G. Bermudez-Humaran et al. Use of wild type or recombinant lactic acid bacteria as an alternative treatment for gastrointestinal inflammatory diseases: a focus on inflammatory bowel diseases and mucositis. Front. Microbiol. 2017;8:800."},{"issue":"3","key":"2475_CR52","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1128\/AEM.03296-13","volume":"80","author":"S Del Carmen","year":"2014","unstructured":"Del Carmen S, de Moreno de LeBlanc A, Martin R, Chain F, Langella P, Bermudez-Humaran LG, et al. Genetically engineered immunomodulatory Streptococcus thermophilus strains producing antioxidant enzymes exhibit enhanced anti-inflammatory activities. Appl Environ Microbiol. 2014;80(3):869\u201377. https:\/\/doi.org\/10.1128\/AEM.03296-13.","journal-title":"Appl Environ Microbiol"},{"key":"2475_CR53","doi-asserted-by":"publisher","first-page":"2691","DOI":"10.3389\/fimmu.2018.02691","volume":"9","author":"M Maddaloni","year":"2018","unstructured":"Maddaloni M, Kochetkova I, Hoffman C, Pascual DW. Delivery of IL-35 by Lactococcus lactis ameliorates collagen-induced arthritis in mice. Front Immunol. 2018;9:2691. https:\/\/doi.org\/10.3389\/fimmu.2018.02691.","journal-title":"Front Immunol"},{"key":"2475_CR54","doi-asserted-by":"publisher","unstructured":"Oddone GM, Mills DA, Block DE. Incorporation of nisI-mediated nisin immunity improves vector-based nisin-controlled gene expression in lactic acid bacteria. Jan 12. PMID: 19141301. Plasmid May 2009;61(3):151\u20138. doi: https:\/\/doi.org\/10.1016\/j.plasmid.2008.12.001.","DOI":"10.1016\/j.plasmid.2008.12.001"},{"key":"2475_CR55","doi-asserted-by":"publisher","first-page":"D792","DOI":"10.1093\/nar\/gkp1005","volume":"38","author":"A Spandidos","year":"2010","unstructured":"Spandidos A, Wang X, Wang H, Seed B. PrimerBank: a resource of human and mouse PCR primer pairs for gene expression detection and quantification. Nucl. Acids Res. 2010;38:D792\u20139 Harvard University primer bank # 6755774c3.","journal-title":"Nucl. Acids Res."},{"key":"2475_CR56","doi-asserted-by":"publisher","first-page":"985","DOI":"10.3389\/fimmu.2017.00985","volume":"8","author":"MF Rabbi","year":"2017","unstructured":"Rabbi MF, et al. Reactivation of intestinal inflammation is suppressed by catestatin in a murine model of colitis via M1 macrophages and not the gut microbiota. Front. Immunol. 2017;8:985.","journal-title":"Front. Immunol."},{"issue":"3","key":"2475_CR57","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0173017","volume":"12","author":"M Yamauchi","year":"2017","unstructured":"Yamauchi M, Moriyama M, Hayashida JN, Maehara T, Ishiguro N, Kubota K, Furukawa S, Ohta M, Sakamoto M, Tanaka A, Nakamura S. Myeloid dendritic cells stimulated by thymic stromal lymphopoietin promote Th2 immune responses and the pathogenesis of oral lichen planus. PLoS One. 2017;12(3):e0173017. https:\/\/doi.org\/10.1371\/journal.pone.0173017.","journal-title":"PLoS One"},{"key":"2475_CR58","doi-asserted-by":"publisher","first-page":"3052","DOI":"10.1002\/eji.201545696","volume":"45","author":"Y Liang","year":"2015","unstructured":"Liang Y, et al. IL-33 promotes innate IFN-\u03b3 production and modulates dendritic cell response in LCMV-induced hepatitis in mice. Eur. J. Immunol. 2015;45:3052\u201363.","journal-title":"Eur. J. Immunol"},{"key":"2475_CR59","first-page":"35","volume":"8","author":"L Sadeghi","year":"2017","unstructured":"Sadeghi L, et al. The immunomodulatory effect of bone-marrow mesenchymal stem cells on expression of TLR3 and TLR9 in mice dendritic cells. Intern J Organ Transplant Med. 2017;8:35\u201342.","journal-title":"Intern J Organ Transplant Med"},{"issue":"12","key":"2475_CR60","doi-asserted-by":"publisher","first-page":"6249","DOI":"10.1128\/IAI.67.12.6249-6256.1999","volume":"67","author":"DW Pascual","year":"1999","unstructured":"Pascual DW, Hone DM, Hall S, van Ginkel FW, Yamamoto M, Walters N, Fujihashi K, Powell RJ, Wu S, Vancott JL, Kiyono H, McGhee JR. Expression of recombinant enterotoxigenic Escherichia coli colonization factor antigen I by Salmonella typhimurium elicits a biphasic T helper cell response. Infect Immun. 1999;67(12):6249\u201356. https:\/\/doi.org\/10.1128\/IAI.67.12.6249-6256.1999.","journal-title":"Infect Immun"},{"issue":"3","key":"2475_CR61","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.jaut.2011.06.002","volume":"37","author":"CR Li","year":"2011","unstructured":"Li CR, Deiro MF, Godebu E, Bradley LM. IL-7 uniquely maintains Foxp3+ adaptive Treg cells that reverse diabetes in NOD mice via integrin-\u03b27-dependent localization. J Autoimmun. 2011;37(3):217\u201327. https:\/\/doi.org\/10.1016\/j.jaut.2011.06.002.","journal-title":"J Autoimmun"},{"key":"2475_CR62","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 Sj\u00f6gren's syndrome. Arthritis Res. Ther. 2012;14:R40.","journal-title":"Arthritis Res. Ther"},{"issue":"5","key":"2475_CR63","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1002\/art.1780290501","volume":"29","author":"RI Fox","year":"1986","unstructured":"Fox RI, Robinson CA, Curd JG, Kozin F, Howell FV. Sjogren\u2019s syndrome. Proposed criteria for classification. Arthritis Rheum. 1986;29(5):577\u201385. https:\/\/doi.org\/10.1002\/art.1780290501.","journal-title":"Arthritis Rheum"},{"issue":"4","key":"2475_CR64","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1080\/08916930410001708715","volume":"37","author":"FC Soliotis","year":"2004","unstructured":"Soliotis FC, Moutsopoulos HM. Sj\u00f6gren\u2019s syndrome. Autoimmunity. 2004;37(4):305\u20137. https:\/\/doi.org\/10.1080\/08916930410001708715.","journal-title":"Autoimmunity"},{"issue":"1","key":"2475_CR65","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1146\/annurev-pathol-012513-104728","volume":"9","author":"CP Mavragani","year":"2014","unstructured":"Mavragani CP, Moutsopoulos HM. Sj\u00f6gren\u2019s syndrome. Annu Rev Path. 2014;9(1):273\u201385. https:\/\/doi.org\/10.1146\/annurev-pathol-012513-104728.","journal-title":"Annu Rev Path"},{"key":"2475_CR66","first-page":"1131","volume":"19","author":"J Qi","year":"2019","unstructured":"Qi J, Li D, Shi G, Zhang X, Pan Y, Dou H, et al. Interleukin-12 exacerbates Sjogren\u2019s syndrome through induction of myeloid-derived suppressor cells. Mol Med Rep. 2019;19:1131\u20138.","journal-title":"Mol Med Rep"},{"issue":"12","key":"2475_CR67","first-page":"2438","volume":"34","author":"X Li","year":"2007","unstructured":"Li X, Li X, Qian L, Wang G, Zhang H, Wang X, Chen K, Zhai Z, Li Q, Wang Y, Harris DC. T regulatory cells are markedly diminished in diseased salivary glands of patients with primary Sj\u00f6gren\u2019s syndrome. J Rheumatol. 2007;34(12):2438\u201345.","journal-title":"J Rheumatol"},{"issue":"5","key":"2475_CR68","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1097\/BOR.0b013e32833c36c5","volume":"22","author":"X Mariette","year":"2010","unstructured":"Mariette X, Gottenberg JE. Pathogenesis of Sj\u00f6gren\u2019s syndrome and therapeutic consequences. Curr Opin Rheumatol. 2010;22(5):471\u20137. https:\/\/doi.org\/10.1097\/BOR.0b013e32833c36c5.","journal-title":"Curr Opin Rheumatol"},{"issue":"1","key":"2475_CR69","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1186\/ar3234","volume":"13","author":"CG Kallenberg","year":"2011","unstructured":"Kallenberg CG, Vissink A, Kroese FG, Abdulahad WH, Bootsma H. What have we learned from clinical trials in primary Sj\u00f6gren\u2019s syndrome about pathogenesis? Arthritis Res Ther. 2011;13(1):205. https:\/\/doi.org\/10.1186\/ar3234.","journal-title":"Arthritis Res Ther"},{"issue":"3","key":"2475_CR70","doi-asserted-by":"publisher","first-page":"730","DOI":"10.3390\/ijms19030730","volume":"19","author":"GR Lee","year":"2018","unstructured":"Lee GR. The balance of Th17 versus Treg cells in autoimmunity. Int J Mol Sci. 2018;19(3):730. https:\/\/doi.org\/10.3390\/ijms19030730.","journal-title":"Int J Mol Sci"},{"issue":"8","key":"2475_CR71","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1111\/j.1601-0825.2009.01582.x","volume":"15","author":"N Roescher","year":"2009","unstructured":"Roescher N, Tak PP, Illei GG. Cytokines in Sj\u00f6gren\u2019s syndrome. Oral Dis. 2009;15(8):519\u201326. https:\/\/doi.org\/10.1111\/j.1601-0825.2009.01582.x.","journal-title":"Oral Dis"}],"container-title":["Arthritis Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-021-02475-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13075-021-02475-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-021-02475-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T07:02:58Z","timestamp":1617692578000},"score":1,"resource":{"primary":{"URL":"https:\/\/arthritis-research.biomedcentral.com\/articles\/10.1186\/s13075-021-02475-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,6]]},"references-count":71,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["2475"],"URL":"https:\/\/doi.org\/10.1186\/s13075-021-02475-1","relation":{},"ISSN":["1478-6362"],"issn-type":[{"value":"1478-6362","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,6]]},"assertion":[{"value":"16 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 March 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 April 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All animal experiments in these described studies were conducted in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animal procedures were approved by the University of Florida Institutional Animal Care and Use Committee.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"99"}}