{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T02:04:17Z","timestamp":1793930657083,"version":"4.8.0"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T00:00:00Z","timestamp":1638316800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T00:00:00Z","timestamp":1640044800000},"content-version":"vor","delay-in-days":20,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS099855-01"],"award-info":[{"award-number":["R01 NS099855-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neuroinflammation"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Tight junctions (TJs) are membrane specializations characteristic of barrier-forming membranes, which function to seal the aqueous pathway between endothelial cells or epithelial cells and, thereby, obstruct intercellular solute and cellular movement. However, previous work from our laboratory found that claudin-5 (CLN-5), a TJ protein prominent at the blood\u2013brain barrier (BBB), was also detected, ectopically, on leukocytes (CLN-5\n                      <jats:sup>+<\/jats:sup>\n                      ) in the blood and central nervous system (CNS) of mice with experimental autoimmune encephalomyelitis (EAE), a neuroinflammatory, demyelinating disease that is a model for multiple sclerosis. CLN-5 was further shown to be transferred from endothelial cells to circulating leukocytes during disease, prompting consideration this action is coupled to leukocyte transendothelial migration (TEM) into the CNS by fostering transient interactions between corresponding leukocyte and endothelial junctional proteins at the BBB.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To begin clarifying the significance of CLN-5\n                      <jats:sup>+<\/jats:sup>\n                      leukocytes, flow cytometry was used to determine their appearance in the blood and CNS during EAE.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Flow cytometric analysis revealed CLN-5\n                      <jats:sup>+<\/jats:sup>\n                      populations among CD4 and CD8 T cells, B cells, monocytes and neutrophils, and these appeared with varying kinetics and to different extents in both blood and CNS. CLN-5 levels on circulating T cells further correlated highly with activation state. And, the percentage of CLN-5\n                      <jats:sup>+<\/jats:sup>\n                      cells among each of the subtypes analyzed was considerably higher in CNS tissue than in blood, consistent with the interpretation that CLN-5\n                      <jats:sup>+<\/jats:sup>\n                      leukocytes gain preferred access to the CNS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Several leukocyte subtypes variably acquire CLN-5 in blood before they enter the CNS, an event that may represent a novel mechanism to guide leukocytes to sites for paracellular diapedesis across the BBB.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-021-02328-3","type":"journal-article","created":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T06:03:50Z","timestamp":1640066630000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Appearance of claudin-5+ leukocyte subtypes in the blood and CNS during progression of EAE"],"prefix":"10.1186","volume":"18","author":[{"given":"Dylan","family":"Krajewski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debayon","family":"Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujun","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan","family":"Jellison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel S.","family":"Pachter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,12,21]]},"reference":[{"issue":"1","key":"2328_CR1","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1007\/s00418-008-0424-9","volume":"130","author":"C Forster","year":"2008","unstructured":"Forster C. Tight junctions and the modulation of barrier function in disease. Histochem Cell Biol. 2008;130(1):55\u201370. https:\/\/doi.org\/10.1007\/s00418-008-0424-9 (Epub 2008\/04\/17).","journal-title":"Histochem Cell Biol"},{"issue":"11","key":"2328_CR2","doi-asserted-by":"publisher","first-page":"2525","DOI":"10.1038\/sj.jid.5700865","volume":"127","author":"CM Niessen","year":"2007","unstructured":"Niessen CM. Tight junctions\/adherens junctions: basic structure and function. J Invest Dermatol. 2007;127(11):2525\u201332. https:\/\/doi.org\/10.1038\/sj.jid.5700865 (Epub 2007\/10\/16).","journal-title":"J Invest Dermatol"},{"issue":"Pt 2","key":"2328_CR3","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1042\/BST0360203","volume":"36","author":"S Garrido-Urbani","year":"2008","unstructured":"Garrido-Urbani S, Bradfield PF, Lee BP, Imhof BA. Vascular and epithelial junctions: a barrier for leucocyte migration. Biochem Soc Trans. 2008;36(Pt 2):203\u201311. https:\/\/doi.org\/10.1042\/BST0360203.","journal-title":"Biochem Soc Trans"},{"issue":"3","key":"2328_CR4","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1016\/j.bbamem.2007.09.003","volume":"1778","author":"Y Wallez","year":"2008","unstructured":"Wallez Y, Huber P. Endothelial adherens and tight junctions in vascular homeostasis, inflammation and angiogenesis. Biochem Biophys Acta. 2008;1778(3):794\u2013809. https:\/\/doi.org\/10.1016\/j.bbamem.2007.09.003.","journal-title":"Biochem Biophys Acta"},{"key":"2328_CR5","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1111\/j.1749-6632.2012.06558.x","volume":"1257","author":"D Vestweber","year":"2012","unstructured":"Vestweber D. Relevance of endothelial junctions in leukocyte extravasation and vascular permeability. Ann N Y Acad Sci. 2012;1257:184\u201392. https:\/\/doi.org\/10.1111\/j.1749-6632.2012.06558.x.","journal-title":"Ann N Y Acad Sci"},{"issue":"1","key":"2328_CR6","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1177\/0300985812469883","volume":"50","author":"WA Muller","year":"2013","unstructured":"Muller WA. Getting leukocytes to the site of inflammation. Vet Pathol. 2013;50(1):7\u201322. https:\/\/doi.org\/10.1177\/0300985812469883.","journal-title":"Vet Pathol"},{"key":"2328_CR7","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a029314","author":"A Buckley","year":"2018","unstructured":"Buckley A, Turner JR. Cell biology of tight junction barrier regulation and mucosal disease. Cold Spring Harb Perspect Biol. 2018. https:\/\/doi.org\/10.1101\/cshperspect.a029314 (Epub 2017\/05\/17).","journal-title":"Cold Spring Harb Perspect Biol"},{"issue":"6","key":"2328_CR8","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1023\/A:1022310429868","volume":"22","author":"JS Alexander","year":"1998","unstructured":"Alexander JS, Dayton T, Davis C, Hill S, Jackson TH, Blaschuk O, Symonds M, Okayama N, Kevil CG, Laroux FS, Berney SM, Kimpel D. Activated T-lymphocytes express occludin, a component of tight junctions. Inflammation. 1998;22(6):573\u201382.","journal-title":"Inflammation"},{"issue":"2","key":"2328_CR9","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.jim.2008.06.001","volume":"337","author":"J Yang","year":"2008","unstructured":"Yang J, Hills D, Taylor E, Pfeffer K, Ure J, Medvinsky A. Transgenic tools for analysis of the haematopoietic system: knock-in CD45 reporter and deletor mice. J Immunol Methods. 2008;337(2):81\u20137. https:\/\/doi.org\/10.1016\/j.jim.2008.06.001.","journal-title":"J Immunol Methods"},{"issue":"4","key":"2328_CR10","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1016\/j.bbrc.2005.04.025","volume":"331","author":"K Inagaki-Ohara","year":"2005","unstructured":"Inagaki-Ohara K, Sawaguchi A, Suganuma T, Matsuzaki G, Nawa Y. Intraepithelial lymphocytes express junctional molecules in murine small intestine. Biochem Biophys Res Commun. 2005;331(4):977\u201383. https:\/\/doi.org\/10.1016\/j.bbrc.2005.04.025.","journal-title":"Biochem Biophys Res Commun"},{"issue":"4","key":"2328_CR11","doi-asserted-by":"publisher","first-page":"2161","DOI":"10.4049\/jimmunol.176.4.2161","volume":"176","author":"SS Sung","year":"2006","unstructured":"Sung SS, Fu SM, Rose CE Jr, Gaskin F, Ju ST, Beaty SR. A major lung CD103 (alphaE)-beta7 integrin-positive epithelial dendritic cell population expressing Langerin and tight junction proteins. J Immunol. 2006;176(4):2161\u201372.","journal-title":"J Immunol"},{"issue":"10","key":"2328_CR12","doi-asserted-by":"publisher","first-page":"2381","DOI":"10.1038\/sj.jid.5700882","volume":"127","author":"SC Zimmerli","year":"2007","unstructured":"Zimmerli SC, Hauser C. Langerhans cells and lymph node dendritic cells express the tight junction component claudin-1. J Invest Dermatol. 2007;127(10):2381\u201390. https:\/\/doi.org\/10.1038\/sj.jid.5700882.","journal-title":"J Invest Dermatol"},{"issue":"1\u20132","key":"2328_CR13","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.imbio.2010.02.006","volume":"216","author":"F Blank","year":"2011","unstructured":"Blank F, Wehrli M, Lehmann A, Baum O, Gehr P, von Garnier C, Rothen-Rutishauser BM. Macrophages and dendritic cells express tight junction proteins and exchange particles in an in vitro model of the human airway wall. Immunobiology. 2011;216(1\u20132):86\u201395. https:\/\/doi.org\/10.1016\/j.imbio.2010.02.006.","journal-title":"Immunobiology"},{"issue":"3","key":"2328_CR14","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1038\/sj\/mn\/7800077","volume":"8","author":"JS Alexander","year":"2001","unstructured":"Alexander JS, Elrod JW, Park JH. Roles of leukocyte and immune cell junctional proteins. Microcirculation. 2001;8(3):169\u201379. https:\/\/doi.org\/10.1038\/sj\/mn\/7800077.","journal-title":"Microcirculation"},{"issue":"6","key":"2328_CR15","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1038\/nri2096","volume":"7","author":"C Weber","year":"2007","unstructured":"Weber C, Fraemohs L, Dejana E. The role of junctional adhesion molecules in vascular inflammation. Nat Rev Immunol. 2007;7(6):467\u201377. https:\/\/doi.org\/10.1038\/nri2096.","journal-title":"Nat Rev Immunol"},{"issue":"19","key":"2328_CR16","doi-asserted-by":"publisher","first-page":"4799","DOI":"10.1182\/blood-2008-04-152330","volume":"113","author":"RR Koenen","year":"2009","unstructured":"Koenen RR, Pruessmeyer J, Soehnlein O, Fraemohs L, Zernecke A, Schwarz N, Reiss K, Sarabi A, Lindbom L, Hackeng TM, Weber C, Ludwig A. Regulated release and functional modulation of junctional adhesion molecule A by disintegrin metalloproteinases. Blood. 2009;113(19):4799\u2013809. https:\/\/doi.org\/10.1182\/blood-2008-04-152330.","journal-title":"Blood"},{"issue":"1","key":"2328_CR17","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1186\/s12974-016-0755-8","volume":"13","author":"D Paul","year":"2016","unstructured":"Paul D, Baena V, Ge S, Jiang X, Jellison ER, Kiprono T, Agalliu D, Pachter JS. Appearance of claudin-5(+) leukocytes in the central nervous system during neuroinflammation: a novel role for endothelial-derived extracellular vesicles. J Neuroinflamm. 2016;13(1):292. https:\/\/doi.org\/10.1186\/s12974-016-0755-8 (Epub 2016\/11\/18).","journal-title":"J Neuroinflamm"},{"issue":"2","key":"2328_CR18","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1007\/s00401-016-1631-4","volume":"133","author":"H Lassmann","year":"2017","unstructured":"Lassmann H, Bradl M. Multiple sclerosis: experimental models and reality. Acta Neuropathol. 2017;133(2):223\u201344. https:\/\/doi.org\/10.1007\/s00401-016-1631-4 (Epub 2016\/10\/22).","journal-title":"Acta Neuropathol"},{"issue":"4","key":"2328_CR19","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1111\/j.1582-4934.2011.01380.x","volume":"16","author":"I Mandel","year":"2012","unstructured":"Mandel I, Paperna T, Glass-Marmor L, Volkowich A, Badarny S, Schwartz I, Vardi P, Koren I, Miller A. Tight junction proteins expression and modulation in immune cells and multiple sclerosis. J Cell Mol Med. 2012;16(4):765\u201375. https:\/\/doi.org\/10.1111\/j.1582-4934.2011.01380.x.","journal-title":"J Cell Mol Med"},{"issue":"3","key":"2328_CR20","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1083\/jcb.200302070","volume":"161","author":"T Nitta","year":"2003","unstructured":"Nitta T, Hata M, Gotoh S, Seo Y, Sasaki H, Hashimoto N, Furuse M, Tsukita S. Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J Cell Biol. 2003;161(3):653\u201360. https:\/\/doi.org\/10.1083\/jcb.200302070.","journal-title":"J Cell Biol"},{"key":"2328_CR21","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/1742-2094-11-10","volume":"11","author":"D Paul","year":"2014","unstructured":"Paul D, Ge S, Lemire Y, Jellison ER, Serwanski DR, Ruddle NH, Pachter JS. Cell-selective knockout and 3D confocal image analysis reveals separate roles for astrocyte-and endothelial-derived CCL2 in neuroinflammation. J Neuroinflamm. 2014;11:10. https:\/\/doi.org\/10.1186\/1742-2094-11-10.","journal-title":"J Neuroinflamm"},{"issue":"5\u20136","key":"2328_CR22","first-page":"469","volume":"17","author":"J Goverman","year":"1997","unstructured":"Goverman J, Brabb T, Paez A, Harrington C, von Dassow P. Initiation and regulation of CNS autoimmunity. Crit Rev Immunol. 1997;17(5\u20136):469\u201380 (Epub 1997\/01\/01).","journal-title":"Crit Rev Immunol"},{"issue":"6","key":"2328_CR23","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.it.2005.03.012","volume":"26","author":"MK Racke","year":"2005","unstructured":"Racke MK, Hu W, Lovett-Racke AE. PTX cruiser: driving autoimmunity via TLR4. Trends Immunol. 2005;26(6):289\u201391. https:\/\/doi.org\/10.1016\/j.it.2005.03.012 (Epub 2005\/06\/01).","journal-title":"Trends Immunol"},{"issue":"6","key":"2328_CR24","doi-asserted-by":"publisher","first-page":"2110","DOI":"10.4049\/jimmunol.1600876","volume":"197","author":"EJ Anstadt","year":"2016","unstructured":"Anstadt EJ, Fujiwara M, Wasko N, Nichols F, Clark RB. TLR tolerance as a treatment for central nervous system autoimmunity. J Immunol. 2016;197(6):2110\u20138. https:\/\/doi.org\/10.4049\/jimmunol.1600876 (Epub 2016\/08\/10).","journal-title":"J Immunol"},{"issue":"23","key":"2328_CR25","doi-asserted-by":"publisher","first-page":"3770","DOI":"10.1016\/j.febslet.2011.04.066","volume":"585","author":"C Larochelle","year":"2011","unstructured":"Larochelle C, Alvarez JI, Prat A. How do immune cells overcome the blood-brain barrier in multiple sclerosis? FEBS Lett. 2011;585(23):3770\u201380. https:\/\/doi.org\/10.1016\/j.febslet.2011.04.066.","journal-title":"FEBS Lett"},{"issue":"1","key":"2328_CR26","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1111\/j.1600-065X.2012.01127.x","volume":"248","author":"Y Takeshita","year":"2012","unstructured":"Takeshita Y, Ransohoff RM. Inflammatory cell trafficking across the blood-brain barrier: chemokine regulation and in vitro models. Immunol Rev. 2012;248(1):228\u201339. https:\/\/doi.org\/10.1111\/j.1600-065X.2012.01127.x (Epub 2012\/06\/26).","journal-title":"Immunol Rev"},{"issue":"7","key":"2328_CR27","doi-asserted-by":"publisher","first-page":"4648","DOI":"10.4049\/jimmunol.181.7.4648","volume":"181","author":"GC Furtado","year":"2008","unstructured":"Furtado GC, Marcondes MC, Latkowski JA, Tsai J, Wensky A, Lafaille JJ. Swift entry of myelin-specific T lymphocytes into the central nervous system in spontaneous autoimmune encephalomyelitis. J Immunol. 2008;181(7):4648\u201355. https:\/\/doi.org\/10.4049\/jimmunol.181.7.4648 (Epub 2008\/09\/20).","journal-title":"J Immunol"},{"issue":"6","key":"2328_CR28","doi-asserted-by":"publisher","first-page":"3750","DOI":"10.4049\/jimmunol.181.6.3750","volume":"181","author":"RA O'Connor","year":"2008","unstructured":"O\u2019Connor RA, Prendergast CT, Sabatos CA, Lau CW, Leech MD, Wraith DC, Anderton SM. Cutting edge: Th1 cells facilitate the entry of Th17 cells to the central nervous system during experimental autoimmune encephalomyelitis. J Immunol. 2008;181(6):3750\u20134. https:\/\/doi.org\/10.4049\/jimmunol.181.6.3750 (Epub 2008\/09\/05).","journal-title":"J Immunol"},{"key":"2328_CR29","doi-asserted-by":"publisher","first-page":"711","DOI":"10.3389\/fimmu.2019.00711","volume":"10","author":"I Wimmer","year":"2019","unstructured":"Wimmer I, Tietz S, Nishihara H, Deutsch U, Sallusto F, Gosselet F, Lyck R, Muller WA, Lassmann H, Engelhardt B. PECAM-1 stabilizes blood-brain barrier integrity and favors paracellular T-Cell diapedesis across the blood-brain barrier during neuroinflammation. Front Immunol. 2019;10:711. https:\/\/doi.org\/10.3389\/fimmu.2019.00711 (Epub 2019\/04\/27).","journal-title":"Front Immunol"},{"issue":"4","key":"2328_CR30","doi-asserted-by":"publisher","first-page":"e0154253","DOI":"10.1371\/journal.pone.0154253","volume":"11","author":"J Qualai","year":"2016","unstructured":"Qualai J, Li LX, Cantero J, Tarrats A, Fernandez MA, Sumoy L, Rodolosse A, McSorley SJ, Genesca M. Expression of CD11c Is associated with unconventional activated T cell subsets with high migratory potential. PLoS ONE. 2016;11(4):e0154253. https:\/\/doi.org\/10.1371\/journal.pone.0154253 (Epub 2016\/04\/28).","journal-title":"PLoS ONE"},{"issue":"7","key":"2328_CR31","doi-asserted-by":"publisher","first-page":"2487","DOI":"10.1167\/iovs.04-1333","volume":"46","author":"H Xu","year":"2005","unstructured":"Xu H, Dawson R, Crane IJ, Liversidge J. Leukocyte diapedesis in vivo induces transient loss of tight junction protein at the blood-retina barrier. Invest Ophthalmol Vis Sci. 2005;46(7):2487\u201394. https:\/\/doi.org\/10.1167\/iovs.04-1333.","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"5","key":"2328_CR32","doi-asserted-by":"publisher","first-page":"2427","DOI":"10.4049\/jimmunol.1400700","volume":"193","author":"RC Winger","year":"2014","unstructured":"Winger RC, Koblinski JE, Kanda T, Ransohoff RM, Muller WA. Rapid remodeling of tight junctions during paracellular diapedesis in a human model of the blood-brain barrier. J Immunol. 2014;193(5):2427\u201337. https:\/\/doi.org\/10.4049\/jimmunol.1400700 (Epub 2014\/07\/27).","journal-title":"J Immunol"},{"issue":"12","key":"2328_CR33","doi-asserted-by":"publisher","first-page":"7579","DOI":"10.4049\/jimmunol.166.12.7579","volume":"166","author":"D Sun","year":"2001","unstructured":"Sun D, Whitaker JN, Huang Z, Liu D, Coleclough C, Wekerle H, Raine CS. Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL\/6 mice. J Immunol. 2001;166(12):7579\u201387. https:\/\/doi.org\/10.4049\/jimmunol.166.12.7579 (Epub 2001\/06\/08).","journal-title":"J Immunol"},{"issue":"5","key":"2328_CR34","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1084\/jem.194.5.669","volume":"194","author":"ES Huseby","year":"2001","unstructured":"Huseby ES, Liggitt D, Brabb T, Schnabel B, Ohlen C, Goverman J. A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis. J Exp Med. 2001;194(5):669\u201376. https:\/\/doi.org\/10.1084\/jem.194.5.669 (Epub 2001\/09\/06).","journal-title":"J Exp Med"},{"issue":"4","key":"2328_CR35","doi-asserted-by":"publisher","first-page":"1952","DOI":"10.1038\/nprot.2006.284","volume":"1","author":"IM Stromnes","year":"2006","unstructured":"Stromnes IM, Goverman JM. Passive induction of experimental allergic encephalomyelitis. Nat Protoc. 2006;1(4):1952\u201360. https:\/\/doi.org\/10.1038\/nprot.2006.284 (Epub 2007\/05\/10).","journal-title":"Nat Protoc"},{"issue":"1\u20132","key":"2328_CR36","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.jneuroim.2009.05.017","volume":"213","author":"M Bettini","year":"2009","unstructured":"Bettini M, Rosenthal K, Evavold BD. Pathogenic MOG-reactive CD8+ T cells require MOG-reactive CD4+ T cells for sustained CNS inflammation during chronic EAE. J Neuroimmunol. 2009;213(1\u20132):60\u20138. https:\/\/doi.org\/10.1016\/j.jneuroim.2009.05.017 (Epub 2009\/06\/23).","journal-title":"J Neuroimmunol"},{"issue":"6","key":"2328_CR37","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1038\/s41423-019-0221-5","volume":"16","author":"L van Kaer","year":"2019","unstructured":"van Kaer L, Postoak JL, Wang C, Yang G, Wu L. Innate, innate-like and adaptive lymphocytes in the pathogenesis of MS and EAE. Cell Mol Immunol. 2019;16(6):531\u20139. https:\/\/doi.org\/10.1038\/s41423-019-0221-5 (Epub 2019\/03\/16).","journal-title":"Cell Mol Immunol"},{"key":"2328_CR38","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1146\/annurev.immunol.021908.132557","volume":"27","author":"C Auffray","year":"2009","unstructured":"Auffray C, Sieweke MH, Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Ann Rev Immunol. 2009;27:669\u201392. https:\/\/doi.org\/10.1146\/annurev.immunol.021908.132557 (Epub 2009\/01\/10).","journal-title":"Ann Rev Immunol"},{"issue":"9","key":"2328_CR39","doi-asserted-by":"publisher","first-page":"e0184626","DOI":"10.1371\/journal.pone.0184626","volume":"12","author":"S Gasco","year":"2017","unstructured":"Gasco S, Zaragoza P, Garcia-Redondo A, Calvo AC, Osta R. Inflammatory and non-inflammatory monocytes as novel prognostic biomarkers of survival in SOD1G93A mouse model of Amyotrophic Lateral Sclerosis. PLoS ONE. 2017;12(9):e0184626. https:\/\/doi.org\/10.1371\/journal.pone.0184626 (Epub 2017\/09\/09).","journal-title":"PLoS ONE"},{"issue":"1","key":"2328_CR40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/2050-7771-2-1","volume":"2","author":"J Yang","year":"2014","unstructured":"Yang J, Zhang L, Yu C, Yang XF, Wang H. Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases. Biomark Res. 2014;2(1):1. https:\/\/doi.org\/10.1186\/2050-7771-2-1 (Epub 2014\/01\/09).","journal-title":"Biomark Res."},{"issue":"14","key":"2328_CR41","doi-asserted-by":"publisher","first-page":"3190","DOI":"10.1182\/blood-2008-07-168575","volume":"113","author":"IL King","year":"2009","unstructured":"King IL, Dickendesher TL, Segal BM. Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood. 2009;113(14):3190\u20137. https:\/\/doi.org\/10.1182\/blood-2008-07-168575 (Epub 2009\/02\/07).","journal-title":"Blood"},{"issue":"3","key":"2328_CR42","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1016\/j.autrev.2017.01.013","volume":"16","author":"CS Casserly","year":"2017","unstructured":"Casserly CS, Nantes JC, Whittaker Hawkins RF, Vallieres L. Neutrophil perversion in demyelinating autoimmune diseases: mechanisms to medicine. Autoimmun Rev. 2017;16(3):294\u2013307. https:\/\/doi.org\/10.1016\/j.autrev.2017.01.013 (Epub 2017\/02\/06).","journal-title":"Autoimmun Rev"},{"key":"2328_CR43","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.clim.2016.06.017","volume":"189","author":"ER Pierson","year":"2018","unstructured":"Pierson ER, Wagner CA, Goverman JM. The contribution of neutrophils to CNS autoimmunity. Clin Immunol. 2018;189:23\u20138. https:\/\/doi.org\/10.1016\/j.clim.2016.06.017 (Epub 2016\/07\/0).","journal-title":"Clin Immunol"},{"key":"2328_CR44","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.mvr.2012.12.001","volume":"86","author":"D Paul","year":"2013","unstructured":"Paul D, Cowan AE, Ge S, Pachter JS. Novel 3D analysis of Claudin-5 reveals significant endothelial heterogeneity among CNS microvessels. Microvasc Res. 2013;86:1\u201310. https:\/\/doi.org\/10.1016\/j.mvr.2012.12.001.","journal-title":"Microvasc Res"},{"issue":"5","key":"2328_CR45","doi-asserted-by":"publisher","first-page":"2173","DOI":"10.1152\/jn.00510.2016","volume":"116","author":"D Wang","year":"2016","unstructured":"Wang D, Li SP, Fu JS, Zhang S, Bai L, Guo L. Resveratrol defends blood-brain barrier integrity in experimental autoimmune encephalomyelitis mice. J Neurophysiol. 2016;116(5):2173\u20139. https:\/\/doi.org\/10.1152\/jn.00510.2016 (Epub 2016\/11\/03).","journal-title":"J Neurophysiol"},{"issue":"36","key":"2328_CR46","doi-asserted-by":"publisher","first-page":"14735","DOI":"10.1073\/pnas.1302569110","volume":"110","author":"TV Lanz","year":"2013","unstructured":"Lanz TV, Becker S, Osswald M, Bittner S, Schuhmann MK, Opitz CA, Gaikwad S, Wiestler B, Litzenburger UM, Sahm F, Ott M, Iwantscheff S, Grabitz C, Mittelbronn M, von Deimling A, Winkler F, Meuth SG, Wick W, Platten M. Protein kinase Cbeta as a therapeutic target stabilizing blood-brain barrier disruption in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci United States Am. 2013;110(36):14735\u201340. https:\/\/doi.org\/10.1073\/pnas.1302569110 (Epub 2013\/08\/21).","journal-title":"Proc Natl Acad Sci United States Am."},{"key":"2328_CR47","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci10110831","author":"A Lasek-Bal","year":"2020","unstructured":"Lasek-Bal A, Kokot A, de Carrillo GD, Student S, Pawletko K, Krzan A, Puz P, Bal W, Jedrzejowska-Szypulka H. Plasma levels of occludin and claudin-5 in acute stroke are correlated with the type and location of stroke but not with the neurological state of patients-preliminary data. Brain Sci. 2020. https:\/\/doi.org\/10.3390\/brainsci10110831 (Epub 2020\/11\/14).","journal-title":"Brain Sci"},{"issue":"2","key":"2328_CR48","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1002\/jnr.490280213","volume":"28","author":"WF Hickey","year":"1991","unstructured":"Hickey WF, Hsu BL, Kimura H. T-lymphocyte entry into the central nervous system. J Neurosci Res. 1991;28(2):254\u201360. https:\/\/doi.org\/10.1002\/jnr.490280213 (Epub 1991\/02\/01).","journal-title":"J Neurosci Res"},{"issue":"3","key":"2328_CR49","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/0165-5728(92)90008-9","volume":"37","author":"PA Ludowyk","year":"1992","unstructured":"Ludowyk PA, Willenborg DO, Parish CR. Selective localisation of neuro-specific T lymphocytes in the central nervous system. J Neuroimmunol. 1992;37(3):237\u201350. https:\/\/doi.org\/10.1016\/0165-5728(92)90008-9 (Epub 1992\/04\/01).","journal-title":"J Neuroimmunol"},{"issue":"1","key":"2328_CR50","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/s0165-5728(97)00237-3","volume":"84","author":"B Engelhardt","year":"1998","unstructured":"Engelhardt B, Martin-Simonet MT, Rott LS, Butcher EC, Michie SA. Adhesion molecule phenotype of T lymphocytes in inflamed CNS. J Neuroimmunol. 1998;84(1):92\u2013104. https:\/\/doi.org\/10.1016\/s0165-5728(97)00237-3.","journal-title":"J Neuroimmunol"},{"issue":"24","key":"2328_CR51","doi-asserted-by":"publisher","first-page":"13932","DOI":"10.1073\/pnas.96.24.13932","volume":"96","author":"N Manjunath","year":"1999","unstructured":"Manjunath N, Shankar P, Stockton B, Dubey PD, Lieberman J, von Andrian UH. A transgenic mouse model to analyze CD8(+) effector T cell differentiation in vivo. Proc Natl Acad Sci United States Am. 1999;96(24):13932\u20137. https:\/\/doi.org\/10.1073\/pnas.96.24.13932 (Epub 1999\/11\/26).","journal-title":"Proc Natl Acad Sci United States Am."},{"key":"2328_CR52","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.bbi.2015.06.021","volume":"50","author":"N Alvarez-Sanchez","year":"2015","unstructured":"Alvarez-Sanchez N, Cruz-Chamorro I, Lopez-Gonzalez A, Utrilla JC, Fernandez-Santos JM, Martinez-Lopez A, Lardone PJ, Guerrero JM, Carrillo-Vico A. Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector\/regulatory balance. Brain Behav Immun. 2015;50:101\u201314. https:\/\/doi.org\/10.1016\/j.bbi.2015.06.021 (Epub 2015\/07\/03).","journal-title":"Brain Behav Immun"},{"issue":"7","key":"2328_CR53","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1016\/j.it.2019.04.010","volume":"40","author":"A Margraf","year":"2019","unstructured":"Margraf A, Ley K, Zarbock A. Neutrophil recruitment: from model systems to tissue-specific patterns. Trends Immunol. 2019;40(7):613\u201334. https:\/\/doi.org\/10.1016\/j.it.2019.04.010 (Epub 2019\/06\/09).","journal-title":"Trends Immunol"},{"issue":"6","key":"2328_CR54","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1177\/135245859700200601","volume":"2","author":"LM Rose","year":"1997","unstructured":"Rose LM, Richards TL, Peterson J, Petersen R, Alvord EC Jr. Resolution of CNS lesions following treatment of experimental allergic encephalomyelitis in macaques with monoclonal antibody to the CD18 leukocyte integrin. Mult Scler. 1997;2(6):259\u201366. https:\/\/doi.org\/10.1177\/135245859700200601 (Epub 1997\/01\/01).","journal-title":"Mult Scler"},{"key":"2328_CR55","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.126453","author":"C Li","year":"2019","unstructured":"Li C, Menoret A, Farragher C, Ouyang Z, Bonin C, Holvoet P, Vella AT, Zhou B. Single cell transcriptomics based-MacSpectrum reveals novel macrophage activation signatures in diseases. JCI Insight. 2019. https:\/\/doi.org\/10.1172\/jci.insight.126453 (Epub 2019\/04\/17).","journal-title":"JCI Insight."},{"issue":"4","key":"2328_CR56","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1038\/s41593-018-0100-x","volume":"21","author":"B Ajami","year":"2018","unstructured":"Ajami B, Samusik N, Wieghofer P, Ho PP, Crotti A, Bjornson Z, Prinz M, Fantl WJ, Nolan GP, Steinman L. Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models. Nat Neurosci. 2018;21(4):541\u201351. https:\/\/doi.org\/10.1038\/s41593-018-0100-x (Epub 2018\/03\/07).","journal-title":"Nat Neurosci"},{"key":"2328_CR57","doi-asserted-by":"publisher","first-page":"43","DOI":"10.3389\/fncel.2016.00043","volume":"10","author":"AM Andrews","year":"2016","unstructured":"Andrews AM, Lutton EM, Merkel SF, Razmpour R, Ramirez SH. Mechanical injury induces brain endothelial-derived microvesicle release: implications for cerebral vascular injury during traumatic brain injury. Front Cell Neurosci. 2016;10:43. https:\/\/doi.org\/10.3389\/fncel.2016.00043.","journal-title":"Front Cell Neurosci"},{"issue":"2","key":"2328_CR58","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1007\/s00401-004-0928-x","volume":"109","author":"H Wolburg","year":"2005","unstructured":"Wolburg H, Wolburg-Buchholz K, Engelhardt B. Diapedesis of mononuclear cells across cerebral venules during experimental autoimmune encephalomyelitis leaves tight junctions intact. Acta Neuropathol. 2005;109(2):181\u201390. https:\/\/doi.org\/10.1007\/s00401-004-0928-x.","journal-title":"Acta Neuropathol"},{"issue":"6","key":"2328_CR59","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1016\/j.immuni.2007.04.015","volume":"26","author":"CV Carman","year":"2007","unstructured":"Carman CV, Sage PT, Sciuto TE, de la Fuente MA, Geha RS, Ochs HD, Dvorak HF, Dvorak AM, Springer TA. Transcellular diapedesis is initiated by invasive podosomes. Immunity. 2007;26(6):784\u201397. https:\/\/doi.org\/10.1016\/j.immuni.2007.04.015 (Epub 2007\/06\/16).","journal-title":"Immunity"},{"issue":"2","key":"2328_CR60","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1038\/ncb1356","volume":"8","author":"J Millan","year":"2006","unstructured":"Millan J, Hewlett L, Glyn M, Toomre D, Clark P, Ridley AJ. Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM-1 to caveola- and F-actin-rich domains. Nat Cell Biol. 2006;8(2):113\u201323. https:\/\/doi.org\/10.1038\/ncb1356 (Epub 2006\/01\/24).","journal-title":"Nat Cell Biol"},{"issue":"1","key":"2328_CR61","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1096\/fj.07-8319com","volume":"22","author":"J Piontek","year":"2008","unstructured":"Piontek J, Winkler L, Wolburg H, Muller SL, Zuleger N, Piehl C, Wiesner B, Krause G, Blasig IE. Formation of tight junction: determinants of homophilic interaction between classic claudins. FASEB J. 2008;22(1):146\u201358. https:\/\/doi.org\/10.1096\/fj.07-8319com.","journal-title":"FASEB J"},{"issue":"3","key":"2328_CR62","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.4049\/jimmunol.162.3.1677","volume":"162","author":"RI Brezinschek","year":"1999","unstructured":"Brezinschek RI, Oppenheimer-Marks N, Lipsky PE. Activated T cells acquire endothelial cell surface determinants during transendothelial migration. J Immunol. 1999;162(3):1677\u201384 (Epub 1999\/02\/11).","journal-title":"J Immunol"},{"issue":"3","key":"2328_CR63","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1182\/blood.V93.3.886","volume":"93","author":"D Sancho","year":"1999","unstructured":"Sancho D, Yanez-Mo M, Tejedor R, Sanchez-Madrid F. Activation of peripheral blood T cells by interaction and migration through endothelium: role of lymphocyte function antigen-1\/intercellular adhesion molecule-1 and interleukin-15. Blood. 1999;93(3):886\u201396.","journal-title":"Blood"},{"key":"2328_CR64","doi-asserted-by":"publisher","first-page":"603","DOI":"10.3389\/fimmu.2015.00603","volume":"6","author":"CV Carman","year":"2015","unstructured":"Carman CV, Martinelli R. T lymphocyte-endothelial interactions: emerging understanding of trafficking and antigen-specific immunity. Front Immunol. 2015;6:603. https:\/\/doi.org\/10.3389\/fimmu.2015.00603 (Epub 2015\/12\/05).","journal-title":"Front Immunol"},{"issue":"9","key":"2328_CR65","doi-asserted-by":"publisher","first-page":"3109","DOI":"10.1091\/mbc.11.9.3109","volume":"11","author":"CW Wong","year":"2000","unstructured":"Wong CW, Wiedle G, Ballestrem C, Wehrle-Haller B, Etteldorf S, Bruckner M, Engelhardt B, Gisler RH, Imhof BA. PECAM-1\/CD31 trans-homophilic binding at the intercellular junctions is independent of its cytoplasmic domain; evidence for heterophilic interaction with integrin alphavbeta3 in Cis. Mol Biol Cell. 2000;11(9):3109\u201321. https:\/\/doi.org\/10.1091\/mbc.11.9.3109 (Epub 2000\/09\/12).","journal-title":"Mol Biol Cell"},{"issue":"3","key":"2328_CR66","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1007\/s00441-013-1779-3","volume":"355","author":"JR Privratsky","year":"2014","unstructured":"Privratsky JR, Newman PJ. PECAM-1: regulator of endothelial junctional integrity. Cell Tissue Res. 2014;355(3):607\u201319. https:\/\/doi.org\/10.1007\/s00441-013-1779-3 (Epub 2014\/01\/18).","journal-title":"Cell Tissue Res"},{"issue":"3","key":"2328_CR67","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.4049\/jimmunol.1100299","volume":"187","author":"SR Ahmed","year":"2011","unstructured":"Ahmed SR, McGettrick HM, Yates CM, Buckley CD, Ratcliffe MJ, Nash GB, Rainger GE. Prostaglandin D2 regulates CD4+ memory T cell trafficking across blood vascular endothelium and primes these cells for clearance across lymphatic endothelium. J Immunol. 2011;187(3):1432\u20139. https:\/\/doi.org\/10.4049\/jimmunol.1100299 (Epub 2011\/07\/01).","journal-title":"J Immunol"},{"issue":"1","key":"2328_CR68","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1002\/cpim.44","volume":"121","author":"M Manglani","year":"2018","unstructured":"Manglani M, Gossa S, McGavern DB. Leukocyte isolation from brain, spinal cord, and meninges for flow cytometric analysis. Curr Protoc Immunol. 2018;121(1):44. https:\/\/doi.org\/10.1002\/cpim.44 (Epub 2018\/07\/25).","journal-title":"Curr Protoc Immunol"},{"key":"2328_CR69","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1152\/physiologyonline.2001.16.1.15","volume":"16","author":"PR Kvietys","year":"2001","unstructured":"Kvietys PR, Sandig M. Neutrophil diapedesis: paracellular or transcellular? News Physiol Sci. 2001;16:15\u20139. https:\/\/doi.org\/10.1152\/physiologyonline.2001.16.1.15 (Epub 2001\/06\/08).","journal-title":"News Physiol Sci"},{"issue":"2","key":"2328_CR70","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1038\/ncb0206-105","volume":"8","author":"E Dejana","year":"2006","unstructured":"Dejana E. The transcellular railway: insights into leukocyte diapedesis. Nat Cell Biol. 2006;8(2):105\u20137. https:\/\/doi.org\/10.1038\/ncb0206-105.","journal-title":"Nat Cell Biol"},{"issue":"1","key":"2328_CR71","doi-asserted-by":"publisher","first-page":"H1","DOI":"10.1530\/VB-19-0033","volume":"2","author":"L Marchetti","year":"2020","unstructured":"Marchetti L, Engelhardt B. Immune cell trafficking across the blood-brain barrier in the absence and presence of neuroinflammation. Vasc Biol. 2020;2(1):H1\u201318. https:\/\/doi.org\/10.1530\/VB-19-0033 (Epub 2020\/09\/15).","journal-title":"Vasc Biol"}],"container-title":["Journal of Neuroinflammation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-021-02328-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12974-021-02328-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-021-02328-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T12:27:08Z","timestamp":1674131228000},"score":1,"resource":{"primary":{"URL":"https:\/\/jneuroinflammation.biomedcentral.com\/articles\/10.1186\/s12974-021-02328-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12]]},"references-count":71,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["2328"],"URL":"https:\/\/doi.org\/10.1186\/s12974-021-02328-3","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-595470\/v1","asserted-by":"object"}]},"ISSN":["1742-2094"],"issn-type":[{"value":"1742-2094","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12]]},"assertion":[{"value":"8 June 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 November 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 December 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 mice were maintained under specific pathogen-free conditions and all animal protocols were in compliance with Animal Care and Use Guidelines of UConn Health (Animal Welfare Assurance # A3471-01).","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 they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"296"}}