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dc.creatorNacka-Aleksić, Mirjana
dc.creatorStojanović, Marija
dc.creatorPilipović, Ivan
dc.creatorStojić-Vukanić, Zorica
dc.creatorKosec, Duško
dc.creatorLeposavić, Gordana
dc.date.accessioned2021-02-18T10:50:36Z
dc.date.available2021-02-18T10:50:36Z
dc.date.issued2018
dc.identifier.issn1932-6203
dc.identifier.urihttp://intor.torlakinstitut.com/handle/123456789/520
dc.description.abstractAn accumulating body of evidence suggests that development of autoimmune pathologies leads to thymic dysfunction and changes in peripheral T-cell compartment, which, in turn, perpetuate their pathogenesis. To test this hypothesis, thymocyte differentiation/maturation in rats susceptible (Dark Agouti, DA) and relatively resistant (Albino Oxford, AO) to experimental autoimmune encephalomyelitis (EAE) induction was examined. Irrespective of strain, immunization for EAE (i) increased the circulating levels of IL-6, a cytokine causally linked with thymic atrophy, and (ii) led to thymic atrophy reflecting partly enhanced thymocyte apoptosis associated with downregulated thymic IL-7 expression. Additionally, immunization diminished the expression of Thy-1, a negative regulator of TCR alpha beta-mediated signaling and activation thresholds, on CD4+CD8+ TCR alpha beta(lo/hi) thymocytes undergoing selection and thereby impaired thymocyte selection/survival. This diminished the generation of mature CD4+ and CD8+ single positive TCR alpha beta(hi) thymocytes and, consequently, CD4+ and CD8+ recent thymic emigrants. In immunized rats, thymic differentiation of natural regulatory CD4+Foxp3+CD25+ T cells (nTregs) was particularly affected reflecting a diminished expression of IL-7, IL-2 and IL-15. The decline in the overall thymic T-cell output and nTreg generation was more pronounced in DA than AO rats. Additionally, differently from immunized AO rats, in DA ones the frequency of CD28- cells secreting cytolytic enzymes within peripheral blood CD4+ T lymphocytes increased, as a consequence of thymic atrophy-related replicative stress (mirrored in CD4+ cell memory pool expansion and p16(INK4a) accumulation). The higher circulating level of TNF-alpha in DA compared with AO rats could also contribute to this difference. Consistently, higher frequency of cytolytic CD4+ granzyme B+ cells (associated with greater tissue damage) was found in spinal cord of immunized DA rats compared with their AO counterparts. In conclusion, the study indicated that strain differences in immunization-induced changes in thymopoiesis and peripheral CD4+CD28- T-cell generation could contribute to rat strain-specific clinical outcomes of immunization for EAE.en
dc.publisherPublic Library Science, San Francisco
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/175050/RS//
dc.rightsopenAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcePLoS One
dc.titleStrain differences in thymic atrophy in rats immunized for EAE correlate with the clinical outcome of immunizationen
dc.typearticle
dc.rights.licenseBY
dc.citation.issue8
dc.citation.other13(8)
dc.citation.rankM22
dc.citation.volume13
dc.identifier.doi10.1371/journal.pone.0201848
dc.identifier.fulltexthttp://intor.torlakinstitut.com/bitstream/id/339/517.pdf
dc.identifier.pmid30086167
dc.identifier.rcubconv_383
dc.identifier.scopus2-s2.0-85051436397
dc.identifier.wos000441129300035
dc.type.versionpublishedVersion


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