Reduced thymic aire expression and abnormal NF-κB2 signaling in a model of systemic autoimmunity

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dc.contributor.authorFletcher, A.
dc.contributor.authorSeach, N.
dc.contributor.authorReiseger, J.
dc.contributor.authorLowen, T.
dc.contributor.authorHammett, M.
dc.contributor.authorScott, H.
dc.contributor.authorBoyd, R.
dc.date.issued2009
dc.description.abstractThe thymic stromal niche normally directs the production and export of a self-tolerant T cell repertoire. Many models of spontaneous autoimmunity, however, develop thymic architectural abnormalities before disease onset. Although this is suspected to affect central tolerance induction, creating an autoimmune predisposition, in-depth analysis of the microenvironment within these thymi is lacking, such that the mechanisms and likely direct effects on the T cell repertoire are unknown or speculative. Here we show that NZB mice, the first described model for systemic autoimmunity, demonstrate a complex thymic phenotype, including a lack of the autoimmune regulator (Aire), early defects in thymic epithelial cell (TEC) expansion, and evidence for altered NF-κB2 signaling. Analysis of medullary TEC revealed a numerical loss of the Aire-expressing MHC class IIhigh (mTEC-high) subset as well reduced Aire protein and mRNA per cell. RelB expression was also reduced, while chemokines CCL19 and CCL21 were increased. Unexpectedly, the proportion of cortex and medulla in the NZB mice was normal from 36 wk, despite worsening architectural abnormalities. These data show that the NZB defect is more complex than previously appreciated, segregating into early numerical TEC deficiencies that correct with age, late degeneration of the niche architecture that does not affect TEC number, and a persistent reduction in Aire and RelB expression per cell acquired upon mTEC-high differentiation.
dc.description.statementofresponsibilityAnne L. Fletcher, Natalie Seach, Jessica J. Reiseger, Tamara E. Lowen, Maree V. Hammett, Hamish S. Scott and Richard L. Boyd
dc.identifier.citationJournal of Immunology, 2009; 182(5):2690-2699
dc.identifier.doi10.4049/jimmunol.0801752
dc.identifier.issn0022-1767
dc.identifier.issn1550-6606
dc.identifier.orcidScott, H. [0000-0002-5813-631X]
dc.identifier.urihttp://hdl.handle.net/2440/52104
dc.language.isoen
dc.publisherAmer Assoc Immunologists
dc.rightsCopyright © 2009 by The American Association of Immunologists, Inc.
dc.source.urihttps://doi.org/10.4049/jimmunol.0801752
dc.subjectLymphoid Tissue
dc.subjectThymus Gland
dc.subjectStromal Cells
dc.subjectEpithelial Cells
dc.subjectAnimals
dc.subjectMice, Inbred BALB C
dc.subjectMice, Inbred C57BL
dc.subjectMice, Inbred NOD
dc.subjectMice, Inbred NZB
dc.subjectMice
dc.subjectAutoimmune Diseases
dc.subjectDisease Models, Animal
dc.subjectDisease Progression
dc.subjectTranscription Factors
dc.subjectImmunophenotyping
dc.subjectSignal Transduction
dc.subjectTranscription, Genetic
dc.subjectDown-Regulation
dc.subjectNF-kappa B p52 Subunit
dc.subjectAIRE Protein
dc.titleReduced thymic aire expression and abnormal NF-κB2 signaling in a model of systemic autoimmunity
dc.title.alternativeReduced thymic aire expression and abnormal NF-kappaB2 signaling in a model of systemic autoimmunity
dc.typeJournal article
pubs.publication-statusPublished

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