Autoimmune-mediated thymic atrophy is accelerated but reversible in RelB-deficient mice

Brendan J O'Sullivan, Suman Yekollu, Roland Ruscher, Ahmed Mehdi, Muralidhara Rao Maradana, Ann P. Chidgey, Ranjeny Thomas

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Polymorphisms impacting thymic function may decrease peripheral tolerance and hasten autoimmune disease. The NF-κB transcription factor subunit, RelB, is essential for the development and differentiation of medullary thymic epithelial cells (mTECs): RelB-deficient mice have reduced thymic cellularity and markedly fewer mTECs, lacking AIRE. The precise mechanism of this mTEC reduction in the absence of RelB is unclear. To address this, we studied mTECs and dendritic cells (DCs), which critically regulate negative selection, and thymic regulatory T-cells (tTreg) in RelB-/- mice, which have spontaneous multiorgan autoimmune disease. RelB-/- thymi were organized, with medullary structures containing AIRE- mTECs, DCs, and CD4+ thymocytes, but fewer tTreg. Granulocytes infiltrated the RelB-/- thymic cortex, capsule, and medulla, producing inflammatory thymic medullary atrophy, which could be treated by granulocyte depletion or RelB+ DC immunotherapy, with concomitant recovery of mTEC and tTreg numbers. These data indicate that central tolerance defects may be accelerated by autoimmune thymic inflammation where impaired RelB signaling impairs the medullary niche, and may be reversible by therapies enhancing peripheral Treg or suppressing inflammation.

Original languageEnglish
Article number1092
Number of pages11
JournalFrontiers in Immunology
Volume9
Issue numberMAY
DOIs
Publication statusPublished - 22 May 2018

Keywords

  • thymic atrophy
  • autoimmune disease
  • immunotherapy
  • RelB
  • polymorphonuclear cells

Cite this

O'Sullivan, B. J., Yekollu, S., Ruscher, R., Mehdi, A., Maradana, M. R., Chidgey, A. P., & Thomas, R. (2018). Autoimmune-mediated thymic atrophy is accelerated but reversible in RelB-deficient mice. Frontiers in Immunology, 9(MAY), [1092]. https://doi.org/10.3389/fimmu.2018.01092
O'Sullivan, Brendan J ; Yekollu, Suman ; Ruscher, Roland ; Mehdi, Ahmed ; Maradana, Muralidhara Rao ; Chidgey, Ann P. ; Thomas, Ranjeny. / Autoimmune-mediated thymic atrophy is accelerated but reversible in RelB-deficient mice. In: Frontiers in Immunology. 2018 ; Vol. 9, No. MAY.
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abstract = "Polymorphisms impacting thymic function may decrease peripheral tolerance and hasten autoimmune disease. The NF-κB transcription factor subunit, RelB, is essential for the development and differentiation of medullary thymic epithelial cells (mTECs): RelB-deficient mice have reduced thymic cellularity and markedly fewer mTECs, lacking AIRE. The precise mechanism of this mTEC reduction in the absence of RelB is unclear. To address this, we studied mTECs and dendritic cells (DCs), which critically regulate negative selection, and thymic regulatory T-cells (tTreg) in RelB-/- mice, which have spontaneous multiorgan autoimmune disease. RelB-/- thymi were organized, with medullary structures containing AIRE- mTECs, DCs, and CD4+ thymocytes, but fewer tTreg. Granulocytes infiltrated the RelB-/- thymic cortex, capsule, and medulla, producing inflammatory thymic medullary atrophy, which could be treated by granulocyte depletion or RelB+ DC immunotherapy, with concomitant recovery of mTEC and tTreg numbers. These data indicate that central tolerance defects may be accelerated by autoimmune thymic inflammation where impaired RelB signaling impairs the medullary niche, and may be reversible by therapies enhancing peripheral Treg or suppressing inflammation.",
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O'Sullivan, BJ, Yekollu, S, Ruscher, R, Mehdi, A, Maradana, MR, Chidgey, AP & Thomas, R 2018, 'Autoimmune-mediated thymic atrophy is accelerated but reversible in RelB-deficient mice', Frontiers in Immunology, vol. 9, no. MAY, 1092. https://doi.org/10.3389/fimmu.2018.01092

Autoimmune-mediated thymic atrophy is accelerated but reversible in RelB-deficient mice. / O'Sullivan, Brendan J; Yekollu, Suman; Ruscher, Roland; Mehdi, Ahmed; Maradana, Muralidhara Rao; Chidgey, Ann P.; Thomas, Ranjeny.

In: Frontiers in Immunology, Vol. 9, No. MAY, 1092, 22.05.2018.

Research output: Contribution to journalArticleResearchpeer-review

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