Title |
Autoimmune-Mediated Thymic Atrophy Is Accelerated but Reversible in RelB-Deficient Mice
|
---|---|
Published in |
Frontiers in immunology, May 2018
|
DOI | 10.3389/fimmu.2018.01092 |
Pubmed ID | |
Authors |
Brendan J. O’Sullivan, Suman Yekollu, Roland Ruscher, Ahmed M. Mehdi, Muralidhara Rao Maradana, Ann P. Chidgey, Ranjeny Thomas |
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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