Diamantina Institute, Translational Research Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, QLD, Australia.
Stem Cells and Immune Regeneration Laboratory, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia.
Front Immunol. 2018 May 22;9:1092. doi: 10.3389/fimmu.2018.01092. eCollection 2018.
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.
影响胸腺功能的多态性可能会降低外周耐受并加速自身免疫性疾病。NF-κB 转录因子亚基 RelB 对于髓质胸腺上皮细胞 (mTEC) 的发育和分化至关重要：RelB 缺陷型小鼠的胸腺细胞数量减少，mTEC 明显减少，缺乏 AIRE。在没有 RelB 的情况下，这种 mTEC 减少的确切机制尚不清楚。为了解决这个问题，我们研究了 RelB 小鼠中的 mTEC 和树突状细胞 (DC)，它们对负选择和胸腺调节性 T 细胞 (tTreg) 的调节至关重要，而 RelB 小鼠则患有自发性多器官自身免疫性疾病。RelB 胸腺具有组织化的结构，包含 AIRE mTEC、DC 和 CD4 胸腺细胞，但 tTreg 较少。粒细胞浸润 RelB 胸腺皮质、包膜和髓质，导致炎症性胸腺髓质萎缩，粒细胞耗竭或 RelB DC 免疫疗法可治疗这种萎缩，并伴随 mTEC 和 tTreg 数量的恢复。这些数据表明，中央耐受缺陷可能会被自身免疫性胸腺炎症加速，其中受损的 RelB 信号转导会损害髓质龛，并且可以通过增强外周 Treg 或抑制炎症的疗法来逆转。
