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Aging and Disease    2012, Vol. 3 Issue (3) : 248-259     DOI:
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Age-Related Disruption of Steady-State Thymic Medulla Provokes Autoimmune Phenotype via Perturbing Negative Selection
Jiangyan Xia1, 2, Hongjun Wang1, Jianfei Guo1, 3, Zhijie Zhang1, Brandon Coder1, Dong-Ming Su1, *
1Department of Molecular Biology and Immunology, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX, 76107, USA
2Southeast University Affiliated Zhongda Hospital, Nanjing, China
3Department of Radiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA
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Abstract  

The hymic medulla plays an essential role in the generation of central tolerance by eliminating self-reactive T-cell clones through thymic negative selection and developing natural regulatory T cells. Age-related FoxN1 decline induces disruption of medullary thymic epithelial cells (mTECs). However, it is unknown whether this perturbs central tolerance to increase autoimmune predisposition in the elderly. Using a loxP-floxed-FoxN1 (FoxN1flox) mouse model, which exhibits a spontaneous ubiquitous deletion of FoxN1 with age to accelerate thymic aging, we investigated whether disruption of steady-state thymic medulla results in an increase of autoimmune-prone associated with age. We demonstrated age-associated ubiquitous loss of FoxN1flox-formed two-dimensional thymic epithelial cysts were primarily located in the medulla. This resulted in disruption of thymic medullary steady state, with evidence of perturbed negative selection, including reduced expression of the autoimmune regulator (Aire) gene and disrupted accumulation of thymic dendritic cells in the medulla, which are required for negative selection. These provoke autoimmune phenotypes, including increased inflammatory cell infiltration in multiple organs in these mice. This finding in an animal model provides a mechanistic explanation of increased susceptibility to autoimmunity in aged humans, although they may not show clinic manifestations without induction.

Keywords Aging      Thymic microstructure      Central immunological tolerance      Negative selection      FoxN1 gene      Autoimmunity     
Corresponding Authors: Dong-Ming Su   
Issue Date: 01 March 2012
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Jiangyan Xia
Hongjun Wang
Jianfei Guo
Zhijie Zhang
Brandon Coder
Dong-Ming Su
Cite this article:   
Jiangyan Xia,Hongjun Wang,Jianfei Guo, et al. Age-Related Disruption of Steady-State Thymic Medulla Provokes Autoimmune Phenotype via Perturbing Negative Selection[J]. Aging and Disease, 2012, 3(3): 248-259.
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http://www.aginganddisease.org/EN/     OR     http://www.aginganddisease.org/EN/Y2012/V3/I3/248
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