Format

Send to

Choose Destination
J Autoimmun. 2018 Jan;86:75-92. doi: 10.1016/j.jaut.2017.09.006. Epub 2017 Sep 18.

Paradoxical development of polymyositis-like autoimmunity through augmented expression of autoimmune regulator (AIRE).

Author information

1
Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan.
2
Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan; Department of Molecular and Environmental Pathology, Institute of Biomedical Sciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan.
3
Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan; Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan.
4
Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan.
5
Department of Molecular and Environmental Pathology, Institute of Biomedical Sciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan.
6
Division of Immune Regulation, Institute for Genome Research, Tokushima University, Tokushima 770-8503, Japan.
7
Department of Bioinformatics and Genomics, Graduate School of Medical Sciences, Kanazawa University, Ishikawa 920-0934, Japan.
8
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan.
9
Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan. Electronic address: mitsuru@tokushima-u.ac.jp.

Abstract

Autoimmunity is prevented by the function of the autoimmune regulator [AIRE (Aire in mice)], which promotes the expression of a wide variety of tissue-restricted antigens (TRAs) from medullary thymic epithelial cells (mTECs) and from a subset of peripheral antigen-presenting cells (APCs). We examined the effect of additive expression of human AIRE (huAIRE) in a model of autoimmune diabetes in NOD mice. Unexpectedly, we observed that mice expressing augmented AIRE/Aire developed muscle-specific autoimmunity associated with incomplete maturation of mTECs together with impaired expression of Aire-dependent TRAs. This led to failure of deletion of autoreactive T cells together with dramatically reduced production of regulatory T cells in the thymus. In peripheral APCs, expression of costimulatory molecules was augmented. We suggest that levels of Aire expression need to be tightly controlled for maintenance of immunological tolerance. Our results also highlight the importance of coordinated action between central tolerance and peripheral tolerance under the common control of Aire.

KEYWORDS:

AIRE; Medullary thymic epithelial cell (mTEC); Muscle; Tolerance

PMID:
28931462
DOI:
10.1016/j.jaut.2017.09.006
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center