Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice.

Abstract

Autoimmune regulator (AIRE) gene mutation is responsible for the development of organ-specific autoimmune disease with monogenic autosomal recessive inheritance. Although Aire has been considered to regulate the elimination of autoreactive T cells through transcriptional control of tissue-specific Ags in thymic epithelial cells, other mechanisms of AIRE-dependent tolerance remain to be investigated. We have established Aire-deficient mice and examined the mechanisms underlying the breakdown of self-tolerance. The production and/or function of immunoregulatory T cells were retained in the Aire-deficient mice. The mice developed Sjogren's syndrome-like pathologic changes in the exocrine organs, and this was associated with autoimmunity against a ubiquitous protein, alpha-fodrin. Remarkably, transcriptional expression of alpha-fodrin was retained in the Aire-deficient thymus. These results suggest that Aire regulates the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus, at least against this ubiquitous protein. Rather, Aire may regulate the processing and/or presentation of self-proteins so that the maturing T cells can recognize the self-Ags in a form capable of efficiently triggering autoreactive T cells. With the use of inbred Aire-deficient mouse strains, we also demonstrate the presence of some additional factor(s) that determine the target-organ specificity of the autoimmune disease caused by Aire deficiency.

• Authors: Noriyuki Kuroda, Tasuku Mitani, Naoki Takeda, Naozumi Ishimaru, Rieko Arakaki, Yoshio Hayashi, Yoshimi Bando, Keisuke Izumi, Takeshi Takahashi, Takashi Nomura, Shimon Sakaguchi, Tomoo Ueno, Yousuke Takahama, Daisuke Uchida, Shijie Sun, Fumiko Kajiura, Yasuhiro Mouri, Hongwei Han, Akemi Matsushima, Gen Yamada, Mitsuru Matsumoto
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 174 Issue 4 Pg. 1862-70 (Feb 15 2005) ISSN: 0022-1767 [Print] United States
• PMID: 15699112 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• APECED protein
• Autoantibodies
• Autoantigens
• Carrier Proteins
• Microfilament Proteins
• Transcription Factors
• fodrin

Topics

• Animals
• Autoantibodies (biosynthesis)
• Autoantigens (biosynthesis, immunology)
• Carrier Proteins (biosynthesis, genetics, immunology)
• Exocrine Glands (immunology, metabolism, pathology)
• Female
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Inbred ICR
• Mice, Knockout
• Mice, Nude
• Microfilament Proteins (biosynthesis, genetics, immunology)
• Organ Specificity (genetics, immunology)
• Polyendocrinopathies, Autoimmune (genetics, immunology, pathology)
• Self Tolerance (genetics)
• Sjogren's Syndrome (genetics, immunology, pathology)
• Species Specificity
• Stromal Cells (immunology, metabolism, pathology)
• T-Lymphocytes, Regulatory (immunology, pathology)
• Thymus Gland (immunology, metabolism, pathology)
• Transcription Factors (deficiency, genetics, physiology)