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* Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima, Japan;
Center for Animal Resources and Development, and Graduate School of Molecular and Genomic Pharmacy, Kumamoto University, Kumamoto, Japan;
Department of Pathology, Tokushima University School of Dentistry, Tokushima, Japan;
Department of Molecular and Environmental Pathology, School of Medicine, University of Tokushima, Tokushima, Japan;
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Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan;
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Laboratory for Immunopathology, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan; and
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Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, Tokushima, Japan
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 Sjögren’s syndrome-like pathologic changes in the exocrine organs, and this was associated with autoimmunity against a ubiquitous protein, 
-fodrin. Remarkably, transcriptional expression of -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.
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