1. Compromised central tolerance of ICA69 induces multiple organ autoimmunity
- Author
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Suzanne Bertera, Gregory R. Owens, William A. Rudert, Antonina Coppola, Massimo Trucco, Yong Fan, Jing He, Asako Tajima, Massimo Pietropaolo, Maria Grupillo, Giulio Gualtierotti, Fan, Y, Gualtierotti,G, Tajima, A, Grupillo, M, Coppola, A, He, J, Bertera, S, Owens, G, Pietropaolo, M, Rudert, WA, and Trucco, M
- Subjects
Primary Sjogren's syndrome ,Genetically modified mouse ,Immunology ,Thyroid Gland ,Autoimmune diabete ,Mice, Transgenic ,Thymus Gland ,Biology ,medicine.disease_cause ,Autoantigens ,Article ,Salivary Glands ,Settore MED/13 - Endocrinologia ,Autoimmune Diseases ,Autoimmunity ,Immune tolerance ,Autoimmune thyroiditis ,Islets of Langerhans ,Mice ,ICA69 ,Mice, Inbred NOD ,Immune Tolerance ,medicine ,Animals ,Immunology and Allergy ,Thymu ,Autoimmune thyroiditi ,NOD mice ,Inflammation ,Autoimmune disease ,Stomach ,medicine.disease ,Gene Expression Regulation ,Autoimmune polyendocrine syndrome ,Central tolerance - Abstract
For reasons not fully understood, patients with an organ-specific autoimmune disease have increased risks of developing autoimmune responses against other organs/tissues. We identified ICA69, a known β-cell autoantigen in Type 1 diabetes, as a potential common target in multi-organ autoimmunity. NOD mice immunized with ICA69 polypeptides exhibited exacerbated inflammation not only in the islets, but also in the salivary glands. To further investigate ICA69 autoimmunity, two genetically modified mouse lines were generated to modulate thymic ICA69 expression: the heterozygous ICA69(del/wt) line and the thymic medullary epithelial cell-specific deletion Aire-ΔICA69 line. Suboptimal central negative selection of ICA69-reactive T-cells was observed in both lines. Aire-ΔICA69 mice spontaneously developed coincident autoimmune responses to the pancreas, the salivary glands, the thyroid, and the stomach. Our findings establish a direct link between compromised thymic ICA69 expression and autoimmunity against multiple ICA69-expressing organs, and identify a potential novel mechanism for the development of multi-organ autoimmune diseases.
- Published
- 2014
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