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Paper Chase

Danger-free autoimmune disease in Aire-deficient mice.

Proc. Natl. Acad. Sci. U.S.A.. Nov 13, 2007;104(46):18193-8.
Gray DH, Gavanescu I, Benoist C, Mathis D.

Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.

Abstract:

The danger theory of immune tolerance asserts that environmental factors hold primacy over lymphocyte autoreactivity in initiating autoimmune disease. We sought to test this contention using the Aire-deficient mouse model of the human disease, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, a multiorgan autoimmune disorder rooted in a lesion in thymic tolerance. Compound screens stimulating a broad range of innate immune system pathways failed to show any modulation of disease characteristics in Aire(-/-) mice on either the C57BL/6 or NOD genetic backgrounds. Furthermore, deficiency in the Toll-like receptor adaptor Myd88 increased the lifespan of NOD.aire(-/-) mice but did not prevent the initiation of autoimmunity. Finally, germ-free NOD.aire(-/-) mice exhibited autoimmunity in all organs normally targeted in this model, indicating that microbial conditioning is not required for activation of autoreactive T cells relevant to this disease. Together, these data suggest that the stochastic genesis of dangerous T cell clones can initiate autoimmune disease without the need for environmental stimulation, underlining the importance of Aire-dependent thymic deletion.