Danger-free autoimmune disease in Aire-deficient mice.
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.
Gray
Daniel H D
DH
Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Gavanescu
Irina
I
Benoist
Christophe
C
Mathis
Diane
D
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D005856:Germ-Free Life; D007113:Immunity, Innate; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000096927:AIRE Protein
D014157:Transcription Factors; D000096927:AIRE Protein