期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 104, 期 46, 页码 18193-18198出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0709160104
关键词
autoimmunity; environment; immunological tolerance
资金
- NCI NIH HHS [T32 CA09382-22, T32 CA009382] Funding Source: Medline
- NIAID NIH HHS [F32 AI62010-01, F32 AI062010] Funding Source: Medline
- NIDDK NIH HHS [R01 DK060027, P30 DK36836, P30 DK036836, R01 DK60027] Funding Source: Medline
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.
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