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http://www.jci.org/cgi/content/full/113/7/990
J Clin Invest. 2004 Apr;113(7):990-7
Waldner H, Collins M, Kuchroo VK.
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard
Medical School, Cambridge, Massachusetts, USA.
We describe the generation of mice that express a transgenic T cell receptor (TCR) (5B6) specific for the encephalitogenic myelin proteolipid protein (PLP) peptide 139-151, on the experimental autoimmune encephalomyelitis-resistant (EAE-resistant) B10.S background.
Despite harboring a high frequency of self-reactive T cells, 5B6 transgenic mice on the B10.S background rarely develop spontaneous EAE, which is in striking contrast to 5B6 transgenic mice on the EAE-susceptible SJL background.
The relative resistance to spontaneous EAE in transgenic B10.S mice is not due to deletion or anergy of T cells, but appears to be controlled by APCs.
Analysis of APCs revealed a lower activation state and a lower T cell-activating capacity for APCs from B10.S mice than for those from EAE-susceptible SJL mice.
When APCs in 5B6 transgenic B10.S mice were activated, for example, via TLR9 or TLR4, T cell tolerance was broken, resulting in EAE.
Our findings demonstrate that activation of APCs via innate immune receptors can break self tolerance and trigger the development of autoimmunity even in a genetically resistant strain.
These findings suggest that the development of autoimmune diseases such as multiple sclerosis is determined at least partly by the endogenous activation state of APCs.