JCI online early table of contents: April 15, 2008

Individuals develop the autoimmune disease autoimmune polyglandular syndrome type 1 (APS1) if both copies of their AIRE gene are mutated such that they make no functional AIRE protein. APS1 is characterized by a specific group of symptoms, and many different mutations in the AIRE gene have been linked to this disease. Recently, individuals with a mutation known as G228W in just one copy of their AIRE gene have been identified and shown to exhibit a different pattern of symptoms to individuals with APS1. Insights into the mechanisms by which the G228W mutation causes autoimmunity have now been provided by Mark Anderson and colleagues, at the University of California, at San Francisco, Diabetes Center.

In the study, mice were engineered such that they expressed the G228W mutation. These mice were found to have a defect in a process known as negative selection, which is the process by which immune cells known as T cells that target our own organs are eliminated, such that T cells able to target the organs of the mouse escaped and caused autoimmunity. This defect occurred because the G228W mutant AIRE bound normal AIRE and sequestered it in nuclear inclusion bodies so that it could not carry out its function. As the G228W mutant AIRE was unable to prevent all normal AIRE from functioning, these data indicate that even low levels of AIRE function are insufficient to prevent autoimmunity.

TITLE: Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire

AUTHOR CONTACT:

Mark S. Anderson
University of California at San Francisco Diabetes Center, San Francisco, California, USA.
Phone: (415) 502-8052; Fax: (415) 564-5813; E-mail:

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