| |
Aire deficiency causes lethal autoimmune disease in NOD mice, but only mild disease in C57BL/6 (B6) mice.
|
|
Genetic background can dictate the target and severity of an autoimmune attack that results from a single genetic mutation, according to Jiang and colleagues on page 805.
Most autoimmune diseases are caused by multiple genetic defects that conspire to break down the immune system's tolerance to self-tissues. One exception is autoimmunity caused by mutations in Aire, the transcriptional regulator that controls tolerance by driving the expression of tissue-restricted genes in thymic epithelial cells. Thymic expression of these genes causes self-reactive T cells to be either deleted or tolerized. Mice and humans with mutations in Aire develop autoimmune symptoms that vary widely in target organ and disease severity.In an attempt to explain this variation, Jiang and colleagues back-crossed Aire-deficient mice onto well-characterized mouse strains and showed that genetic background decides their fate. Autoimmune-prone nonobese diabetic (NOD) mice coped poorly without Aire, suffering severe attacks on multiple organs including the pancreas, stomach, and lung. C57BL/6 mice fared better with a mild disease that was focused primarily on the prostate.
Congenic and intercross analyses of the NOD.Aire–/– and C57BL/6/Aire–/– mice showed that pancreatitis was controlled by the same MHC haplotype (H-2g7) that predisposes NOD mice to diabetes, whereas gastritis was controlled by unknown genes on chromosome 3. Further studies are required to determine how these modifier genes influence the disease manifestations caused by the absence of Aire. 
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
