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Modifier loci condition autoimmunity provoked by Aire deficiency
Wenyu Jiang1, Mark S Anderson, Roderick Bronson
1Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
The Journal of Experimental Medicine
|September 21, 2005
Summary
Genetic background significantly impacts autoimmune disease targeting in Aire-deficient mice. Different genetic loci control which organs are affected and disease severity, influencing autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy presentation.
Area of Science:
- Immunology
- Genetics
- Autoimmunity
Background:
- Loss-of-function mutations in the autoimmune regulator (Aire) gene cause autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
- Autoimmune manifestations in Aire deficiency exhibit significant variability in targeted organs and disease severity.
- Genetic background is hypothesized to influence this observed variability.
Purpose of the Study:
- To investigate the genetic basis for the variability in organ targeting and disease severity in Aire-deficient mice.
- To identify specific genetic loci that control the pattern and severity of autoimmune manifestations.
Main Methods:
- Backcrossing Aire knockout mice to diverse genetic backgrounds.
- Phenotypic analysis of targeted organs (stomach, eye, pancreas, liver, ovary, thyroid, salivary gland).
- Autoantibody profiling and oligoclonal reactivity assessment.
- Congenic analysis and whole genome scanning.
Main Results:
- The genetic background strongly influenced the pattern and severity of organ targeting in Aire-deficient mice.
- Nonobese diabetic background exacerbated autoimmunity, while C57BL/6 background showed mild disease.
- Distinct genetic control patterns were identified for autoimmunity targeting each organ.
- Key genetic regions, including MHC and loci on Chr1 and Chr3, were implicated in controlling autoimmune targeting.
Conclusions:
- Genetic background is a critical determinant of autoimmune disease manifestation in Aire deficiency.
- Specific genetic loci regulate the susceptibility and pattern of organ-specific autoimmunity.
- Understanding these genetic factors is crucial for deciphering the etiology of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and related autoimmune diseases.