Human APECED; a Sick Thymus Syndrome?

Area of Science:

• Immunology
• Genetics
• Endocrinology

Background:

• Autoimmune Regulator (AIRE) gene mutations cause autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a rare autoimmune disorder.
• APECED patients exhibit multiple endocrine deficiencies and chronic mucocutaneous candidiasis.
• AIRE's role in thymic negative selection is established, but doesn't fully explain human APECED phenotypes.

Purpose of the Study:

• Investigate pathogenetic mechanisms beyond failed negative selection in AIRE-deficient humans.
• Explore the role of autoantibodies against cytokines, including type I interferons and Th17-derived cytokines.
• Examine potential defects in regulatory T cells and their impact on T cell development.

Main Methods:

• Analysis of human patient phenotypes and autoantibody profiles.
• Review of murine studies on AIRE function in thymic epithelial cells.
• Examination of T cell regulatory defects, including regulatory T cells and recent thymic emigrants.

Main Results:

• AIRE deficiency leads to high-titer autoantibodies against type I interferons, preceding clinical symptoms.
• Autoantibodies targeting Th17-produced cytokines correlate with impaired anti-candida defenses.
• Defects in regulatory T cells and recent thymic emigrants suggest thymic milieu abnormalities.

Conclusions:

• AIRE deficiency causes widespread T cell development and regulatory disruption originating in the thymus.
• Autoantibodies against type I interferons and other cytokines are key pathogenic features in human APECED.
• Abnormal thymic environment and potential peripheral AIRE absence contribute to APECED pathogenesis.