Decreased AIRE expression and global thymic hypofunction in Down syndrome

Area of Science:

• Immunology
• Developmental Biology
• Genetics

Background:

• Down syndrome (DS) is associated with immune system abnormalities, including thymus hypotrophy and increased susceptibility to infections and autoimmunity.
• The autoimmune regulator (AIRE) gene, crucial for immune tolerance, is located on chromosome 21, the location of the trisomic chromosome in DS.

Purpose of the Study:

• To investigate the expression of AIRE and other immune-related genes in the thymus of individuals with Down syndrome.
• To elucidate the molecular mechanisms underlying the immune phenotype observed in DS and determine if immune abnormalities originate during early development.

Main Methods:

• Comparative analysis of thymus tissue from 14 DS patients and 42 age-matched controls using immunohistochemistry, quantitative PCR, and DNA microarrays.
• Transcriptome analysis to identify differentially expressed genes and network analysis (FunNet) to understand functional relationships.

Main Results:

• Significantly reduced AIRE-positive cells in DS thymuses compared to controls (p < 0.0001).
• Hypoexpression of 407 genes in DS thymuses, including those involved in antigen processing, T cell differentiation, and selection.
• Reduced expression of AIRE-partner genes (e.g., TOP2A, LAMNB1, NUP93) in DS.

Conclusions:

• The thymus in Down syndrome exhibits global hypofunction originating from early developmental stages.
• Immune abnormalities in DS are not solely due to premature aging but represent a primary developmental immunodeficiency.
• DS should be considered a non-monogenic primary immunodeficiency with thymus dysfunction.