Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation

Area of Science:

• Genetics and Immunology
• Molecular Biology
• Proteomics

Background:

• Trisomy 21 (T21) leads to Down syndrome (DS), but the underlying molecular mechanisms causing its diverse clinical manifestations remain unclear.
• An activated interferon response linked to T21 has been observed in cell models, suggesting Down syndrome could be partly classified as an interferonopathy.

Purpose of the Study:

• To investigate the systemic effects of T21 on signaling pathways in individuals with Down syndrome.
• To identify specific proteins and molecular pathways deregulated by T21 in vivo.

Main Methods:

• Proteomics analysis of blood samples from 263 individuals, including 165 with Down syndrome.
• Quantification and identification of differentially expressed proteins associated with T21.

Main Results:

• Dozens of proteins were found to be consistently deregulated by T21.
• Key affected proteins involve immune control, complement cascade, and growth factor signaling.
• Individuals with DS showed elevated pro-inflammatory cytokines (e.g., IL-6, TNF-α) and significant complement consumption.

Conclusions:

• The findings support the hypothesis that increased interferon signaling due to T21 contributes to chronic immune dysregulation in Down syndrome.
• The observed molecular changes resemble those in type I interferonopathies and autoinflammatory conditions.
• Further research into immune-modulatory strategies is warranted for therapeutic applications in Down syndrome.