(A) Chromosome 21 encodes four types of interferon receptors. In cells with two copies of this chromosome (disomy 21), the binding of interferons to the receptors activates two kinases, JAK1and TYK2. These kinases activate the transcription factor STAT1, which then transcribes a set of genes known as interferon stimulated genes (ISGs). (B) In cells with three copies of chromosome 21 (trisomy 21), as in Down syndrome, the increased abundance of interferon receptors increases the transcription of ISGs, including the genes that encode interferons themselves. This ultimately leads to increased positive feedback and hyperactivated interferon signaling, which can damage the cell.