W165 - Monocytes from Individuals with down Syndrome Demonstrate Evidence of TLR Signatures

Abstract Text: Down syndrome (DS), or trisomy 21, is associated with immune dysfunction as evidenced by decreased vaccine responses, increased severity of viral infections, and increased incidence of certain autoimmune diseases, including Down syndrome-associated arthritis (DA). While studies have demonstrated evidence of dysregulated adaptive immunity in DS, there has been little focus on innate immune cells, which are key to setting the inflammatory tone. While recent work has shown that DS individuals have increased type I interferon (IFN) responses, due to the presence of the genes encoding subunits of the IFN receptor on chromosome 21, little work has examined innate immune receptor signaling in monocytes in DS. We isolated CD14+ monocytes from individuals with DS (n=8) or age and sex matched healthy controls (HC, n=8), treated with agonists of TLR2, TLR4, TLR7 or TLR8, and identified the transcriptional signature using bulk RNA sequencing (RNA-Seq). We found that monocytes from individuals with DS had evidence of enhanced TLR signatures compared to HC at baseline, however DS monocytes had similar magnitude of gene induction after TLR agonist treatment. Additionally, these baseline differences were not explained by type I IFN responses. To learn more about DA and the role of monocytes in this disease, we performed single cell RNA-Seq on monocytes from individuals with DS without arthritis (n=7), DA (n=6), juvenile idiopathic arthritis (JIA) (n=6), or HC (n=8). Together, our data provide new insights into the innate immune responses of monocytes from DS subjects with implications for the refractory nature of DA.