EXTENSIVE PERTURBATION OF THE IMMUNE SYSTEM AMONG INDIVIDUALS WITH TRISOMY 21.

HSIEH, ELENA W ; ARAYA PAULA; MARMOLEJO, JUANA; ESPINOSA, JOAQUIN M; SMITH, KEITH; MACCIONI, MARIANA; WAUGH, KATHERINE; SULLIVAN, KELLY D ; BATURIN, DMITRY ; PANDEY, AHWAN ; PORTER, CHRISTOGHER C; BUTCHER, ERIC; RACHUBINSKI, ANGELA L; DIMASI, TIANA A

ILLINOIS

Congreso; 2ND INTERNATIONAL CONFERENCE OF THE T21RS; 2017

International Conference of the T21RS

Individuals born with trisomy of HSA21 (T21) experience intellectual disabilities and a unique disease spectrum. Interestingly, while T21 predisposes individuals to respiratory tract infections, autoimmune disorders, and leukemia, this genetic condition also protects them from solid tumors. Previous studies of the T21 immune system are contradictory. We therefore simultaneously characterized approximately 150 immune cell subsets from the whole blood of individuals with T21 by mass cytometry. We identified a T21 immune signature that is quantitatively, phenotypically, and functionally distinct from age- and sex-matched controls. This global immune dysregulation encompassed some published, hypothesized, controversial, and completely novel results. For instance, individuals with T21 have an increased amount of age-associated B cells (ABCs). ABCs are a B cell subset that accumulates with age, is strongly associated with viral infections and autoimmunity, and is induced by concurrent stimulation through the B cell receptor (BCR), a virus recognition receptor (TLR7), and an anti-virus/cancer cytokine (IFN-γ). To our knowledge, ABCs have not been previously investigated in T21. Additionally, distinct immune cell subsets, such as ABCs, had increased surface expression of IFN receptors that are located on HSA21. We hypothesize that aberrant IFN signaling contributes to the global immune dysregulation in T21, and that variable aspects of the T21 immune signature correlate with various manifestations of T21. We are currently testing this hypothesis using clinical surveys and expanded mass cytometry characterization of leukocytes for single-cell-resolution examination of cytokines, including IFNs, and additional signaling proteins both up- and downstream of IFNs after brief stimulations with IFNs and agents that cause cytokine production, such as TLR7. Collectively, these analyses of immunity in T21 could identify possible nodes of intervention facilitated through precicison medicine.