An NT5E loss-of-function variant permits tissue inflammation and hypertension in systemic lupus erythematosus.

Adenosine, generated by CD73/NT5E, is a critical endogenous regulator of immune-mediated inflammation. Genetic variants in NT5E have been linked to vascular and inflammatory phenotypes. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease marked by persistent inflammation. Using a systems biology approach, we examined immunologic and genetic alterations in adenosine signaling in SLE. Whereas gene signatures associated with extracellular adenosine production were elevated in lupus-affected tissues, adenosine-mediated immunosuppressive pathways were broadly downregulated and correlated with increased proinflammatory signatures. Analysis of the NT5E single-nucleotide polymorphism rs2229524, which introduces a non-synonymous amino acid change, predicted impaired enzymatic function and was associated with reduced adenosine immunomodulation and increased rates of pericarditis and hypertension in SLE patients. These findings highlight the importance of extracellular adenosine signaling in regulating immune-mediated inflammation in SLE and highlight the role of a loss-of-function NT5E variant in contributing to tissue injury.