Deficiency of adenosine deaminase 2 skews adaptive immune repertoires towards specific sets of T and B cell receptors
Adenosine deaminase 2 deficiency (DADA2) is a genetic disorder caused by biallelic hypomorphic or loss-of-function mutations in the ADA2 gene that encodes a protein deaminase regulating extracellular adenosine metabolism. Clinical features encompass inflammatory vasculopathy, early-onset strokes, and a complex presentation involving both immunodeficiency and autoinflammation/autoimmunity. : We profiled immunoglobulin levels and peripheral B and T cell phenotypes in 47 previously reported DADA2 patients. Levels of 21 cytokines/chemokines were quantified in patients with or without anti-TNF treatment. To characterize the DADA2 immune architecture, we performed T and B cell receptor (TCR/BCR) immunosequencing. We trained a binary LightGBM classifier to distinguish DADA2 T and B cell immune repertoires from heathy individuals. Flow cytometric profiling revealed contraction of B and T cell memory compartments. In addition, we observed elevated levels of TNF, IL-8, IL-17A as well as interferons, APRIL, BAFF and sCD40L. High serum levels of TNF, BAFF and sCD40L persisted under anti-TNF therapy. Next-generation immunosequencing of peripheral lymphocytes showed restricted TCR repertoires and B cells, which were particularly skewed towards IGHV4-34 rearrangements. Our machine learning algorithm separated DADA2 with high accuracy from healthy individuals based on immunogenetic parameters regarding B cell clone fraction, CDR3 length, and selected Kidera factors. Our findings underscore ADA2's significant influence on the adaptive immune system, which results in a highly specific immunogenetic signature in DADA2 patients.