Deficiency of adenosine deaminase 2 skews adaptive immune repertoires toward specific sets of T- and B-cell receptors.

BACKGROUND: Adenosine deaminase 2 deficiency (DADA2) is a genetic disorder caused by biallelic hypomorphic or loss-of-function mutations in the ADA2 gene, which 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.

OBJECTIVE: Our aim was to determine a DADA2-specific adaptive immune architecture.

METHODS: We profiled immunoglobulin levels and peripheral B- and T-cell phenotypes in 47 previously reported and 5 unreported patients with DADA2. Levels of 21 cytokines and chemokines were quantified in patients with or without anti-TNF treatment. To characterize the DADA2 immune architecture, we performed T- and B-cell receptor immunosequencing. We trained a binary LightGBM classifier to distinguish DADA2 T- and B-cell immune repertoires from healthy individuals.

RESULTS: We detected hypogammaglobulinemia in 65% of patients with DADA2 (34 of 52) and cytopenias in 48% (25 of 52). Flow cytometric profiling revealed contraction of B- and T-cell memory compartments. In addition, we observed elevated levels of TNF, IL-8, several interferons, a proliferation-inducing ligand (APRIL), B-cell activating factor (BAFF), and soluble CD40 ligand (sCD40L). High serum levels of TNF, BAFF, and sCD40L persisted under anti-TNF therapy. Next-generation immunosequencing of peripheral lymphocytes showed restricted T-cell receptor repertoires and B cells, which were particularly skewed toward immunoglobulin heavy chain V4-34 rearrangements. With high accuracy, our machine learning algorithm separated individuals with DADA2 from healthy individuals on the basis of immunogenetic parameters regarding B-cell clone fraction, CDR3 length, and selected Kidera factors.

CONCLUSIONS: Our findings underscore the significant influence of ADA2 on the adaptive immune system, which results in a highly specific immunogenetic signature in patients with DADA2.