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

Abstract

Background: 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.

Objective: 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 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.

Results: We detected hypogammaglobulinemia in 65% of DADA2 patients (34/52) and cytopenias in 48% (25/52). Flow cytometric profiling revealed contraction of B and T cell memory compartments. In addition, we observed elevated levels of TNF, IL-8, several interferons, 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.

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