Intrinsic Defects in B Cell Development and Differentiation, T Cell Exhaustion and Altered Unconventional T Cell Generation Characterize Human Adenosine Deaminase Type 2 Deficiency

Abstract

Purpose Deficiency of adenosine deaminase type 2 (ADA2) (DADA2) is a rare inborn error of immunity caused by deleterious biallelic mutations in ADA2. Clinical manifestations are diverse, ranging from severe vasculopathy with lacunar strokes to immunodeficiency with viral infections, hypogammaglobulinemia and bone marrow failure. Limited data are available on the phenotype and function of leukocytes from DADA2 patients. The aim of this study was to perform in-depth immunophenotyping and functional analysis of the impact of DADA2 on human lymphocytes. Methods In-depth immunophenotyping and functional analyses were performed on ten patients with confirmed DADA2 and compared to heterozygous carriers of pathogenic ADA2 mutations and normal healthy controls. Results The median age of the patients was 10 years (mean 20.7 years, range 1–44 years). Four out of ten patients were on treatment with steroids and/or etanercept or other immunosuppressives. We confirmed a defect in terminal B cell differentiation in DADA2 and reveal a block in B cell development in the bone marrow at the pro-B to pre-B cell stage. We also show impaired differentiation of CD4+ and CD8+ memory T cells, accelerated exhaustion/senescence, and impaired survival and granzyme production by ADA2 deficient CD8+ T cells. Unconventional T cells (i.e. iNKT, MAIT, Vδ2+ γδT) were diminished whereas pro-inflammatory monocytes and CD56bright immature NK cells were increased. Expression of the IFN-induced lectin SIGLEC1 was increased on all monocyte subsets in DADA2 patients compared to healthy donors. Interestingly, the phenotype and function of lymphocytes from healthy heterozygous carriers were often intermediate to that of healthy donors and ADA2-deficient patients. Conclusion Extended immunophenotyping in DADA2 patients shows a complex immunophenotype. Our findings provide insight into the cellular mechanisms underlying some of the complex and heterogenous clinical features of DADA2. More research is needed to design targeted therapy to prevent viral infections in these patients with excessive inflammation as the overarching phenotype.

Deficiency of Human Adenosine Deaminase Type 2 – A Diagnostic Conundrum for the Hematologist

“…Features of macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH), haemolytic anemia (non-immune), and persistent cytopenias (with a hypercellular bone marrow) were noted in this patient ( 53 ). MAS/HLH was also been reported in the first descriptions of this disease, besides many published and unpublished observations ( 1 , 26 , 38 ).…”

“…The authors also reported arrest in B cell development in the bone marrow at the pro-B to pre-B cell stage and defect in terminal B cell differentiation. Authors have also shown that healthy heterozygous carrier state for DADA2 showed intermediate values of lymphocyte phenotypes and functions in comparison to DADA2 patients and healthy controls, further highlighting the role of heterozygous state ( 26 ). Thus, immune defect in patients with DADA2 deficiency may present with myriad immunological aberrations ( 26 ).…”

“…Authors have also shown that healthy heterozygous carrier state for DADA2 showed intermediate values of lymphocyte phenotypes and functions in comparison to DADA2 patients and healthy controls, further highlighting the role of heterozygous state ( 26 ). Thus, immune defect in patients with DADA2 deficiency may present with myriad immunological aberrations ( 26 ). Immunological abnormalities reported in patients with DADA2 have been summarized in Figure 1 .…”

“…A recent report on DADA2 patients using in-depth immunophenotyping and functional analysis of lymphocytes revealed a multitude of immunological aberrations. These include impaired class switching and differentiation of B cells, reduced memory and regulatory T cells, increased senescent T cells, diminished mucosa associated invariant T cells and invariant NKT cells, and decreased classical monocytes ( 26 ). The authors also reported arrest in B cell development in the bone marrow at the pro-B to pre-B cell stage and defect in terminal B cell differentiation.…”

The Growing Spectrum of DADA2 Manifestations—Diagnostic and Therapeutic Challenges Revisited

“…Besides mild immunodeficiency, the associated impairment of the immune system may cause various autoinflammatory symptoms. Additionally, the hematopoietic system may be affected, resulting in mild to severe cytopenia of all lineages (anemia, lymphopenia and thrombocytopenia) ( 1 – 4 , 8 – 15 ).…”