Dysregulation in B-cell responses and T follicular helper cell function in ADA2 deficiency patients

Adenosine deaminase 2 deficiency (DADA2) is an autoinflammatory disease characterized by inflammatory vasculopathy, early strokes associated often with hypogammaglobulinemia. Pure red cell aplasia, thrombocytopenia, and neutropenia have been reported. The defect is due to biallelic loss of function ofADA2gene, coding for a protein known to regulate the catabolism of extracellular adenosine. We therefore investigated immune phenotype and B- and T-cell responses in 14 DADA2 patients to address ifADA2mutation affects B- and T-cell function. Here, we show a significant decrease in memory B cells, in particular class switch memory, and an expansion of CD21(low)B cells in DADA2 patients. In vitro stimulated B lymphocytes were able to secrete nonfunctional ADA2 protein, suggesting a cell intrinsic defect resulting in an impairment of B-cell proliferation and differentiation. Moreover, CD4(+)and CD8(+)T cells were diminished; however, the frequency of circulating T follicular helper cells was significantly increased but they had an impairment in IL-21 production possibly contributing to an impaired B cell help. Our findings suggest thatADA2mutation could lead to a B-cell intrinsic defect but also to a defective Tfh cell function, which could contribute to the immunodeficient phenotype reported in DADA2 patients.

Automated summary

DADA2 patients show decreased memory B cells, particularly in class switch memory, and an expansion of CD21(low)B cells. In vitro stimulated B lymphocytes can secrete nonfunctional ADA2 protein, suggesting a cell intrinsic defect leading to impaired B-cell proliferation and differentiation. Additionally, CD4(+) and CD8(+) T cells are reduced, while circulating T follicular helper cells are significantly increased but have impaired IL-21 production, potentially contributing to impaired B cell help.