TY - JOUR
T1 - Dysregulation in B-cell responses and T follicular helper cell function in ADA2 deficiency patients
AU - Schena, Francesca
AU - Penco, Federica
AU - Volpi, Stefano
AU - Pastorino, Claudia
AU - Caorsi, Roberta
AU - Kalli, Francesca
AU - Fenoglio, Daniela
AU - Salis, Annalisa
AU - Bertoni, Arinna
AU - Prigione, Ignazia
AU - Bocca, Paola
AU - Insalaco, Antonella
AU - De Benedetti, Fabrizio
AU - Antonini, Francesca
AU - Grossi, Alice
AU - Signa, Sara
AU - Damonte, Gianluca
AU - Ceccherini, Isabella
AU - Filaci, Gilberto
AU - Traggiai, Elisabetta
AU - Gattorno, Marco
PY - 2020
Y1 - 2020
N2 - 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 of ADA2 gene, 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 if ADA2 mutation 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 CD21low 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 that ADA2 mutation 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.
AB - 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 of ADA2 gene, 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 if ADA2 mutation 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 CD21low 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 that ADA2 mutation 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.
KW - Adenosine deaminase 2
KW - B cell
KW - Follicular helper T cells
KW - Hypogammaglobulinemia
KW - Immunodeficiency
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U2 - 10.1002/eji.202048549
DO - 10.1002/eji.202048549
M3 - Article
C2 - 32707604
AN - SCOPUS:85089891990
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
ER -