B-cell development and functions and therapeutic options in adenosine deaminase-deficient patients

Immacolata Brigida, Aisha V. Sauer, Francesca Ferrua, Stefania Giannelli, Samantha Scaramuzza, Valentina Pistoia, Maria Carmina Castiello, Barbara H. Barendregt, Maria Pia Cicalese, Miriam Casiraghi, Chiara Brombin, Jennifer Puck, Klaus Müller, Lucia Dora Notarangelo, Davide Montin, Joris M. Van Montfrans, Maria Grazia Roncarolo, Elisabetta Traggiai, Jacques J M Van Dongen, Mirjam Van Der BurgAlessandro Aiuti

Research output: Contribution to journalArticlepeer-review


Background Adenosine deaminase (ADA) deficiency causes severe cellular and humoral immune defects and dysregulation because of metabolic toxicity. Alterations in B-cell development and function have been poorly studied. Enzyme replacement therapy (ERT) and hematopoietic stem cell (HSC) gene therapy (GT) are therapeutic options for patients lacking a suitable bone marrow (BM) transplant donor. Objective We sought to study alterations in B-cell development in ADA-deficient patients and investigate the ability of ERT and HSC-GT to restore normal B-cell differentiation and function. Methods Flow cytometry was used to characterize B-cell development in BM and the periphery. The percentage of gene-corrected B cells was measured by using quantitative PCR. B cells were assessed for their capacity to proliferate and release IgM after stimulation. Results Despite the severe peripheral B-cell lymphopenia, patients with ADA-deficient severe combined immunodeficiency showed a partial block in central BM development. Treatment with ERT or HSC-GT reverted most BM alterations, but ERT led to immature B-cell expansion. In the periphery transitional B cells accumulated under ERT, and the defect in maturation persisted long-term. HSC-GT led to a progressive improvement in B-cell numbers and development, along with increased levels of gene correction. The strongest selective advantage for ADA-transduced cells occurred at the transition from immature to naive cells. B-cell proliferative responses and differentiation to immunoglobulin secreting IgM after B-cell receptor and Toll-like receptor triggering were severely impaired after ERT and improved significantly after HSC-GT. Conclusions ADA-deficient patients show specific defects in B-cell development and functions that are differently corrected after ERT and HSC-GT.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
Issue number3
Publication statusPublished - Mar 2014


  • adenosine deaminase-deficient severe combined immunodeficiency
  • antibodies
  • B-cell development
  • Gene therapy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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