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

  • Author(s): Brigida, I
  • Sauer, AV
  • Ferrua, F
  • Giannelli, S
  • Scaramuzza, S
  • Pistoia, V
  • Castiello, MC
  • Barendregt, BH
  • Cicalese, MP
  • Casiraghi, M
  • Brombin, C
  • Puck, J
  • Müller, K
  • Notarangelo, LD
  • Montin, D
  • van Montfrans, JM
  • Roncarolo, MG
  • Traggiai, E
  • van Dongen, JJM
  • van der Burg, M
  • Aiuti, A
  • et al.

Published Web Location

http://www.sciencedirect.com/science/article/pii/S0091674913029631
No data is associated with this publication.
Abstract

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.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.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.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.ADA-deficient patients show specific defects in B-cell development and functions that are differently corrected after ERT and HSC-GT.

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