Blood Journal
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Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID

  1. Aisha V. Sauer1,*,
  2. Immacolata Brigida1,2,*,
  3. Nicola Carriglio1,2,
  4. Raisa Jofra Hernandez1,
  5. Samantha Scaramuzza1,
  6. Daniela Clavenna3,
  7. Francesca Sanvito3,
  8. Pietro L. Poliani4,
  9. Nicola Gagliani1,
  10. Filippo Carlucci5,6,
  11. Antonella Tabucchi5,6,
  12. Maria Grazia Roncarolo1,
  13. Elisabetta Traggiai7,
  14. Anna Villa1,8, and
  15. Alessandro Aiuti1,2
  1. 1San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy;
  2. 2Department of Public Health and Cell Biology, Tor Vergata University, Rome, Italy;
  3. 3Pathology Unit, Department of Oncology, San Raffaele Scientific Institute, Milan, Italy;
  4. 4Department of Pathology, University of Brescia, Brescia, Italy;
  5. 5Department of Internal Medicine, Endocrine-Metabolic Sciences and Biochemistry, University of Siena, Siena, Italy;
  6. 6Unità Operativa Complessa Clinical Pathology, Azienda Ospedaliera Universitaria Senese, Siena, Italy;
  7. 7Second Division of Pediatrics, Istituto di Ricovero e Cura a Carattere Scientifico, Institute G. Gaslini, Genova, Italy; and
  8. 8Consiglio Nazionale delle Ricerch–Istituto di Ricerca Genetica e Biomedica, Milan, Italy


Adenosine acts as anti-inflammatory mediator on the immune system and has been described in regulatory T cell (Treg)–mediated suppression. In the absence of adenosine deaminase (ADA), adenosine and other purine metabolites accumulate, leading to severe immunodeficiency with recurrent infections (ADA-SCID). Particularly ADA-deficient patients with late-onset forms and after enzyme replacement therapy (PEG-ADA) are known to manifest immune dysregulation. Herein we provide evidence that alterations in the purine metabolism interfere with Treg function, thereby contributing to autoimmune manifestations in ADA deficiency. Tregs isolated from PEG-ADA–treated patients are reduced in number and show decreased suppressive activity, whereas they are corrected after gene therapy. Untreated murine ADA−/− Tregs show alterations in the plasma membrane CD39/CD73 ectonucleotidase machinery and limited suppressive activity via extracellular adenosine. PEG-ADA–treated mice developed multiple autoantibodies and hypothyroidism in contrast to mice treated with bone marrow transplantation or gene therapy. Tregs isolated from PEG-ADA–treated mice lacked suppressive activity, suggesting that this treatment interferes with Treg functionality. The alterations in the CD39/CD73 adenosinergic machinery and loss of function in ADA-deficient Tregs provide new insights into a predisposition to autoimmunity and the underlying mechanisms causing defective peripheral tolerance in ADA-SCID. Trials were registered at as NCT00598481/NCT00599781.

  • Submitted July 13, 2011.
  • Accepted December 7, 2011.
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