+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Autoimmune Dysregulation and Purine Metabolism in Adenosine Deaminase Deficiency

      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          Genetic defects in the adenosine deaminase ( ADA) gene are among the most common causes for severe combined immunodeficiency (SCID). ADA-SCID patients suffer from lymphopenia, severely impaired cellular and humoral immunity, failure to thrive, and recurrent infections. Currently available therapeutic options for this otherwise fatal disorder include bone marrow transplantation (BMT), enzyme replacement therapy with bovine ADA (PEG-ADA), or hematopoietic stem cell gene therapy (HSC-GT). Although varying degrees of immune reconstitution can be achieved by these treatments, breakdown of tolerance is a major concern in ADA-SCID. Immune dysregulation such as autoimmune hypothyroidism, diabetes mellitus, hemolytic anemia, and immune thrombocytopenia are frequently observed in milder forms of the disease. However, several reports document similar complications also in patients on long-term PEG-ADA and after BMT or GT treatment. A skewed repertoire and decreased immune functions have been implicated in autoimmunity observed in certain B-cell and/or T-cell immunodeficiencies, but it remains unclear to what extent specific mechanisms of tolerance are affected in ADA deficiency. Herein we provide an overview about ADA-SCID and the autoimmune manifestations reported in these patients before and after treatment. We also assess the value of the ADA-deficient mouse model as a useful tool to study both immune and metabolic disease mechanisms. With focus on regulatory T- and B-cells we discuss the lymphocyte subpopulations particularly prone to contribute to the loss of self-tolerance and onset of autoimmunity in ADA deficiency. Moreover we address which aspects of immune dysregulation are specifically related to alterations in purine metabolism caused by the lack of ADA and the subsequent accumulation of metabolites with immunomodulatory properties.

          Related collections

          Most cited references 96

          • Record: found
          • Abstract: found
          • Article: not found

          Adenosine receptors: therapeutic aspects for inflammatory and immune diseases.

          Adenosine is a key endogenous molecule that regulates tissue function by activating four G-protein-coupled adenosine receptors: A1, A2A, A2B and A3. Cells of the immune system express these receptors and are responsive to the modulatory effects of adenosine in an inflammatory environment. Animal models of asthma, ischaemia, arthritis, sepsis, inflammatory bowel disease and wound healing have helped to elucidate the regulatory roles of the various adenosine receptors in dictating the development and progression of disease. This recent heightened awareness of the role of adenosine in the control of immune and inflammatory systems has generated excitement regarding the potential use of adenosine-receptor-based therapies in the treatment of infection, autoimmunity, ischaemia and degenerative diseases.
            • Record: found
            • Abstract: found
            • Article: not found

            Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1.

            Gene transfer into hematopoietic stem cells has been used successfully for correcting lymphoid but not myeloid immunodeficiencies. Here we report on two adults who received gene therapy after nonmyeloablative bone marrow conditioning for the treatment of X-linked chronic granulomatous disease (X-CGD), a primary immunodeficiency caused by a defect in the oxidative antimicrobial activity of phagocytes resulting from mutations in gp91(phox). We detected substantial gene transfer in both individuals' neutrophils that lead to a large number of functionally corrected phagocytes and notable clinical improvement. Large-scale retroviral integration site-distribution analysis showed activating insertions in MDS1-EVI1, PRDM16 or SETBP1 that had influenced regulation of long-term hematopoiesis by expanding gene-corrected myelopoiesis three- to four-fold in both individuals. Although insertional influences have probably reinforced the therapeutic efficacy in this trial, our results suggest that gene therapy in combination with bone marrow conditioning can be successfully used to treat inherited diseases affecting the myeloid compartment such as CGD.
              • Record: found
              • Abstract: found
              • Article: not found

              Immune cell regulation by autocrine purinergic signalling.

               W Junger (2011)
              Stimulation of almost all mammalian cell types leads to the release of cellular ATP and autocrine feedback through a diverse array of purinergic receptors. Depending on the types of purinergic receptors that are involved, autocrine signalling can promote or inhibit cell activation and fine-tune functional responses. Recent work has shown that autocrine signalling is an important checkpoint in immune cell activation and allows immune cells to adjust their functional responses based on the extracellular cues provided by their environment. This Review focuses on the roles of autocrine purinergic signalling in the regulation of both innate and adaptive immune responses and discusses the potential of targeting purinergic receptors for treating immune-mediated disease.

                Author and article information

                Front Immunol
                Front Immunol
                Front. Immun.
                Frontiers in Immunology
                Frontiers Research Foundation
                27 August 2012
                : 3
                1San Raffaele Telethon Institute for Gene Therapy Milan, Italy
                2Università degli Studi di Roma Tor Vergata Rome, Italy
                Author notes

                Edited by: Rosa Bacchetta, San Raffaele Scientific Institute, Italy

                Reviewed by: Rosa Bacchetta, San Raffaele Scientific Institute, Italy; Mirjam van Der Burg, Erasmus MC, Netherlands

                *Correspondence: Alessandro Aiuti, San Raffaele Telethon Institute for Gene Therapy, Via Olgettina 58, Dibit 2A2, Milan 20132, Italy. e-mail: aiuti.alessandro@ 123456hsr.it

                This article was submitted to Frontiers in Primary Immunodeficiencies, a specialty of Frontiers in Immunology.

                Copyright © 2012 Sauer, Brigida, Carriglio and Aiuti.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                Page count
                Figures: 6, Tables: 1, Equations: 0, References: 143, Pages: 19, Words: 15565
                Review Article


                severe combined immunodeficiency, gene therapy, ada-scid, autoimmunity, adenosine deaminase


                Comment on this article