Restoring balance to B cells in ADA deficiency
Eline T. Luning Prak
Eline T. Luning Prak
Published May 24, 2012
Citation Information: J Clin Invest. 2012;122(6):1960-1962. https://doi.org/10.1172/JCI63782.
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Commentary

Restoring balance to B cells in ADA deficiency

Abstract

It is paradoxical that immunodeficiency disorders are associated with autoimmunity. Adenosine deaminase (ADA) deficiency, a cause of X-linked severe combined immunodeficiency (SCID), is a case in point. In this issue of the JCI, Sauer and colleagues investigate the B cell defects in ADA-deficient patients. They demonstrate that ADA patients receiving enzyme replacement therapy had B cell tolerance checkpoint defects. Remarkably, gene therapy with a retrovirus that expresses ADA resulted in the apparent correction of these defects, with normalization of peripheral B cell autoantibody frequencies. In vitro, agents that either block ADA or overexpress adenosine resulted in altered B cell receptor and TLR signaling. Collectively, these data implicate a B cell–intrinsic mechanism for alterations in B cell tolerance in the setting of partial ADA deficiency that is corrected by gene therapy.

Authors

Eline T. Luning Prak

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Figure 1

Restoring immune balance in ADA deficiency.

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Restoring immune balance in ADA deficiency. (A) In the absence of ADA, i...
(A) In the absence of ADA, intracellular and extracellular levels of the ADA substrates dATP and adenosine increase, and numbers of B, T, and NK cells are drastically reduced. Immune cells are hypofunctional except for Tregs, which have higher levels of ectoenzymes that can metabolize purinergic substrates to adenosine. Extracellular adenosine, in turn, can engage inhibitory adenosine 2A receptors (Ad2Ar) on NK cells and T cells. T, NK, and B cell functional responses are diminished (blue background). There is increased chronic innate immune stimulation, leading in part to fibrosis, inflammation, and hypersensitivity reactions. (B) In the setting of ADA enzyme replacement therapy, extracellular levels of adenosine and dATP are markedly reduced, whereas intracellular levels are still elevated. The reduced levels of extracellular adenosine diminish the inhibitory activity of Tregs. There is still moderate lymphopenia, but inappropriate lymphocyte activation due to altered TLR and BCR signaling and tolerance checkpoint defects (pink background), resulting in autoimmune manifestations. (C) After successful gene therapy, intracellular and extracellular levels of adenosine and dATP normalize, lymphocyte numbers increase, and proper homeostasis and selection mechanisms are restored (green background).