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.

Regulation of Adenosine Deaminase on Induced Mouse Experimental Autoimmune Uveitis

“…Our unpublished results showed that ADA has a suppressive effect on Foxp3 + T cell; conceivably, a low Foxp3 + T cell activity offsets the suppressive effect of ADA on Th1 responses. These results agree with previous reports showing that both adenosine and ADA interfere with regulatory T cell function (35; 44; 45). Because of previous concerns that prolonged ADA treatment is more likely to cause immune dysregulation (4), we looked at the therapeutic effect of a single injection of ADA and found that a single, appropriately timed injection could be effective.…”

Autoimmune Dysregulation and Purine Metabolism in Adenosine Deaminase Deficiency

“…Hence, ADA plays an essential role in the establishment of early B-cell tolerance and the removal of developing autoreactive B cells in humans (Luning Prak, 2012; Sauer et al, 2012b). …”

“…Strikingly, ADA-deficient patients treated with HSC-GT displayed quasi-normal early B-cell tolerance checkpoints as evidenced by restored efficient removal of developing autoreactive and anti-nuclear B cells. Hence, ADA plays an essential role in the establishment of early B-cell tolerance and the removal of developing autoreactive B cells in humans (Luning Prak, 2012 ; Sauer et al, 2012b ).…”

“…In addition to its effects on T- and B-cells, adenosine is an important regulator, physiologically involved in inhibiting a variety of activated immune cells and in protecting tissues from acute inflammatory damage (Panther et al, 2003 ; Sitkovsky et al, 2004 ). Indeed we showed that Tregs require a balanced adenosine metabolism to exert their suppressive activity, since excessively high adenosine concentrations, or excessive conversion of extracellularly produced adenosine by PEG-ADA interferes with their suppressive function (Luning Prak, 2012 ; Sauer et al, 2012a ).…”

“…With a progressive loss of lymphocyte functions, the occurrence of neutralizing anti-ADA antibodies and autoimmune manifestations, long-term immunological reconstitution in PEG-ADA patients is often incomplete. It has been hypothesized that partial ADA correction resulting in low enzymatic activity may mimic late-onset patients, which typically display a higher prevalence of autoimmune manifestations (Ochs et al, 1992 ; Ozsahin et al, 1997 ; Luning Prak, 2012 ). Indeed, recent data underlined the importance of intracellular ADA expression and superior efficacy of gene therapy over PEG-ADA treatment for the development of functional T- and B-cell tolerance, including Tregs (Sauer et al, 2012a , b ).…”