Nucleotide pool imbalance and adenosine deaminase deficiency induce alterations of N-region insertions during V(D)J recombination

Gangi-Peterson, Lisa; Sorscher, David H.; Reynolds, Jon; Kepler, Thomas B.; Mitchell, Beverly S.

doi:10.1172/jci4320

Cited by 51 publications

(41 citation statements)

References 42 publications

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“…Inhibition of ribonucleotide reductase can lead to nucleotide pool depletion, which can then interfere with the formation of N nucleotides in coding joints and impair T and B cell gene rearrangement. In line with these conclusions, alterations in N region insertions have been reported in human ADA-deficient patients (41). Therefore, while B cell maturation in the bone marrow appeared to be normal in ADA-deficient mice, the Ag binding diversity of the B cell repertoire may remain limited.…”

Section: Discussionsupporting

confidence: 55%

Impaired Germinal Center Maturation in Adenosine Deaminase Deficiency

Aldrich

Chen

Blackburn

et al. 2003

The Journal of Immunology

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Mice deficient in the enzyme adenosine deaminase (ADA) have small lymphoid organs that contain reduced numbers of peripheral lymphocytes, and they are immunodeficient. We investigated B cell deficiency in ADA-deficient mice and found that B cell development in the bone marrow was normal. However, spleens were markedly smaller, their architecture was dramatically altered, and splenic B lymphocytes showed defects in proliferation and activation. ADA-deficient B cells exhibited a higher propensity to undergo B cell receptor-mediated apoptosis than their wild-type counterparts, suggesting that ADA plays a role in the survival of cells during Ag-dependent responses. In keeping with this finding, IgM production by extrafollicular plasmablast cells was higher in ADA-deficient than in wild-type mice, thus indicating that activated B cells accumulate extrafollicularly as a result of a poor or nonexistent germinal center formation. This hypothesis was subsequently confirmed by the profound loss of germinal center architecture. A comparison of levels of the ADA substrates, adenosine and 2′-deoxyadenosine, as well resulting dATP levels and S-adenosylhomocysteine hydrolase inhibition in bone marrow and spleen suggested that dATP accumulation in ADA-deficient spleens may be responsible for impaired B cell development. The altered splenic environment and signaling abnormalities may concurrently contribute to a block in B cell Ag-dependent maturation in ADA-deficient mouse spleens.

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Section: Discussionsupporting

confidence: 55%

Impaired Germinal Center Maturation in Adenosine Deaminase Deficiency

Aldrich

Chen

Blackburn

et al. 2003

The Journal of Immunology

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“…24 B-cell function and in particular antigen diversity is affected by the build up of dATP as a consequence of ADA deficiency. 25 These defects are not fully repaired by ERT whereby only 50% of patients are able to discontinue Ig replacement therapy. 16,26 After HCT, however, most patients are able to discontinue Ig replacement and make vaccinespecific responses, suggesting relatively complete humoral recovery.…”

Section: Discussionmentioning

confidence: 99%

Outcome of hematopoietic stem cell transplantation for adenosine deaminase–deficient severe combined immunodeficiency

Hassan¹,

Booth²,

Brightwell³

et al. 2012

Blood

159

134

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Deficiency of the purine salvage enzyme adenosine deaminase leads to SCID (ADA-SCID). Hematopoietic cell transplantation (HCT) can lead to a permanent cure of SCID; however, little data are available on outcome of HCT for ADA-SCID in particular. In this multicenter retrospective study, we analyzed outcome of HCT in 106 patients with ADA-SCID who received a total of 119 transplants. HCT from matched sibling and family donors (MSDs, MFDs) had significantly better overall survival (86% and 81%) in comparison with HCT from matched unrelated (66%; P < .05) and haploidentical donors (43%; P < .001). Superior overall survival was also seen in patients who received unconditioned transplants in comparison with myeloablative procedures (81% vs 54%; P < .003), although in unconditioned haploidentical donor HCT, nonengraftment was a major problem. Long-term immune recovery showed that regardless of transplant type, overall T-cell numbers were similar, although a faster rate of T-cell recovery was observed after MSD/MFD HCT. Humoral immunity and donor B-cell engraftment was achieved in nearly all evaluable surviving patients and was seen even after unconditioned HCT. These data detail for the first time the outcomes of HCT for ADA-SCID and show that, if patients survive HCT, long-term cellular and humoral immune recovery is achieved. (Blood. 2012;120(17):3615-3624)

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“…Studies on both ADA-deficient murine and human models show that dATP inhibits ribonucleotide reductase, an enzyme necessary for DNA replication and repair, 4 induces apoptosis in immature thymocytes, 5 and interferes with terminal deoxynucleotidyl transferase activity, thereby limiting V(D)J recombination and antigen receptor diversity. 6 dAdo accumulation inactivates the enzyme S-adenosylhomocysteine hydrolase 7 and results in inhibition of transmethylation reactions necessary for effective lymphocyte activation. Elevated levels of Ado, acting through cell-surface G protein-coupled receptors, may contribute to immune dysfunction and pulmonary inflammation associated with ADA deficiency.…”

Section: Ada-scidmentioning

confidence: 99%

How I treat ADA deficiency

Gaspar

Aiuti

Porta

et al. 2009

Blood

196

208

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Adenosine deaminase deficiency is a disorder of purine metabolism leading to severe combined immunodeficiency (ADA-SCID). Without treatment, the condition is fatal and requires early intervention. Haematopoietic stem cell transplantation is the major treatment for ADA-SCID, although survival following different donor sources varies considerably. Unlike other SCID forms, 2 other options are available for ADA-SCID: enzyme replacement therapy (ERT) with pegylated bovine ADA, and autologous haematopoietic stem cell gene therapy (GT). Due to the rarity of the condition, the lack of large scale outcome studies, and availability of different treatments, guidance on treatment strategies is limited. We have reviewed the currently available evidence and together with our experience of managing this condition propose a consensus management strategy. IntroductionAdenosine deaminase (ADA) deficiency is a rare inherited disorder of purine metabolism characterized by the accumulation of metabolic substrates that lead to abnormalities of immune system development and function and a variety of systemic defects. The initial and most devastating presentation of the disease is the result of the immune defects; affected infants characteristically present with severe opportunistic infection and failure to thrive and an immunologic profile consistent with severe combined immunodeficiency (ADA-SCID). Without treatment, the condition is fatal in the first year of life and therefore necessitates early intervention. Allogeneic hematopoietic stem cell transplantation (HSCT) has long been considered the mainstay of treatment of ADA-SCID. However, unlike other SCID forms, 2 other treatment options are available for ADA-SCID, namely, enzyme replacement therapy (ERT) with pegylated bovine ADA (Pegadamase, Adagen, or PEG-ADA) and autologous HSC gene therapy (GT).The availability of different treatment modalities presents an opportunity for improved patient care but also presents difficulties in deciding on the specific choice of treatment for individual patients. Making the correct choice is further complicated by the fact that ADA deficiency is not purely an immune defect, unlike other SCID forms, and the systemic manifestations, which can be of major clinical consequence, must also be managed. The rarity of the condition (estimated at anything from 1:200 000 to 1:1 million births) means that any one center has access to only small numbers of patients precluding large-scale prospective studies from which formal and robust outcome data can be accrued. For these reasons, we have gathered experts with experience in management of patients using the different treatment modalities to collect and review the available retrospective data and to construct a consensus management strategy that may be of use to physicians managing this difficult patient population. ADA-SCIDSCID arises from a variety of molecular defects that have profound effects on lymphocyte development and function, including defects in the lymphocyte-specific signaling molecules (comm...

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Nucleotide pool imbalance and adenosine deaminase deficiency induce alterations of N-region insertions during V(D)J recombination

Cited by 51 publications

References 42 publications

Impaired Germinal Center Maturation in Adenosine Deaminase Deficiency

Impaired Germinal Center Maturation in Adenosine Deaminase Deficiency

Outcome of hematopoietic stem cell transplantation for adenosine deaminase–deficient severe combined immunodeficiency

How I treat ADA deficiency

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