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Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy.

ABSTRACT: Adenosine deaminase (ADA) gene defects are among the most common causes of SCID. Restoration of purine metabolism and immune functions can be achieved by enzyme replacement therapy, or more effectively by bone marrow transplant or HSC gene therapy (HSC-GT). However, autoimmune complications and autoantibody production, including anti-nuclear antibodies (ANAs), frequently occur in ADA-SCID patients after treatment. To assess whether ADA deficiency affects the establishment of B cell tolerance, we tested the reactivity of recombinant antibodies isolated from single B cells of ADA-SCID patients before and after HSC-GT. We found that before HSC-GT, new emigrant/transitional and mature naive B cells from ADA-SCID patients contained more autoreactive and ANA-expressing clones, indicative of defective central and peripheral B cell tolerance checkpoints. We further observed impaired B cell receptor (BCR) and TLR functions in B cells after ADA inhibition, which may underlie the defects in B cell tolerance. Strikingly, after HSC-GT, ADA-SCID patients displayed quasi-normal early B cell tolerance checkpoints, as evidenced by restored removal of developing autoreactive and ANA-expressing B cells. Hence, ADA plays an essential role in controlling autoreactive B cell counterselection by regulating BCR and TLR functions.

SUBMITTER: Sauer AV

PROVIDER: S-EPMC3366410 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy.

Sauer Aisha V AV Morbach Henner H Brigida Immacolata I Ng Yen-Shing YS Aiuti Alessandro A Meffre Eric E

The Journal of clinical investigation 20120524 6

Adenosine deaminase (ADA) gene defects are among the most common causes of SCID. Restoration of purine metabolism and immune functions can be achieved by enzyme replacement therapy, or more effectively by bone marrow transplant or HSC gene therapy (HSC-GT). However, autoimmune complications and autoantibody production, including anti-nuclear antibodies (ANAs), frequently occur in ADA-SCID patients after treatment. To assess whether ADA deficiency affects the establishment of B cell tolerance, we ...[more]

PMID: 22622038

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Project description:Background and methods: Deficiency of adenosine deaminase 2 (DADA2) is the first molecularly described monogenic vasculitis syndrome. DADA2 is caused by autosomal-recessive loss-of-function mutations in the ADA2 gene (previously known as CECR1). Vasculitis, vasculopathy and inflammation are dominant clinical features of this disease; however wide spectrum of clinical manifestations includes immunodeficiency, lymphoproliferation, as well as hematologic manifestations. ADA2 is primarily secreted by stimulated monocytes and macrophages. It has been shown that monocytes differentiation to macrophages, and neutrophils play a pathogenic role in DADA2, but little is known about T lymphocytes in this disease. Results: We performed combined single cell RNA sequencing and TCR sequencing to profile T cell repertoire in ten patients with DADA2. Although there are no significant alterations of T cell subsets, we observed activation of both CD8+ and CD4+ T cells, and inflammatory status in these patients. We did not observe clonal expansion of T cells: majority TCRs are expressed at basal level in patients and healthy donors. TCR usage is individual-specific in patients and not disease-specific, indicating unlikely a common pathogenic background or predisposition to a common pathogen in this cohort of patients. We recognized activation of interferon pathways as signature of T cells, and STAT1 as a hub gene in the gene network of T cell activation and cytotoxicity. Overall, T cells in DADA2 patients have altered cell-cell interactions with monocytes, as compared to that in healthy donors, many of these ligand-receptor interactions likely drive upregulation of STAT1 in both T cells and lymphocytes in patients. Conclusion: In conclusion, our single cell analysis of T cells discloses subsets, clonality and transcriptome of a previously undercharacterized cell type in DADA2. Activation of immune response especially IFN pathways remain the core signature of T cells and monocytes. Modulation of IFN pathway, as well as ligand-receptor pairs between immune cells may contribute a novel and directed therapeutic approach in the treatment of DADA2.

Dataset Information

Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy.

Publications

Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy.

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