RAG deficiencies: Recent advances in disease pathogenesis and novel therapeutic approaches

Bosticardo, Marita; Pala, Francesca; Notarangelo, Luigi D.

doi:10.1002/eji.202048880

Cited by 29 publications

(20 citation statements)

References 102 publications

(165 reference statements)

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“…Co-expression of Rag1 and Rag2 during thymocyte development is essential for the assembly of functional genes encoding the TCR by recognizing and cleaving conserved recombination signal sequences located adjacent to clusters of V, D, and J gene segments ( Zhang et al, 2006 ; Bosticardo et al, 2021 ). The mechanisms responsible for the lymphoid-specific and developmental stage-specific regulation of Rag1 and Rag2 expression are poorly understood.…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Analysis Identifies Rag1 and Rag2 as Novel Notch1 Transcriptional Targets in Thymocytes

Dong

Guo

Wang

et al. 2021

Front. Cell Dev. Biol.

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Recombination activating genes 1 (Rag1) and Rag2 are expressed in immature lymphocytes and essential for generating the vast repertoire of antigen receptors. Yet, the mechanisms governing the transcription of Rag1 and Rag2 remain to be fully determined, particularly in thymocytes. Combining cDNA microarray and ChIP-seq analysis, we identify Rag1 and Rag2 as novel Notch1 transcriptional targets in acute T-cell lymphoblastic leukemia (T-ALL) cells. We further demonstrate that Notch1 transcriptional complexes directly bind the Rag1 and Rag2 locus in not only T-ALL but also primary double negative (DN) T-cell progenitors. Specifically, dimeric Notch1 transcriptional complexes activate Rag1 and Rag2 through a novel cis-element bearing a sequence-paired site (SPS). In T-ALL and DN cells, dimerization-defective Notch1 causes compromised Rag1 and Rag2 expression; conversely, dimerization-competent Notch1 achieves optimal upregulation of both. Collectively, these results reveal Notch1 dimerization-mediated transcription as one of the mechanisms for activating Rag1 and Rag2 expression in both primary and transformed thymocytes. Our data suggest a new role of Notch1 dimerization in compelling efficient TCRβ rearrangements in DN progenitors during T-cell development.

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Section: Resultsmentioning

confidence: 99%

Genome-Wide Analysis Identifies Rag1 and Rag2 as Novel Notch1 Transcriptional Targets in Thymocytes

Dong

Guo

Wang

et al. 2021

Front. Cell Dev. Biol.

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“…87,99,100 V(D)J recombination, allowing assembly of and signaling through Neurodevelopmental problems are often present in patients with DNA-PKcs and LIG4 deficiency. [101][102][103][104][105][106] Hypomorphic mutations in RAG1/2 may cause a spectrum of phenotypes ranging from Omenn syndrome (a condition with oligoclonal and activated autologous T cells that infiltrate and damage the skin and other organs) to combined immune deficiency with immune dysregulation. 102 Thymic tissues obtained from patients with hypomorphic mutations in these genes, showed a reduced medullary compartment and in particular impaired AIRE expression, which could account for the immune dysregulation and autoimmunity frequently observed in these patients.…”

Section: Severe Combined Immune Deficiency (Scid) Includes a Variety ...mentioning

confidence: 99%

“…[101][102][103][104][105][106] Hypomorphic mutations in RAG1/2 may cause a spectrum of phenotypes ranging from Omenn syndrome (a condition with oligoclonal and activated autologous T cells that infiltrate and damage the skin and other organs) to combined immune deficiency with immune dysregulation. 102 Thymic tissues obtained from patients with hypomorphic mutations in these genes, showed a reduced medullary compartment and in particular impaired AIRE expression, which could account for the immune dysregulation and autoimmunity frequently observed in these patients. 107 Ataxia telangiectasia (AT) is a complex disorder with severe neurological complications, increased cancer susceptibility and immunodeficiency.…”

Section: Severe Combined Immune Deficiency (Scid) Includes a Variety ...mentioning

confidence: 99%

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Inborn errors of immunity associated with defects of thymic development

Pala

Notarangelo

Bosticardo

2022

Pediatric Allergy Immunology

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The main function of the thymus is to support the establishment of a wide repertoire of T lymphocytes capable of eliminating foreign pathogens, yet tolerant to selfantigens. Thymocyte development in the thymus is dependent on the interaction with thymic stromal cells, a complex mixture of cells comprising thymic epithelial cells (TEC), mesenchymal and endothelial cells. The exchange of signals between stromal cells and thymocytes is referred to as "thymic cross-talk". Genetic defects affecting either side of this interaction result in defects in thymic development that ultimately lead to a decreased output of T lymphocytes to the periphery. In the present review, we aim at providing a summary of inborn errors of immunity (IEI) characterized by Tcell lymphopenia due to defects of the thymic stroma, or to hematopoietic-intrinsic defects of T-cell development, with a special focus on recently discovered disorders.Additionally, we review the novel diagnostic tools developed to discover and study new genetic causes of IEI due to defects in thymic development. Finally, we discuss therapeutic approaches to correct thymic defects that are currently available, in addition to potential novel therapies that could be applied in the future.

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“…The striking life-threatening disease in OS illustrates the critical role of mature T and B cells in the gastrointestinal tract and beyond. Gene therapy and gene editing are potential therapeutic approaches ( 104 ).…”

Section: Defects In T and B Cellsmentioning

confidence: 99%

Understanding inborn errors of immunity: A lens into the pathophysiology of monogenic inflammatory bowel disease

Ouahed

2022

Front. Immunol.

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Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gastrointestinal tract, including Crohn’s disease, ulcerative colitis and inflammatory bowel disease-undefined (IBD-U). IBD are understood to be multifactorial, involving genetic, immune, microbial and environmental factors. Advances in next generation sequencing facilitated the growing identification of over 80 monogenic causes of IBD, many of which overlap with Inborn errors of immunity (IEI); Approximately a third of currently identified IEI result in gastrointestinal manifestations, many of which are inflammatory in nature, such as IBD. Indeed, the gastrointestinal tract represents an opportune system to study IEI as it consists of the largest mass of lymphoid tissue in the body and employs a thin layer of intestinal epithelial cells as the critical barrier between the intestinal lumen and the host. In this mini-review, a selection of pertinent IEI resulting in monogenic IBD is described involving disorders in the intestinal epithelial barrier, phagocytosis, T and B cell defects, as well as those impairing central and peripheral tolerance. The contribution of disrupted gut-microbiota-host interactions in disturbing intestinal homeostasis among patients with intestinal disease is also discussed. The molecular mechanisms driving pathogenesis are reviewed along with the personalized therapeutic interventions and investigational avenues this growing knowledge has enabled.

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RAG deficiencies: Recent advances in disease pathogenesis and novel therapeutic approaches

Cited by 29 publications

References 102 publications

Genome-Wide Analysis Identifies Rag1 and Rag2 as Novel Notch1 Transcriptional Targets in Thymocytes

Genome-Wide Analysis Identifies Rag1 and Rag2 as Novel Notch1 Transcriptional Targets in Thymocytes

Inborn errors of immunity associated with defects of thymic development

Understanding inborn errors of immunity: A lens into the pathophysiology of monogenic inflammatory bowel disease

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