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    Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature
    (American Association for the Advancement of Science (AAAS), 2025-01-10)
    Marita Bosticardo
    ;
    Kerry Dobbs
    ;
    Ottavia M. Delmonte
    ;
    Andrew J. Martins
    ;
    Francesca Pala
    <jats:p> Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of <jats:italic>RAG</jats:italic> -mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic <jats:italic>RAG</jats:italic> variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons. T helper 2 (T <jats:sub>H</jats:sub> 2) cell skewing and a prominent inflammatory signature characterize Omenn syndrome, whereas more hypomorphic forms of RAG deficiency are associated with a type 1 immune profile both in blood and tissues. We used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analysis to define the cell lineage–specific contribution to the immunopathology of the distinct RAG phenotypes. These insights may help improve the diagnosis and clinical management of the various forms of the disease. </jats:p>
    Scopus© Citations 2  1
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    The Latin American Society for Immunodeficiencies Registry
    (2024)
    Gisela Seminario
    ;
    Maria Edith Gonzalez-Serrano
    ;
    Carolina Sanchez Aranda
    ;
    Anete Sevciovic Grumach
    ;
    Gesmar Rodrigues Silva Segundo
    Scopus© Citations 1  3
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    Outcomes of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome
    (2023)
    Roxane Labrosse
    ;
    Julia I. Chu
    ;
    Myriam A. Armant
    ;
    John K. Everett
    ;
    Danilo Pellin
    <jats:title>Abstract</jats:title> <jats:p>Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, autoimmunity, and lymphoid malignancies. Gene therapy (GT) to modify autologous CD34+ cells is an emerging alternative treatment with advantages over standard allogeneic hematopoietic stem cell transplantation for patients who lack well-matched donors, avoiding graft-versus-host-disease. We report the outcomes of a phase 1/2 clinical trial in which 5 patients with severe WAS underwent GT using a self-inactivating lentiviral vector expressing the human WAS complementary DNA under the control of a 1.6-kB fragment of the autologous promoter after busulfan and fludarabine conditioning. All patients were alive and well with sustained multilineage vector gene marking (median follow-up: 7.6 years). Clinical improvement of eczema, infections, and bleeding diathesis was universal. Immune function was consistently improved despite subphysiologic levels of transgenic WAS protein expression. Improvements in platelet count and cytoskeletal function in myeloid cells were most prominent in patients with high vector copy number in the transduced product. Two patients with a history of autoimmunity had flares of autoimmunity after GT, despite similar percentages of WAS protein–expressing cells and gene marking to those without autoimmunity. Patients with flares of autoimmunity demonstrated poor numerical recovery of T cells and regulatory T cells (Tregs), interleukin-10–producing regulatory B cells (Bregs), and transitional B cells. Thus, recovery of the Breg compartment, along with Tregs appears to be protective against development of autoimmunity after GT. These results indicate that clinical and laboratory manifestations of WAS are improved with GT with an acceptable safety profile. This trial is registered at clinicaltrials.gov as #NCT01410825.</jats:p>
      12Scopus© Citations 30
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      12Scopus© Citations 13
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      4Scopus© Citations 27