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Cell Mar 2023CD3δ SCID is a devastating inborn error of immunity caused by mutations in CD3D, encoding the invariant CD3δ chain of the CD3/TCR complex necessary for normal...
CD3δ SCID is a devastating inborn error of immunity caused by mutations in CD3D, encoding the invariant CD3δ chain of the CD3/TCR complex necessary for normal thymopoiesis. We demonstrate an adenine base editing (ABE) strategy to restore CD3δ in autologous hematopoietic stem and progenitor cells (HSPCs). Delivery of mRNA encoding a laboratory-evolved ABE and guide RNA into a CD3δ SCID patient's HSPCs resulted in a 71.2% ± 7.85% (n = 3) correction of the pathogenic mutation. Edited HSPCs differentiated in artificial thymic organoids produced mature T cells exhibiting diverse TCR repertoires and TCR-dependent functions. Edited human HSPCs transplanted into immunodeficient mice showed 88% reversion of the CD3D defect in human CD34+ cells isolated from mouse bone marrow after 16 weeks, indicating correction of long-term repopulating HSCs. These findings demonstrate the preclinical efficacy of ABE in HSPCs for the treatment of CD3δ SCID, providing a foundation for the development of a one-time treatment for CD3δ SCID patients.
Topics: Humans; Animals; Mice; T-Lymphocytes; Severe Combined Immunodeficiency; Gene Editing; Mice, SCID; CD3 Complex; Receptors, Antigen, T-Cell
PubMed: 36944331
DOI: 10.1016/j.cell.2023.02.027 -
Blood Sep 2023Although absence of interleukin-7 (IL-7) signaling completely abrogates T and B lymphopoiesis in mice, patients with severe combined immunodeficiency caused by mutations...
Although absence of interleukin-7 (IL-7) signaling completely abrogates T and B lymphopoiesis in mice, patients with severe combined immunodeficiency caused by mutations in the IL-7 receptor α chain (IL-7Rα) still generate peripheral blood B cells. Consequently, human B lymphopoiesis has been thought to be independent of IL-7 signaling. Using flow cytometric analysis and single-cell RNA sequencing of bone marrow samples from healthy controls and patients who are IL-7Rα deficient, in combination with in vitro modeling of human B-cell differentiation, we demonstrate that IL-7R signaling plays a crucial role in human B lymphopoiesis. IL-7 drives proliferation and expansion of early B-cell progenitors but not of pre-BII large cells and has a limited role in the prevention of cell death. Furthermore, IL-7 guides cell fate decisions by enhancing the expression of BACH2, EBF1, and PAX5, which jointly orchestrate the specification and commitment of early B-cell progenitors. In line with this observation, early B-cell progenitors of patients with IL-7Rα deficiency still expressed myeloid-specific genes. Collectively, our results unveil a previously unknown role for IL-7 signaling in promoting the B-lymphoid fate and expanding early human B-cell progenitors while defining important differences between mice and humans. Our results have implications for hematopoietic stem cell transplantation strategies in patients with T- B+ severe combined immunodeficiency and provide insights into the role of IL-7R signaling in leukemogenesis.
Topics: Humans; Animals; Mice; Interleukin-7; Severe Combined Immunodeficiency; Receptors, Interleukin-7; Cell Differentiation; Hematopoiesis
PubMed: 37369082
DOI: 10.1182/blood.2023019721 -
Jornal de Pediatria 2021Inborn Errors of Immunity (IEI), also known as primary immunodeficiencies, correspond to a heterogeneous group of congenital diseases that primarily affect immune... (Review)
Review
OBJECTIVES
Inborn Errors of Immunity (IEI), also known as primary immunodeficiencies, correspond to a heterogeneous group of congenital diseases that primarily affect immune response components. The main clinical manifestations comprise increased susceptibility to infections, autoimmunity, inflammation, allergies and malignancies. The aim of this article is to review the literature on combined immunodeficiencies (CIDs) focusing on the diagnosis and treatment and the particularities of the clinical management of these patients.
SOURCE OF DATA
Critical integrative review, aimed to present articles related to primary immunodeficiencies combined with a searchin the PubMed and SciELO databases, with evaluation of publications from the last twenty years that were essential for the construction of knowledge on this group of diseases.
SUMMARY OF DATA
We highlight the main characteristics of CIDs, dividing them according to their pathophysiological mechanisms, such as defects in the development of T cells, TCR signaling, co-stimulatory pathways, cytokine signaling, adhesion, migration and organization of the cytoskeleton, apoptosis pathways, DNA replication and repair and metabolic pathways. In CIDs, clinical manifestations vary widely, from sinopulmonary bacterial infections and diarrhea to opportunistic infections, caused by mycobacteria and fungi. Neonatal screening makes it possible to suspect these diseases before clinical manifestations appear.
CONCLUSIONS
The CIDs or IEI constitute a complex group of genetic diseases with T-cell involvement. Neonatal screening for these diseases has improved the prognosis of these patients, especially in severe ones, known as SCIDs.
Topics: Humans; Immunologic Deficiency Syndromes; Infant, Newborn; Neonatal Screening; Severe Combined Immunodeficiency; T-Lymphocytes
PubMed: 33340461
DOI: 10.1016/j.jped.2020.10.014 -
Microorganisms Jun 2023Severe combined immunodeficiency (SCID) is a primary inherited immunodeficiency disease that presents before the age of three months and can be fatal. It is usually due... (Review)
Review
Severe combined immunodeficiency (SCID) is a primary inherited immunodeficiency disease that presents before the age of three months and can be fatal. It is usually due to opportunistic infections caused by bacteria, viruses, fungi, and protozoa resulting in a decrease in number and impairment in the function of T and B cells. Autosomal, X-linked, and sporadic forms exist. Evidence of recurrent opportunistic infections and lymphopenia very early in life should prompt immunological investigation and suspicion of this rare disorder. Adequate stem cell transplantation is the treatment of choice. This review aimed to provide a comprehensive approach to the microorganisms associated with severe combined immunodeficiency (SCID) and its management. We describe SCID as a syndrome and summarize the different microorganisms that affect children and how they can be investigated and treated.
PubMed: 37375091
DOI: 10.3390/microorganisms11061589 -
Current Opinion in Immunology Feb 2023Increased immunogloblulin-E (IgE) levels associated with eosinophilia represent a common finding observed in Omenn syndrome, a severe immunodeficiency caused by... (Review)
Review
Increased immunogloblulin-E (IgE) levels associated with eosinophilia represent a common finding observed in Omenn syndrome, a severe immunodeficiency caused by decreased V(D)J recombination, leading to restricted T- and B-cell receptor repertoire. V(D)J recombination is initiated by the lymphoid-restricted recombination-activating gene (RAG) recombinases. The lack of RAG proteins causes a block in lymphocyte differentiation, resulting in TB severe combined immunodeficiency. Conversely, hypomorphic mutations allow the generation of few T and B cells, leading to a spectrum of immunological phenotypes, in which immunodeficiency associates to inflammation, immune dysregulation, and autoimmunity. Elevated IgE levels are frequently observed in hypomorphic RAG patients. Here, we describe the role of RAG genes in lymphocyte differentiation and maintenance of immune tolerance.
Topics: Humans; DNA-Binding Proteins; Immunologic Deficiency Syndromes; Severe Combined Immunodeficiency; Mutation; Immunoglobulin E
PubMed: 36529093
DOI: 10.1016/j.coi.2022.102279 -
Diagnostics (Basel, Switzerland) Sep 2022Eczema is a classical characteristic not only in atopic dermatitis but also in various genodermatosis. Patients suffering from primary immunodeficiency diseases such as... (Review)
Review
Eczema is a classical characteristic not only in atopic dermatitis but also in various genodermatosis. Patients suffering from primary immunodeficiency diseases such as hyper-immunoglobulin E syndromes, Wiskott-Aldrich syndrome, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, STAT5B deficiency, Omenn syndrome, atypical complete DiGeorge syndrome; metabolic disorders such as acrodermatitis enteropathy, multiple carboxylase deficiency, prolidase deficiency; and other rare syndromes like severe dermatitis, multiple allergies and metabolic wasting syndrome, Netherton syndrome, and peeling skin syndrome frequently perform with eczema-like lesions. These genodermatosis may be misguided in the context of eczematous phenotype. Misdiagnosis of severe disorders unavoidably affects appropriate treatment and leads to irreversible outcomes for patients, which underlines the importance of molecular diagnosis and genetic analysis. Here we conclude clinical manifestations, molecular mechanism, diagnosis and management of several eczema-related genodermatosis and provide accessible advice to physicians.
PubMed: 36140582
DOI: 10.3390/diagnostics12092177 -
The Journal of Allergy and Clinical... Feb 2021Newborn screening for severe combined immunodeficiency, the most profound form of primary immune system defects, has long been recognized as a measure that would... (Review)
Review
Newborn screening for severe combined immunodeficiency, the most profound form of primary immune system defects, has long been recognized as a measure that would decrease morbidity and improve outcomes by helping patients avoid devastating infections and receive prompt immune-restoring therapy. The T-cell receptor excision circle test, developed in 2005, proved to be successful in pilot studies starting in the period 2008 to 2010, and by 2019 all states in the United States had adopted versions of it in their public health programs. Introduction of newborn screening for severe combined immunodeficiency, the first immune disorder accepted for population-based screening, has drastically changed the presentation of this disorder while providing important lessons for public health programs, immunologists, and transplanters.
Topics: Female; Humans; Infant, Newborn; Male; Neonatal Screening; Severe Combined Immunodeficiency
PubMed: 33551023
DOI: 10.1016/j.jaci.2020.10.020 -
Pediatric Allergy and Immunology :... Jan 2022Primary atopic disorders (PADs) are monogenic diseases characterized by allergy or atopy-related symptoms as fundamental features. In patients with PADs, primary immune... (Review)
Review
Primary atopic disorders (PADs) are monogenic diseases characterized by allergy or atopy-related symptoms as fundamental features. In patients with PADs, primary immune deficiency and immune dysregulation symptoms are usually coexist. Chronic skin disease, manifesting with erythroderma, severe atopic dermatitis or eczema, and urticaria, is one of the main features observed in PADs, such as hyper-IgE syndromes, Omenn syndrome, Wiskott-Aldrich syndrome, IPEX-linked syndrome, skin barrier disorders, as well as some autoinflammatory diseases. The recognition of PADs in the context of an allergic phenotype is crucial to ensure prompt diagnosis and appropriate treatment. This article provides an overview of the main PADs with skin involvement.
Topics: Eczema; Humans; Hypersensitivity, Immediate; Job Syndrome; Skin Diseases; Urticaria
PubMed: 35080318
DOI: 10.1111/pai.13633 -
Blood Aug 2022
Topics: Humans; Severe Combined Immunodeficiency
PubMed: 35980683
DOI: 10.1182/blood.2022017211