Expanding IPEX: Inborn Errors of Regulatory T Cells

Article Hematology

DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity

Charlotte Boussard et al.

Summary: DOCK11 deficiency leads to impaired cellular function and immune dysregulation, resulting in autoimmune disorders.

BLOOD (2023)

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Article Allergy

Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome

Jennifer W. Leiding et al.

Summary: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. The study found that patients with this variant present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Early identification and prompt treatment implementation are crucial for the survival of these patients.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY (2023)

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Article Allergy

Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation

Mansi Narula et al.

Summary: Mutations in the FOXP3 gene in patients with IPEX syndrome lead to immune dysregulation, with varied clinical presentations. Using epigenetic quantification and immunologic characterization, it was found that there is an increased number of TSDR-demethylated cells in the FOXP3 gene in IPEX patients, along with markers of a polarized type 2 inflammatory immune response. These findings enhance our understanding of IPEX diagnosis and heterogeneity.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY (2023)

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Review Immunology

Regulatory T cells in peripheral tissue tolerance and diseases

Nardos Cheru et al.

Summary: Maintenance of peripheral tolerance by CD4(+)Foxp3(+) regulatory T cells is crucial for regulating autoreactive T cells. Dysfunction of Foxp3 leads to autoimmune diseases. Tregs not only maintain immune homeostasis, but also establish tissue microenvironment and homeostasis of non-lymphoid tissues. Tissue resident Tregs show unique profiles and interact with both immune and non-immune cells, exerting suppressive function and adopting to local microenvironment through bidirectional interactions.

FRONTIERS IN IMMUNOLOGY (2023)

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Review Pharmacology & Pharmacy

Homology-Directed-Repair-Based Genome Editing in HSPCs for the Treatment of Inborn Errors of Immunity and Blood Disorders

Daniel Allen et al.

Summary: Genome engineering through targeted nucleases, especially CRISPR-Cas9, has revolutionized gene therapy research and has the potential to treat blood and immune system diseases. CRISPR-Cas9 homology-directed repair (HDR) represents a promising method for site-specific gene insertion or correction. Other methods, like viral gene addition, gene knockout through non-homologous end joining (NHEJ), and base or prime editing, also show promise but have significant limitations for treating genetic immune or blood disorders. This review aims to highlight the transformative benefits of HDR-mediated gene therapy and propose solutions for current challenges, in order to advance HDR-based gene therapy in CD34(+) hematopoietic stem progenitor cells (HSPCs).

PHARMACEUTICS (2023)

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Article Hematology

Real-world experience with low-dose IL-2 for children and young adults with refractory chronic graft-versus-host disease

Holly Wobma et al.

Summary: The majority of patients with chronic graft-versus-host disease (cGVHD) are steroid refractory (SR), creating a need for safe and effective therapies. This study reports additional real-world experience with subcutaneous low-dose interleukin-2 (LD IL-2) in 15 children and young adults. The results show that LD IL-2 is a well-tolerated, steroid-sparing agent with a high response rate in children and young adults with SR-cGVHD.

BLOOD ADVANCES (2023)

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Article Biochemistry & Molecular Biology

Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott-Aldrich syndrome

A. Magnani et al.

Summary: This article presents the long-term follow-up results of gene therapy for patients with Wiskott-Aldrich syndrome, showing that lentiviral gene therapy provides sustained clinical benefits for these patients.

NATURE MEDICINE (2022)

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Article Pediatrics

Genetic diagnosis of immune dysregulation can lead to targeted therapy for interstitial lung disease: A case series and single center approach

Holly Wobma et al.

Summary: In recent years, an increasing number of monogenic disorders characterized by immune dysregulation have been identified, some of which can lead to severe lung disease in late childhood or adolescence. It is important for pulmonologists to recognize features of multisystem immune dysregulation, perform genetic workup, and initiate targeted therapies to halt or reverse pulmonary disease progression.

PEDIATRIC PULMONOLOGY (2022)

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Article Immunology

Gain-of-function IKZF1 variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation

Akihiro Hoshino et al.

Summary: This study identified IKZF1 variants in the DNA binding domain that cause inflammatory, autoimmune, allergic symptoms, and abnormal plasma cell proliferation. These variants act as gain-of-function alleles, leading to increased gene expression associated with T(H)2 and plasma cell differentiation. Treatment with Lenalidomide can correct these abnormalities.

SCIENCE IMMUNOLOGY (2022)

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Article Medicine, Research & Experimental

The ABACHAI clinical trial protocol: Safety and efficacy of abatacept (s.c.) in patients with CTLA-4 insufficiency or LRBA deficiency: A non controlled phase 2 clinical trial

Mate Krausz et al.

Summary: Both CTLA-4 insufficiency and LRBA deficiency are immune dysregulation syndromes with similar clinical manifestations. Treatment with abatacept may improve clinical outcomes and quality of life in patients. This study aims to evaluate the safety and efficacy of abatacept for patients with CTLA-4 insufficiency or LRBA deficiency.

CONTEMPORARY CLINICAL TRIALS COMMUNICATIONS (2022)

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Article Allergy

DEF6 deficiency, a mendelian susceptibility to EBV infection, lymphoma, and autoimmunity

Benjamin Fournier et al.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY (2021)

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Review Immunology

Inborn errors of IKAROS and AIOLOS

Motoi Yamashita et al.

Summary: IKAROS is a pioneer protein in the IKZF family of transcription factors, playing a crucial role in lymphocyte development. Inborn errors of IKAROS have been found in patients with B cell deficiency and hypogammaglobulinemia, leading to recurrent sinopulmonary infections, autoimmunity, and hematologic malignancies. Missense mutations involving asparagine at the 159th position can result in combined immunodeficiency. Other transcription factors like AIOLOS, HELIOS, and PEGASUS have also been associated with B cell deficiency, Evans syndrome, and hereditary thrombocytopenia, respectively.

CURRENT OPINION IN IMMUNOLOGY (2021)

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Article Oncology

Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD

Benjamin Watkins et al.

Summary: The study showed that adding abatacept to URD HCT was safe and effective in reducing AGVHD and improving SGFS. These results suggest that abatacept may have a significant positive impact on transplant outcomes related to AGVHD, particularly in HLA-mismatched HCT.

JOURNAL OF CLINICAL ONCOLOGY (2021)

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Article Cell & Tissue Engineering

Bach2 Deficiency Promotes Intestinal Epithelial Regeneration by Accelerating DNA Repair in Intestinal Stem Cells

Yuanchuang Li et al.

Summary: Bach2 deficiency promotes intestinal epithelial cell proliferation and accelerates DNA repair in intestinal stem cells after radiation damage.

STEM CELL REPORTS (2021)

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Article Hematology

Enhanced homology-directed repair for highly efficient gene editing in hematopoietic stem/progenitor cells

Suk See De Ravin et al.

Summary: Inhibition of p53-binding protein 1 (53BP1) significantly increased long-term homology-directed repair efficiency, leading to highly efficient long-term correction of X-CGD CD34(+) cells.

BLOOD (2021)

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Review Immunology

Gene Therapies for Primary Immune Deficiencies

Lisa A. Kohn et al.

Summary: Gene therapy is an innovative treatment for PIDs, showing clinical efficacy and safety profiles, especially with the use of SIN vectors. Recent advancements have made gene therapy equal or better than allogeneic HSCT, and further improvements in methods are expected to enhance the consistency and reliability of efficacy for a growing list of PIDs.

FRONTIERS IN IMMUNOLOGY (2021)

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Article Allergy

Inborn errors of immunity with atopic phenotypes: A practical guide for allergists

Riccardo Castagnoli et al.

Summary: Inborn errors of immunity (IEI) are a group of disorders caused by mutations in genes associated with immune regulation and defense, leading to various symptoms including recurrent infections, autoimmunity, inflammatory manifestations, lymphoproliferation, and malignancy. It is increasingly recognized that common allergic symptoms could also indicate underlying immunodeficiency and/or immune dysregulation.

WORLD ALLERGY ORGANIZATION JOURNAL (2021)

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Review Immunology

Comprehensive comparison between 222 CTLA-4 haploinsufficiency and 212 LRBA deficiency patients: a systematic review

M. Jamee et al.

Summary: CTLA-4 haploinsufficiency and LRBA deficiency are newly identified inborn errors of immunity with shared molecular pathomechanisms, however, they differ in clinical and immunological characteristics. Further investigations into treatment regimens are required to improve the survival rate of transplanted patients with CHAI and LATAIE.

CLINICAL AND EXPERIMENTAL IMMUNOLOGY (2021)

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Article Immunology

Regulation of CTLA-4 recycling by LRBA and Rab11

Daniel Janman et al.

Summary: CTLA-4 is distributed across different compartments marked by Rab GTPases, and manipulation of these GTPases affects its expression and trafficking. LRBA deficiency leads to ineffective recycling of CTLA-4 and degradation.

IMMUNOLOGY (2021)

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Review Biochemistry & Molecular Biology

Immune checkpoint deficiencies and autoimmune lymphoproliferative syndromes

Laura Gamez-Diaz et al.

Summary: Autoimmune lymphoproliferative syndrome (ALPS) is an inherited non-malignant and noninfectious lymphoproliferative syndrome caused by mutations affecting the extrinsic apoptotic pathway. ALPS-like syndromes, such as CTLA-4 insufficiency and LRBA deficiency, exhibit similar clinical symptoms, characterized by low levels of CTLA-4 protein on the surface of Treg cells leading to autoimmune manifestations. Despite differences in inheritance and penetrance, these immune checkpoint deficiencies share overlapping but heterogeneous clinical presentations.

BIOMEDICAL JOURNAL (2021)

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Article Endocrinology & Metabolism

Polymorphism in BACH2 gene is a marker of polyglandular autoimmunity

Marta Fichna et al.

Summary: The study revealed an association between BACH2 polymorphism and polyglandular autoimmunity, suggesting that specific variants could identify individuals prone to developing APS.

ENDOCRINE (2021)

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Article Allergy

Treatment with rapamycin can restore regulatory T-cell function in IPEX patients

Laura Passerini et al.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY (2020)

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Article Allergy

Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score

Victoria Katharina Tesch et al.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY (2020)

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Article Multidisciplinary Sciences

CRISPR-based gene editing enables FOXP3 gene repair in IPEX patient cells

M. Goodwin et al.

SCIENCE ADVANCES (2020)

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Article Immunology

Human interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance

Zinan Zhang et al.

JOURNAL OF EXPERIMENTAL MEDICINE (2019)

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Article Immunology

A novel human IL2RB mutation results in T and NK cell-driven immune dysregulation

Isabel Z. Fernandez et al.

JOURNAL OF EXPERIMENTAL MEDICINE (2019)

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Article Multidisciplinary Sciences

Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis

Nina K. Serwas et al.

NATURE COMMUNICATIONS (2019)

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Article Allergy

Abatacept as a Long-Term Targeted Therapy for LRBA Deficiency

Ayca Kiykim et al.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE (2019)

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Article Immunology

Bach2 Deficiency Leads to Spontaneous Expansion of IL-4-Producing T Follicular Helper Cells and Autoimmunity

Heng Zhang et al.

FRONTIERS IN IMMUNOLOGY (2019)

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Review Immunology

Primary immunodeficiencies caused by mutations in actin regulatory proteins

Erin Janssen et al.

IMMUNOLOGICAL REVIEWS (2019)

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Article Hematology

Dose-escalated interleukin-2 therapy for refractory chronic graft-versus-host disease in adults and children

Jennifer S. Whangbo et al.

BLOOD ADVANCES (2019)

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Article Allergy

Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects

Charlotte Schwab et al.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY (2018)

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Article Allergy

Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation

Fayhan J. Alroqi et al.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY (2018)

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Article Allergy

Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study

Federica Barzaghi et al.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY (2018)

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Article Cell Biology

Overview of the Cytoskeleton from an Evolutionary Perspective

Thomas D. Pollard et al.

COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY (2018)

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Review Immunology

T Follicular Helper Cells in Autoimmune Disorders

Noemie Gensous et al.

FRONTIERS IN IMMUNOLOGY (2018)

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Article Medicine, Research & Experimental

A Rapamycin-Based GMP-Compatible Process for the Isolation and Expansion of Regulatory T Cells for Clinical Trials

Henrieta Fraser et al.

MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT (2018)

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Article Immunology

Clinical, Immunological, and Molecular Heterogeneity of 173 Patients With the Phenotype of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome

Eleonora Gambineri et al.

FRONTIERS IN IMMUNOLOGY (2018)

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Article Medicine, Research & Experimental

DOCK8 enforces immunological tolerance by promoting IL-2 signaling and immune synapse formation in Tregs

Erin Janssen et al.

JCI INSIGHT (2017)

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Review Immunology

DOCK8 deficiency: Insights into pathophysiology, clinical features and management

Catherine M. Biggs et al.

CLINICAL IMMUNOLOGY (2017)

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Article Immunology

BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency

Behdad Afzali et al.

NATURE IMMUNOLOGY (2017)

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Article Medicine, Research & Experimental

A DOCK8-WIP-WASp complex links T cell receptors to the actin cytoskeleton

Erin Janssen et al.

JOURNAL OF CLINICAL INVESTIGATION (2016)

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Review Medicine, Research & Experimental

mTOR inhibitors effects on regulatory T cells and on dendritic cells

Giovanni Stallone et al.

JOURNAL OF TRANSLATIONAL MEDICINE (2016)

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Article Oncology

Monitoring regulatory T cells in clinical samples: consensus on an essential marker set and gating strategy for regulatory T cell analysis by flow cytometry

Saskia J. A. M. Santegoets et al.

CANCER IMMUNOLOGY IMMUNOTHERAPY (2015)

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Article Oncology

Wiskott-Aldrich syndrome/X-linked thrombocytopenia in China: Clinical characteristic and genotype-phenotype correlation

Da-Wei Liu et al.

PEDIATRIC BLOOD & CANCER (2015)

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Article Surgery

Superiority of Rapamycin Over Tacrolimus in Preserving Nonhuman Primate Treg Half-Life and Phenotype After Adoptive Transfer

K. Singh et al.

AMERICAN JOURNAL OF TRANSPLANTATION (2014)

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Article Immunology

Follicular bronchiolitis as phenotype associated with CD25 deficiency

L. Bezrodnik et al.

CLINICAL AND EXPERIMENTAL IMMUNOLOGY (2014)

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Article Immunology

Exacerbated experimental arthritis in Wiskott-Aldrich syndrome protein deficiency: Modulatory role of regulatory B cells

Gerben Bouma et al.

EUROPEAN JOURNAL OF IMMUNOLOGY (2014)

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Article Allergy

Dedicator of cytokinesis 8-deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells

Erin Janssen et al.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY (2014)

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Article Immunology

Bach2 Regulates Homeostasis of Foxp3+ Regulatory T Cells and Protects against Fatal Lung Disease in Mice

Eui Ho Kim et al.

JOURNAL OF IMMUNOLOGY (2014)

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Article Biochemistry & Molecular Biology

Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations

Desiree Schubert et al.

NATURE MEDICINE (2014)

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Article Multidisciplinary Sciences

Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4

Hye Sun Kuehn et al.

SCIENCE (2014)

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Article Immunology

Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity

Kevin Goudy et al.

CLINICAL IMMUNOLOGY (2013)

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Article Multidisciplinary Sciences

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes

Shin-ichi Tsukumo et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2013)

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Article Multidisciplinary Sciences

Forkhead Transcription Factor FOXP3 Upregulates CD25 Expression through Cooperation with RelA/NF-κB

Cristina Camperio et al.

PLOS ONE (2012)

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Review Immunology

Competition for IL-2 between regulatory and effector T cells to chisel immune responses

Thomas Hoefer et al.

FRONTIERS IN IMMUNOLOGY (2012)

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Article Immunology

Regulation of IL-2 gene expression by Siva and FOXP3 in human T cells

Virginia K. Hench et al.

BMC IMMUNOLOGY (2011)

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Article Allergy

Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome

Karin R. Engelhardt et al.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY (2009)

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Article Medicine, General & Internal

Combined Immunodeficiency Associated with DOCK8 Mutations

Qian Zhang et al.

NEW ENGLAND JOURNAL OF MEDICINE (2009)

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Article Immunology

CTLA4 expression is an indicator and regulator of steady-state CD4+FoxP3+ T cell homeostasis

Anita L. Tang et al.

JOURNAL OF IMMUNOLOGY (2008)

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Article Multidisciplinary Sciences

CTLA-4 control over Foxp3+ regulatory T cell function

Kajsa Wing et al.

SCIENCE (2008)

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Article Hematology

Nonredundant roles for Stat5a/b in directly regulating Foxp3

Zhengju Yao et al.

BLOOD (2007)

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Article Multidisciplinary Sciences

Foxp3-dependent programme of regulatory T-cell differentiation

Marc A. Gavin et al.

NATURE (2007)

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Article Medicine, Research & Experimental

Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis

Stephanie Humblet-Baron et al.

JOURNAL OF CLINICAL INVESTIGATION (2007)

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Article Biochemistry & Molecular Biology

Epigenetic control of the foxp3 locus in regulatory T cells

Stefan Floess et al.

PLOS BIOLOGY (2007)

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Article Allergy

CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes

Amy A. Caudy et al.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY (2007)

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Article Biochemistry & Molecular Biology

Identification of a DOCK180-related guanine nucleotide exchange factor that is capable of mediating a positive feedback activation of Cdc42

Qiong Lin et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2006)

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Article Immunology

Cutting edge:: Decreased accumulation and regulatory function of CD4+CD25high T cells in human STAT 5b deficiency

Aileen C. Cohen et al.

JOURNAL OF IMMUNOLOGY (2006)

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Article Immunology

Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells

Nabila Seddiki et al.

JOURNAL OF EXPERIMENTAL MEDICINE (2006)

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Review Immunology

Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution

RH Buckley

ANNUAL REVIEW OF IMMUNOLOGY (2004)

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Article Medicine, General & Internal

Growth hormone insensitivity associated with a STAT5b mutation

EM Kofoed et al.

NEW ENGLAND JOURNAL OF MEDICINE (2003)

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Review Rheumatology

Autoimmunity in Wiskott-Aldrich syndrome

SH Schurman et al.

CURRENT OPINION IN RHEUMATOLOGY (2003)

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Article Immunology

Interleukin 2 signaling is required for CD4+ regulatory T cell function

GC Furtado et al.

JOURNAL OF EXPERIMENTAL MEDICINE (2002)

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Article Genetics & Heredity

X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy

RS Wildin et al.

NATURE GENETICS (2001)

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Article Genetics & Heredity

The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3

CL Bennett et al.

NATURE GENETICS (2001)

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Article Medicine, Research & Experimental

JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome

TA Chatila et al.

JOURNAL OF CLINICAL INVESTIGATION (2000)

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Letter Pediatrics

Impaired interienkin-2 production in T-cells from a patient with Wiskott-Aldrich syndrome: basis of clinical effect of interleukin-2 replacement therapy

H Azuma et al.

EUROPEAN JOURNAL OF PEDIATRICS (2000)

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Review Biochemistry & Molecular Biology

The role of Stat5a and Stat5b in signaling by IL-2 family cytokines

JX Lin et al.

ONCOGENE (2000)

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Expanding IPEX: Inborn Errors of Regulatory T Cells

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