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Frontiers in Immunology 2023Hemophagocytic inflammatory syndrome (HIS) is a rare form of secondary hemophagocytic lymphohistiocytosis caused by an impaired equilibrium between natural killer and... (Review)
Review
Hemophagocytic inflammatory syndrome (HIS) is a rare form of secondary hemophagocytic lymphohistiocytosis caused by an impaired equilibrium between natural killer and cytotoxic T-cell activity, evolving in hypercytokinemia and multiorgan failure. In the context of inborn errors of immunity, HIS occurrence has been reported in severe combined immunodeficiency (SCID) patients, including two cases of adenosine deaminase deficient-SCID (ADA-SCID). Here we describe two additional pediatric cases of ADA-SCID patients who developed HIS. In the first case, HIS was triggered by infectious complications while the patient was on enzyme replacement therapy; the patient was treated with high-dose corticosteroids and intravenous immunoglobulins with HIS remission. However, the patient required HLA-identical sibling donor hematopoietic stem cell transplantation (HSCT) for a definitive cure of ADA-SCID, without HIS relapse up to 13 years after HSCT. The second patient presented HIS 2 years after hematopoietic stem cell gene therapy (GT), secondarily to Varicella-Zoster vaccination and despite and lymphocytes' reconstitution in line with other ADA SCID patients treated with GT. The child responded to trilinear immunosuppressive therapy (corticosteroids, Cyclosporine A, Anakinra). We observed the persistence of gene-corrected cells up to 5 years post-GT, without HIS relapse. These new cases of children with HIS, together with those reported in the literature, support the hypothesis that a major dysregulation in the immune system can occur in ADA-SCID patients. Our cases show that early identification of the disease is imperative and that a variable degree of immunosuppression could be an effective treatment while allogeneic HSCT is required only in cases of refractoriness. A deeper knowledge of immunologic patterns contributing to HIS pathogenesis in ADA-SCID patients is desirable, to identify new targeted treatments and ensure patients' long-term recovery.
Topics: Humans; Child; Lymphohistiocytosis, Hemophagocytic; Severe Combined Immunodeficiency; Agammaglobulinemia; Cyclosporine
PubMed: 37435083
DOI: 10.3389/fimmu.2023.1187959 -
The Journal of Allergy and Clinical... Apr 2014The approach to the diagnosis of severe combined immunodeficiency disease (SCID) and related disorders varies among institutions and countries.
Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience.
BACKGROUND
The approach to the diagnosis of severe combined immunodeficiency disease (SCID) and related disorders varies among institutions and countries.
OBJECTIVES
The Primary Immune Deficiency Treatment Consortium attempted to develop a uniform set of criteria for diagnosing SCID and related disorders and has evaluated the results as part of a retrospective study of SCID in North America.
METHODS
Clinical records from 2000 through 2009 at 27 centers in North America were collected on 332 children treated with hematopoietic stem cell transplantation (HCT), enzyme replacement therapy, or gene therapy for SCID and related disorders. Eligibility for inclusion in the study and classification into disease groups were established by using set criteria and applied by an expert review group.
RESULTS
Two hundred eighty-five (86%) of the patients were determined to be eligible, and 47 (14%) were not eligible. Of the 285 eligible patients, 84% were classified as having typical SCID; 13% were classified as having leaky SCID, Omenn syndrome, or reticular dysgenesis; and 3% had a history of enzyme replacement or gene therapy. Detection of a genotype predicting an SCID phenotype was accepted for eligibility. Reasons for noneligibility were failure to demonstrate either impaired lymphocyte proliferation or maternal T-cell engraftment. Overall (n = 332) rates of testing were as follows: proliferation to PHA, 77%; maternal engraftment, 35%; and genotype, 79% (mutation identified in 62%).
CONCLUSION
Lack of complete laboratory evaluation of patients before HCT presents a significant barrier to definitive diagnosis of SCID and related disorders and prevented inclusion of subjects in our observational HCT study. This lesson is critical for patient care, as well as the design of future prospective treatment studies for such children because a well-defined and consistent study population is important for precision in outcomes analysis.
Topics: Humans; Immunologic Deficiency Syndromes; North America; Practice Guidelines as Topic; Retrospective Studies; Severe Combined Immunodeficiency
PubMed: 24290292
DOI: 10.1016/j.jaci.2013.09.044 -
Blood Jul 2009Thymocytes and thymic epithelial cell (TEC) cross-talk is crucial to preserve thymic architecture and function, including maturation of TECs and dendritic cells, and...
Early defects in human T-cell development severely affect distribution and maturation of thymic stromal cells: possible implications for the pathophysiology of Omenn syndrome.
Thymocytes and thymic epithelial cell (TEC) cross-talk is crucial to preserve thymic architecture and function, including maturation of TECs and dendritic cells, and induction of mechanisms of central tolerance. We have analyzed thymic maturation and organization in 9 infants with various genetic defects leading to complete or partial block in T-cell development. Profound abnormalities of TEC differentiation (with lack of AIRE expression) and severe reduction of thymic dendritic cells were identified in patients with T-negative severe combined immunodeficiency, reticular dysgenesis, and Omenn syndrome. The latter also showed virtual absence of thymic Foxp3(+) T cells. In contrast, an IL2RG-R222C hypomorphic mutation permissive for T-cell development allowed for TEC maturation, AIRE expression, and Foxp3(+) T cells. Our data provide evidence that severe defects of thymopoiesis impinge on TEC homeostasis and may affect deletional and nondeletional mechanisms of central tolerance, thus favoring immune dysreactive manifestations, as in Omenn syndrome.
Topics: Cell Differentiation; DNA-Binding Proteins; Dendritic Cells; Forkhead Transcription Factors; Humans; Infant; Interleukin Receptor Common gamma Subunit; Lymphopenia; Mutation; Nuclear Proteins; Severe Combined Immunodeficiency; Stromal Cells; T-Lymphocytes; T-Lymphocytes, Regulatory; Thymus Gland; Transcription Factors; AIRE Protein
PubMed: 19414857
DOI: 10.1182/blood-2009-03-211029 -
The Journal of Allergy and Clinical... Oct 2022
Topics: Humans; Infant, Newborn; Israel; Lymphopenia; Neonatal Screening; Severe Combined Immunodeficiency
PubMed: 36216463
DOI: 10.1016/j.jaip.2022.08.014 -
The Journal of Allergy and Clinical... Sep 2023Inborn errors affecting components of the T-cell receptor signaling cascade cause combined immunodeficiency with various degrees of severity. Recently, homozygous...
BACKGROUND
Inborn errors affecting components of the T-cell receptor signaling cascade cause combined immunodeficiency with various degrees of severity. Recently, homozygous variants in LCP2 were reported to cause pediatric onset of severe combined immunodeficiency with neutrophil, platelet, and T- and B-cell defects.
OBJECTIVE
We sought to unravel the genetic cause of combined immunodeficiency and early-onset immune dysregulation in a 26-year-old man who presented with specific antibody deficiency, autoimmunity, and inflammatory bowel disease since early childhood.
METHODS
The patient was subjected to whole-exome sequencing of genomic DNA and examination of blood neutrophils, platelets, and T and B cells. Expression levels of the Src homology domain 2-containing leukocyte protein of 76 kDa (SLP76) and tonic and ligand-induced PI3K signaling were evaluated by flow-cytometric detection of phosphorylated ribosomal protein S6 in B and T cells.
RESULTS
Compound heterozygous missense variants were identified in LCP2, affecting the proline-rich repeat domain of SLP76 (p.P190R and p.R204W). The patient's total B- and T-cell numbers were within the normal range, as was platelet function. However, neutrophil function, numbers of unswitched and class-switched memory B cells, and serum IgA were decreased. Moreover, intracellular SLP76 protein levels were reduced in the patient's B cells, CD4 and CD8 T cells, and natural killer cells. Tonic and ligand-induced levels of phosphorylated ribosomal protein S6 and ligand-induced phosphorylated PLCγ1 were decreased in the patient's B cells and CD4 and CD8 T cells.
CONCLUSIONS
Biallelic variants in LCP2 impair neutrophil function and T-cell and B-cell antigen-receptor signaling and can cause combined immunodeficiency with early-onset immune dysregulation, even in the absence of platelet defects.
Topics: Male; Child; Humans; Child, Preschool; Adult; Phosphatidylinositol 3-Kinases; CD8-Positive T-Lymphocytes; Ligands; Ribosomal Protein S6; Signal Transduction; Severe Combined Immunodeficiency; Mutation
PubMed: 37211057
DOI: 10.1016/j.jaci.2023.04.020 -
Molecular Therapy : the Journal of the... May 2017Prior to the first successful bone marrow transplant in 1968, patients born with severe combined immunodeficiency (SCID) invariably died. Today, with a widening... (Review)
Review
Prior to the first successful bone marrow transplant in 1968, patients born with severe combined immunodeficiency (SCID) invariably died. Today, with a widening availability of newborn screening, major improvements in the application of allogeneic procedures, and the emergence of successful hematopoietic stem and progenitor cell (HSC/P) gene therapy, the majority of these children can be identified and cured. Here, we trace key steps in the development of clinical gene therapy for SCID and other primary immunodeficiencies (PIDs), and review the prospects for adoption of new targets and technologies.
Topics: Adenosine Deaminase; Clinical Trials as Topic; Gammaretrovirus; Gene Expression; Genetic Therapy; Genetic Vectors; Hematopoietic Stem Cell Transplantation; History, 20th Century; History, 21st Century; Humans; Immunologic Deficiency Syndromes; Lentivirus; Severe Combined Immunodeficiency; Transplantation, Homologous
PubMed: 28366768
DOI: 10.1016/j.ymthe.2017.03.018 -
Nihon Rinsho Men'eki Gakkai Kaishi =... 2017Severe combined immunodeficiency (SCID) is impaired in lymphocyte development and function. Affected children have extreme susceptibility to infections, which are fatal... (Review)
Review
Severe combined immunodeficiency (SCID) is impaired in lymphocyte development and function. Affected children have extreme susceptibility to infections, which are fatal in the first year of life without treatment. The estimate of incidence is one in approximately 50,000 live birth. The first series of diseases were described in 1950s, and all patients died in infancy. The first transplant for SCID was carried out in 1968, and it has been described that SCID patients could be treated by hematopoietic stem cell transplantation (HSCT) since then. Adenosine deaminase and common gamma chain were identified to be causative genes for SCID in 1972 and 1993, respectively. SCID arises from a variety of genetic defects. The early intervention of healthy SCID infants without infections affords higher survival rate, and newborn screening (NBS) was suggested. T-cell receptor (TCR) exicision circles (TRECs) are circular DNA formed from the leftover fragment generated from the TCR rearrangement. TRECs can be measured from a small aliquot of DNA such as Guthrie card by quantitative PCR. SCID patients lack TRECs, and TRECs quantification is useful for NBS for SCID. NBS for SCID have been already carried out in most of the Unite States, and the early introduction is desired in Japan to save SCID children.
Topics: Adenosine Deaminase; Child; Child, Preschool; DNA, Circular; Disease Susceptibility; Gene Rearrangement; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Infant; Infant, Newborn; Lymphocytes; Mass Screening; Mutation; Receptors, Antigen, T-Cell; Severe Combined Immunodeficiency
PubMed: 28747600
DOI: 10.2177/jsci.40.145 -
Gut Microbes Nov 2016Hypomorphic Rag mutations in humans cause Omenn Syndrome (OS) a severe immunodeficiency associated with autoimmune-like manifestations mediated by oligoclonal activated...
Hypomorphic Rag mutations in humans cause Omenn Syndrome (OS) a severe immunodeficiency associated with autoimmune-like manifestations mediated by oligoclonal activated T and B cells. The clinical and immunological spectrum of OS presentation is extremely broad. However, the role played by environmental triggers in the disease pathogenesis remains largely unknown. We have recently shown in a murine model that gut microbiota has a substantial role in determining the distinctive immune dysregulation of OS. Here, we describe how dysbiosis and loss of T cell tolerance to commensals influence the expression of autoimmunity at the barrier site and beyond, and the disease hallmark hyper-IgE. We discuss how commensal antigens and gut-derived pathogenic T cells could potentially modulate skin immunity to determine cutaneous degenerations in OS. These mechanisms may have broader implications for a deeper understanding of the role of gut microbes in influencing barriers integrity and host physiology.
Topics: Animals; Autoimmunity; B-Lymphocytes; DNA-Binding Proteins; Homeodomain Proteins; Humans; Immunoglobulin E; Severe Combined Immunodeficiency; T-Lymphocytes
PubMed: 27575988
DOI: 10.1080/19490976.2016.1228517 -
British Journal of Haematology Mar 2018Reticular Dysgenesis is a rare immunodeficiency which is clinically characterized by the combination of Severe Combined Immunodeficiency (SCID) with agranulocytosis and... (Review)
Review
Reticular Dysgenesis is a rare immunodeficiency which is clinically characterized by the combination of Severe Combined Immunodeficiency (SCID) with agranulocytosis and sensorineural deafness. Mutations in the gene encoding adenylate kinase 2 (AK2) were identified to cause this phenotype. In this review, we will demonstrate important clinical differences between reticular dysgenesis and other SCID entities and summarize recent concepts in the understanding of the pathophysiology of the disease and the management strategies for this difficult condition.
Topics: Adenylate Kinase; Animals; Disease Models, Animal; Hearing Loss, Sensorineural; Humans; Immunologic Deficiency Syndromes; Leukopenia; Mutation; Severe Combined Immunodeficiency
PubMed: 29270983
DOI: 10.1111/bjh.15045 -
The Journal of Clinical Investigation Apr 2010Rag2 plays an essential role in the generation of antigen receptors. Mutations that impair Rag2 function can lead to severe combined immunodeficiency (SCID), a condition...
Rag2 plays an essential role in the generation of antigen receptors. Mutations that impair Rag2 function can lead to severe combined immunodeficiency (SCID), a condition characterized by complete absence of T and B cells, or Omenn syndrome (OS), a form of SCID characterized by the virtual absence of B cells and the presence of oligoclonal autoreactive T cells. Here, we present a comparative study of a panel of mutations that were identified in the noncanonical plant homeodomain (PHD) of Rag2 in patients with SCID or OS. We show that PHD mutant mouse Rag2 proteins that correspond to those found in these patients greatly impaired endogenous recombination of Ig gene segments in a Rag2-deficient pro-B cell line and that this correlated with decreased protein stability, impaired nuclear localization, and/or loss of the interaction between Rag2 and core histones. Our results demonstrate that point mutations in the PHD of Rag2 compromise the functionality of the entire protein, thus explaining why the phenotype of cells expressing PHD point mutants differs from those expressing core Rag2 protein that lacks the entire C-terminal region and is therefore devoid of the regulation imposed by the PHD. Together, our findings reveal the various deleterious effects of PHD Rag2 mutations and demonstrate the crucial role of this domain in regulating antigen receptor gene assembly. We believe these results reveal new mechanisms of immunodeficiency in SCID and OS.
Topics: Animals; Cells, Cultured; DNA-Binding Proteins; Gene Rearrangement, B-Lymphocyte; Gene Rearrangement, T-Lymphocyte; Homeodomain Proteins; Humans; Mice; Mice, SCID; Mutation; Nuclear Proteins; Protein Structure, Tertiary; Recombination, Genetic; Severe Combined Immunodeficiency; VDJ Recombinases
PubMed: 20234091
DOI: 10.1172/JCI41305