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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 -
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 -
The Journal of Allergy and Clinical... Nov 2020Severe early-onset erythroderma and gut inflammation, with massive tissue infiltration of oligoclonal activated T cells are the hallmark of Omenn syndrome (OS).
BACKGROUND
Severe early-onset erythroderma and gut inflammation, with massive tissue infiltration of oligoclonal activated T cells are the hallmark of Omenn syndrome (OS).
OBJECTIVE
The impact of altered gut homeostasis in the cutaneous manifestations of OS remains to be clarified.
METHODS
We analyzed a cohort of 15 patients with OS and the 129Sv/C57BL/6 knock-in Rag2 (Rag2) mouse model. Homing phenotypes of circulating lymphocytes were analyzed by flow cytometry. Inflammatory cytokines and chemokines were examined in the sera by ELISA and in skin biopsies by immunohistochemistry and in situ RNA hybridization. Experimental colitis was induced in mice by dextran sulfate sodium salt.
RESULTS
We show that memory/activated T cells from patients with OS and from the Rag2 mouse model of OS abundantly express the skin homing receptors cutaneous lymphocyte associated antigen and CCR4 (Ccr4), associated with high levels of chemokine C-C motif ligands 17 and 22. Serum levels of LPS are also elevated. A broad T1/T2/T17 inflammatory signature is detected in the periphery and in the skin. Increased Tlr4 expression in the skin of Rag2 mice is associated with enhanced cutaneous inflammation on local and systemic administration of LPS. Likewise, boosting colitis in Rag2 mice results in increased frequency of Ccr4 splenic T cells and worsening of skin inflammation, as indicated by epidermal thickening, enhanced epithelial cell activation, and dermal infiltration by T1 effector T cells.
CONCLUSIONS
These results support the existence of an interplay between gut and skin that can sustain skin inflammation in OS.
Topics: Animals; Cohort Studies; DNA-Binding Proteins; Dermatitis; Disease Models, Animal; Gastrointestinal Microbiome; Humans; Inflammation; Intestines; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Receptors, CCR4; Severe Combined Immunodeficiency; Skin; Th1 Cells; Tight Junctions
PubMed: 32311393
DOI: 10.1016/j.jaci.2020.04.005 -
Frontiers in Immunology 2020Genetic defects in recombination activating genes (RAG) 1 and 2 cause a broad spectrum of severe immune defects ranging from early severe and repeated infections to... (Review)
Review
Genetic defects in recombination activating genes (RAG) 1 and 2 cause a broad spectrum of severe immune defects ranging from early severe and repeated infections to inflammation and autoimmune manifestations. A correlation between recombination activity and immune phenotype has been described. Hematopoietic cell transplantation is the treatment of care; however, the availability of next generation sequencing and whole genome sequencing has allowed the identification of novel genetic RAG variants in immunodeficient patients at various ages, raising therapeutic questions. This review addresses the recent advances of novel therapeutic approaches for RAG deficiency. As conventional myeloablative conditioning regimens are associated with acute toxicities and transplanted-related mortality, innovative minimal conditioning regimens based on the use of monoclonal antibodies are now emerging and show promising results. To overcome shortage of compatible donors, gene therapy has been developed in various RAG preclinical models. Overall, the transplantation of autologous gene corrected hematopoietic precursors and the use of non-genotoxic conditioning will open a new era, offering a cure to an increasing number of RAG patients regardless of donor availability and severity of clinical conditions.
Topics: Animals; Antibodies, Monoclonal; DNA-Binding Proteins; Diffusion of Innovation; Genetic Predisposition to Disease; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Homeodomain Proteins; Humans; Immunocompromised Host; Nuclear Proteins; Phenotype; Severe Combined Immunodeficiency; Transplantation Conditioning
PubMed: 33329604
DOI: 10.3389/fimmu.2020.607926 -
Italian Journal of Pediatrics Nov 2010Human SCID (Severe Combined Immunodeficiency) is a prenatal disorder of T lymphocyte development, that depends on the expression of numerous genes. The knowledge of the... (Review)
Review
Human SCID (Severe Combined Immunodeficiency) is a prenatal disorder of T lymphocyte development, that depends on the expression of numerous genes. The knowledge of the genetic basis of SCID is essential for diagnosis (e.g., clinical phenotype, lymphocyte profile) and treatment (e.g., use and type of pre-hematopoietic stem cell transplant conditioning).Over the last years novel genetic defects causing SCID have been discovered, and the molecular and immunological mechanisms of SCID have been better characterized. Distinct forms of SCID show both common and peculiar (e.g., absence or presence of nonimmunological features) aspects, and they are currently classified into six groups according to prevalent pathophysiological mechanisms: impaired cytokine-mediated signaling; pre-T cell receptor defects; increased lymphocyte apoptosis; defects in thymus embryogenesis; impaired calcium flux; other mechanisms.This review is the updated, extended and largely modified translation of the article "Cossu F: Le basi genetiche delle SCID", originally published in Italian language in the journal "Prospettive in Pediatria" 2009, 156:228-238.
Topics: Genetic Therapy; Genotype; Hematopoietic Stem Cell Transplantation; Humans; Infant, Newborn; Neonatal Screening; Severe Combined Immunodeficiency; T-Lymphocytes
PubMed: 21078154
DOI: 10.1186/1824-7288-36-76 -
Allergology International : Official... Jun 2006Omenn syndrome (OS) is a form of severe combined immunodeficiency (SCID) characterized by erythrodermia, hepatosplenomegaly, lymphadenopathy, and alopecia. In patients... (Review)
Review
Omenn syndrome (OS) is a form of severe combined immunodeficiency (SCID) characterized by erythrodermia, hepatosplenomegaly, lymphadenopathy, and alopecia. In patients with OS, B cells are mostly absent, T-cell counts are normal to elevated, and T cells are frequently activated and express a restricted T-cell receptor (TCR) repertoire. Thus far, inherited hypomorphic mutations of the recombination activating genes either 1 or 2 (RAG1/2) have been detected in most OS patients. We have recently experienced a rare case of OS showing the revertant mosaicism due to multiple second-site mutations leading to typical OS clinical features with RAG1-deficient SCID. In this review, we will focus on the variation of several phenotypes of OS.
Topics: DNA-Binding Proteins; Genetic Diseases, Inborn; Genetic Variation; Homeodomain Proteins; Humans; Japan; Mutation; Nuclear Proteins; Phenotype; Severe Combined Immunodeficiency; White People
PubMed: 17075247
DOI: 10.2332/allergolint.55.115 -
Orphanet Journal of Rare Diseases Jan 2017Nude severe combined immunodeficiency is a rare inherited disease caused by autosomal recessive loss-of-function mutations in FOXN1. This gene encodes a transcription... (Review)
Review
Nude severe combined immunodeficiency is a rare inherited disease caused by autosomal recessive loss-of-function mutations in FOXN1. This gene encodes a transcription factor essential for the development of the thymus, the primary lymphoid organ that supports T-cell development and selection. To date nine cases have been reported presenting with the clinical triad of absent thymus resulting in severe T-cell immunodeficiency, congenital alopecia universalis and nail dystrophy. Diagnosis relies on testing for FOXN1 mutations, which allows genetic counselling and guides therapeutic management. Options for treating the underlying immune deficiency include HLA-matched genoidentical haematopoietic cell transplantation containing mature donor T-cells or thymus tissue transplantation. Experience from other severe combined immune deficiency syndromes suggests that early diagnosis, supportive care and definitive management result in better patient outcomes. Without these the prognosis is poor due to early-onset life threatening infections.
Topics: Alopecia; Animals; Forkhead Transcription Factors; Mice, Nude; Mice, SCID; Mutation; Receptors, Interleukin-7; Severe Combined Immunodeficiency; T-Lymphocytes
PubMed: 28077132
DOI: 10.1186/s13023-016-0557-1 -
Pediatric Annals Nov 2023
Topics: Infant, Newborn; Humans; Severe Combined Immunodeficiency; Immunologic Deficiency Syndromes; Neonatal Screening
PubMed: 37935399
DOI: 10.3928/19382359-20231004-01 -
Immunity Apr 2003The type II bare lymphocyte syndrome (BLS) or major histocompatibility complex class II (MHCII) deficiency is a severe combined immunodeficiency (SCID) that is... (Review)
Review
The type II bare lymphocyte syndrome (BLS) or major histocompatibility complex class II (MHCII) deficiency is a severe combined immunodeficiency (SCID) that is characterized by the absence of constitutive and inducible expression of MHCII determinants on immune cells. Four complementation groups of BLS have been defined, and they result from mutations in DNA-bound activators and the coactivator for MHCII transcription. Recently, all complementation groups of BLS patients have been accounted for. Studies of the syndrome and specific mutations reveal important lessons for the genetics of the immune response.
Topics: Ankyrin Repeat; DNA-Binding Proteins; Enhancer Elements, Genetic; Genes, MHC Class II; Histocompatibility Antigens Class II; Humans; Mutation; Severe Combined Immunodeficiency; Transcription Factors; Transcription, Genetic
PubMed: 12705848
DOI: 10.1016/s1074-7613(03)00086-4 -
BMC Medical Genetics Nov 2009Children with Severe Combined Immunodeficiency (SCID) lack autologous T lymphocytes and present with multiple infections early in infancy. Omenn syndrome is...
BACKGROUND
Children with Severe Combined Immunodeficiency (SCID) lack autologous T lymphocytes and present with multiple infections early in infancy. Omenn syndrome is characterized by the sole emergence of oligoclonal auto-reactive T lymphocytes, resulting in erythroderma and enteropathy. Omenn syndrome (OS) shares the genetic aetiology of T-B-NK+ SCID, with mutations in RAG1, RAG2, or DCLRE1C.
METHODS
Patients diagnosed with T-B-NK+ SCID or phenotypes suggestive of Omenn syndrome were investigated by molecular genetic studies using gene tightly linked microsatellite markers followed by direct sequencing of the coding regions and splice sites of the respective candidate genes.
RESULTS
We report the molecular genetic basis of T-B-NK+ SCID in 22 patients and of OS in seven patients all of Arab descent from Saudi Arabia. Among the SCID patients, six (from four families) displayed four homozygous missense mutations in RAG1 including V433M, R624H, R394W, and R559S. Another four patients (from three familes) showed 3 novel homozygous RAG2 mutations including K127X, S18X, and Q4X; all of which predict unique premature truncations of RAG2 protein. Among Omenn patients, four (from two families) have S401P and R396H mutations in RAG1, and a fifth patient has a novel I444M mutation in RAG2. Seven other patients (six SCID and one OS) showed a gross deletion in exons 1-3 in DCLRE1C. Altogether, mutations in RAG1/2 and DCLRE1C account for around 50% and 25%, respectively, in our study cohort, a proportion much higher than in previous reported series. Seven (24%) patients lack a known genetic aetiology, strongly suggesting that they carry mutations in novel genes associated with SCID and Omenn disorders that are yet to be discovered in the Saudi population.
CONCLUSION
Mutation-free patients who lack a known genetic aetiology are likely to carry mutations in the regulatory elements in the SCID-causing genes or in novel genes that are yet to be discovered. Our efforts are underway to investigate this possibility by applying the whole genome scans on these cases via the use of Affymetrix high density DNA SNP chips in addition to homozygosity mapping.
Topics: B-Lymphocytes; Cohort Studies; Genotype; Homozygote; Humans; Infant; Killer Cells, Natural; Microsatellite Repeats; Mutation; Saudi Arabia; Sequence Analysis, DNA; Severe Combined Immunodeficiency; Syndrome; T-Lymphocytes; VDJ Recombinases
PubMed: 19912631
DOI: 10.1186/1471-2350-10-116