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Rebecca H. Buckley - One of the best experts on this subject based on the ideXlab platform.

  • the genetic landscape of severe Combined Immunodeficiency in the united states and canada in the current era 2010 2018
    The Journal of Allergy and Clinical Immunology, 2019
    Co-Authors: Christopher C Dvorak, Morton J. Cowan, Donald B Kohn, Luigi D. Notarangelo, Rebecca H. Buckley, Sungyun Pai, Brent R Logan, Linda M Griffith, Elie Haddad, William T Shearer
    Abstract:

    In a 250 patient cohort from the US and Canada in the current era (2010–2018), we show that over 90% of patients with severe Combined Immunodeficiency (SCID) can be genetically-characterized.

  • transplantation outcomes for severe Combined Immunodeficiency 2000 2009
    The New England Journal of Medicine, 2014
    Co-Authors: Sungyun Pai, Neena Kapoor, Roberta E Parrott, Rebecca H. Buckley, Christopher C Dvorak, Brent R Logan, Linda M Griffith, Imelda C Hanson, Alexandra H Filipovich, Soma Jyonouchi
    Abstract:

    Background The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe Combined Immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth. Methods We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009). Results Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infect...

  • the long quest for neonatal screening for severe Combined Immunodeficiency
    The Journal of Allergy and Clinical Immunology, 2012
    Co-Authors: Rebecca H. Buckley
    Abstract:

    Early recognition of severe Combined Immunodeficiency (SCID) is a pediatric emergency because a diagnosis before live vaccines or nonirradiated blood products are given and before development of infections permits lifesaving unfractionated HLA-identical or T cell–depleted haploidentical hematopoietic stem cell transplantation, enzyme replacement therapy, or gene therapy. The need for newborn screening for this condition has been recognized for the past 15 years. However, implementation of screening required development of an assay for T-cell lymphopenia that could be performed on dried bloodspots routinely collected from newborn infants for the past 48 years. This was accomplished 6 years ago, and there have already been 7 successful pilot studies. A recommendation to add SCID to the routine newborn-screening panel was approved by the Secretary's Advisory Committee on Heritable Disorders of Newborns and Children in 2010 and was soon after approved by the Secretary of Health and Human Services. It is important for allergists, immunologists, and other health care providers to take an active role in promoting newborn screening for SCID and other T-lymphocyte abnormalities in their states. Even more important will be their roles in establishing accurate diagnoses for infants with positive screen results and in ensuring that they are given the best possible treatment.

  • Transplantation of hematopoietic stem cells in human severe Combined Immunodeficiency: longterm outcomes
    Immunologic Research, 2011
    Co-Authors: Rebecca H. Buckley
    Abstract:

    Severe Combined Immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T- and B-cell function and, in some types, also of NK cells and function. Mutations in thirteen different genes have been found to cause this condition, which is uniformly fatal in the first 2 years of life unless immune reconstitution can be accomplished. In the 42 years since the first bone marrow transplant was given in 1968, the standard treatment for all forms of SCID has been allogeneic bone marrow transplantation. Both HLA-identical unfractionated and T-cell-depleted HLA-haploidentical bone marrow transplants have been very successful in effecting immune reconstitution, especially if performed in the first 3.5 months of life and without pre-transplant chemotherapy. This paper summarizes the longterm outcome, according to molecular type, of 166 consecutive SCID infants given non-conditioned related donor bone marrow transplants at this institution over the past 28.3 years and reviews published reports of longterm outcomes of transplants in SCID performed at other centers.

  • thymic function after hematopoietic stem cell transplantation for the treatment of severe Combined Immunodeficiency
    The New England Journal of Medicine, 2000
    Co-Authors: Dhavalkumar D Patel, Roberta E Parrott, Maria E Gooding, Kimberly M Curtis, Barton F Haynes, Rebecca H. Buckley
    Abstract:

    Background Immune function can be restored in infants with severe Combined Immunodeficiency by transplantation of unfractionated bone marrow from HLA-identical donors or T-cell–depleted marrow stem cells from haploidentical donors, with whom there is a single haplotype mismatch, without the need for chemotherapy before transplantation or prophylaxis against graft-versus-host disease. The role of the thymus in this process is unknown. Methods We analyzed the phenotypes of circulating T cells and the proliferative responses of peripheral-blood mononuclear cells to phytohemagglutinin in 83 patients with severe Combined Immunodeficiency who received allogeneic marrow transplants without T-cell ablation from related donors over an 18-year period. We also tested for the presence of episomes of T-cell antigen receptors (extrachromosomal DNA circles formed during intrathymic T-cell development) to assess thymus-dependent T-cell reconstitution. Results Before and early after transplantation, the numbers of circula...

Jennifer M. Puck - One of the best experts on this subject based on the ideXlab platform.

  • newborn screening for severe Combined Immunodeficiency and t cell lymphopenia
    Immunological Reviews, 2019
    Co-Authors: Jennifer M. Puck
    Abstract:

    : The development of a T cell receptor excision circle (TREC) assay utilizing dried blood spots (DBS) made possible universal newborn screening (NBS) for severe Combined Immunodeficiency (SCID) as a public health measure. Upon being flagged by an abnormal screening test in a SCID screening program, an infant can receive further diagnostic testing for SCID in the neonatal period, prior to onset of infectious complications, to permit immediate institution of protective measures and definitive, life-saving treatment to establish a functional immune system. SCID screening is now the accepted standard of care in state public health departments across the United States, and it is being adopted in many countries. It has proven effective, with infants having this otherwise inapparent but serious, rare disorder achieving survival and immune reconstitution. In addition to bringing to attention infants with the primary screening target diseases, typical SCID and leaky SCID (due to hypomorphic mutations in known SCID genes), the NBS assay for insufficient TRECs in DBS also reveals infants with non-SCID T lymphopenic conditions. Experience has accumulated regarding the range and limitations of diagnoses of newborns with low TRECs and low T cells. Previously unknown immune defects have been discovered, as well as conditions not formerly recognized to have low T cells in the neonatal period.

  • history and current status of newborn screening for severe Combined Immunodeficiency
    Seminars in Perinatology, 2015
    Co-Authors: Antonia Kwan, Jennifer M. Puck
    Abstract:

    The development of a T-cell receptor excision circle (TREC) assay utilizing dried blood spots in universal newborn screening has allowed the early detection of T-cell lymphopenia in newborns. Diagnosis of severe Combined Immunodeficiency (SCID) in affected infants in the neonatal period, while asymptomatic, permits early treatment and restoration of a functional immune system. SCID was the first Immunodeficiency disease to be added to the Recommended Uniform Screening Panel of Core Conditions in the United States in 2010, and it is now implemented in 26 states in the U.S. This review covers the development of newborn screening for SCID, the biology of the TREC test, its current implementation in the U.S., new findings for SCID in the newborn screening era, and future directions.

  • Neonatal screening for severe Combined Immunodeficiency.
    Current opinion in pediatrics, 2011
    Co-Authors: Jennifer M. Puck
    Abstract:

    Purpose of reviewPopulation-based newborn screening for severe Combined Immunodeficiency (SCID) and related disorders has been instituted in five states, with several more planning to add this testing to their newborn screening panels. This review summarizes the rationale, development and implementa

  • early vs delayed diagnosis of severe Combined Immunodeficiency a family perspective survey
    Clinical Immunology, 2011
    Co-Authors: Alice Y. Chan, Christopher Scalchunes, Marcia Boyle, Jennifer M. Puck
    Abstract:

    Infants affected with severe Combined Immunodeficiency (SCID) are susceptible to severe and recurrent infections and do not survive unless provided with immune reconstituting treatments. In the absence of population-based newborn screening, infants with SCID who do not have an affected older relative are ascertained only after they have developed infections. However, only limited data are available from the perspective of patients and families to indicate what proportion of SCID cases might benefit from earlier detection by pre-symptomatic screening, whether adequate treatment facilities are available, and how screening could improve SCID treatment outcomes. A survey of parents of children with SCID evaluated family history, pre- and post-diagnosis events, outcomes, and impact of SCID on families. Affected infants diagnosed with SCID as neonates had better survival, demonstrating the potential benefit of universal newborn screening.

  • development of population based newborn screening for severe Combined Immunodeficiency
    The Journal of Allergy and Clinical Immunology, 2005
    Co-Authors: K Chan, Jennifer M. Puck
    Abstract:

    Background Severe Combined Immunodeficiency (SCID) is a treatable, inherited lack of cellular and humoral immunity caused by diverse mutations in several different genes and leading to death in infancy unless immune reconstitution is provided. Currently no population screening exists for SCID, but early diagnosis would improve outcome. Objective Because all patients with SCID make few or no T cells, we asked whether the absence of T-cell receptor excision circles (TRECs), DNA episomes in newly formed T cells, could identify SCID regardless of genotype. Methods DNA isolated from dried blood spots was assayed by real-time PCR to quantitate TRECs. Control PCR was performed on a segment of the β-actin gene. After pilot studies with adult and cord blood control subjects, blood from SCID patients was spotted onto filters and tested, followed by screening of actual blood spots from the Maryland Newborn Screening Program. Finally, newborn blood spots were recovered and tested from 2 infants after their diagnosis of SCID. Results In contrast to filters from the newborn screening program, which had a mean of 1020 TRECs in two 3-mm punches, samples from 23 infants with SCID had Conclusion TRECs are a stable analyte that can identify T-cell lymphopenia in newborn dried blood spots so that infants with SCID can receive early, life-saving treatment.

Chaim M. Roifman - One of the best experts on this subject based on the ideXlab platform.

  • Fatal Combined Immunodeficiency associated with heterozygous mutation in STAT1
    The Journal of allergy and clinical immunology, 2013
    Co-Authors: Nigel Sharfe, Amit Nahum, Andrea Newell, Harjit Dadi, Bo Ngan, Sergio L. Pereira, Jo-anne Herbrick, Chaim M. Roifman
    Abstract:

    Background Mutations in the gene for the signal transducer and activator of transcription 1, STAT1, have been shown to be associated with death at an early age due to overwhelming viral infection (complete STAT1 deficiency) or, more commonly, selective deficiencies to mycobacterial or fungal infection (typically heterozygous STAT1 mutations). Objectives To define the molecular basis of progressive Combined Immunodeficiency in a group of patients with fatal infections. Methods We studied a group of unrelated patients who displayed an unusual progressive form of Combined Immunodeficiency. Whole exome sequencing assisted in confirming a common genetic defect in this group, which consisted of a heterozygous mutation of the STAT1 gene. STAT1 protein level as well as function was assessed, and a detailed evaluation of the immune system, including analysis of thymus tissue, was performed. Results Patients were found to carry de novo heterozygous mutations in STAT1 encoding T385A, I294T, or C284R amino acid substitutions. STAT1 expression appeared significantly decreased as a result of these changes but not completely absent, with diminished signaling responses. This group display progressive loss in lymphocyte number and function accompanied by increasing autoimmune features as well as severe, fatal infections. Conclusions These findings show that some heterozygous aberrations of STAT1 can be associated with progressive Combined Immunodeficiency, quite distinct from the limited susceptibilities to infection previously reported for heterozygous STAT1 mutations. These mutations were not inherited, rather, arose de novo in each case. Accompanied by significant patient mortality, this finding suggests that this class of STAT1 mutation is ultimately fatal due to overwhelming infection.

  • defining Combined Immunodeficiency
    The Journal of Allergy and Clinical Immunology, 2012
    Co-Authors: Chaim M. Roifman, Raz Somech, Amit Nahum, Fotini D Kavadas, Linda Pires, Ilan Dalal, Eyal Grunebaum
    Abstract:

    Background Although the extreme condition of typical profound T-cell dysfunction (TD), severe Combined Immunodeficiency (SCID), has been carefully defined, we are currently in the process of better defining less typical T-cell deficiencies, which tend to present with autologous circulating T-cell Combined Immunodeficiency (CID). Because autologous cells might interfere with the outcome of bone marrow transplantation, protocols usually include conditioning regimens. Therefore it is important to define the numbers of autologous cells usually detected in patients with CID versus those with SCID. Objectives We sought to determine the number of circulating T cells in patients with SCID as opposed to those with CID, to study their function, and to evaluate their possible detection during newborn screening using T-cell receptor excision circle (TREC) analysis. Methods Numbers of circulating CD3 + T cells (as determined by means of flow cytometry), in vitro responses to PHA, and TREC levels, all measured at presentation, were compiled from the research charts of the entire cohort of patients followed prospectively for T-cell Immunodeficiency at the Hospital for Sick Children. Clinical data were ascertained retrospectively from the patient's hospital charts. Results One hundred three patients had CD3 + determinations, and 80 of them had a genetic diagnosis. All patients considered to have typical SCID had CD3 + T-cell counts of fewer than 500 cells/μL. Some variability was observed among different genotypes. In vitro responses to PHA were recorded in 88 patients, of whom 68 had a genetic diagnosis. All patients with low CD3 + T-cell numbers ( + autologous circulating T cells per microliter. Although patients with Omenn syndrome and ζ chain–associated protein, 70 kDa (ZAP70) , and purine nucleoside phosphorylase (PNP) deficiencies had low responses, patients with the p.R222C mutation in the IL-2 receptor γ (IL2RG) gene as well as IL-10 receptor and CD40 ligand deficiencies had normal or near-normal mitogen responses. Finally, 51 patients had TREC levels measured. All patients with typical SCID, Omenn syndrome, and ZAP70 deficiency had low TREC levels. In contrast, patients with mutations in forkhead box protein 3 (FOXP3) , CD40 ligand (CD40L) , and IL-10 receptor α (IL10RA) , as well as patients with the p.R222C mutation in the IL2RG gene, had normal TREC levels. Conclusion Patients with typical SCID can be defined as having fewer than 500 circulating CD3 + T cells. Most patients with autologous T cells still have profound TD, as defined by reduced in vitro function and thymus output. Some patients with conditions including TD have normal TREC levels and will therefore not be detected in a TREC-based newborn screening program.

  • Omenn syndrome: inflammation in leaky severe Combined Immunodeficiency.
    Journal of Allergy and Clinical Immunology, 2008
    Co-Authors: Anna Villa, Luigi D. Notarangelo, Chaim M. Roifman
    Abstract:

    Omenn syndrome (OS) was reported until recently as a distinct form (phenotype and genotype) of severe Combined Immunodeficiency (SCID). Similar to other patients with SCID, patients with OS present early in infancy with viral or fungal pneumonitis, chronic diarrhea, and failure to thrive. Unlike typical SCID, patients with OS have enlarged lymphoid tissue, severe erythroderma, increased IgE levels, and eosinophilia. The inflammation observed in these patients is believed to be triggered by clonally expanded T cells, which are predominantly of the T H 2 type. These abnormal T cells, in the absence of proper regulation by other components of the immune system, secrete a host of cytokines that promote autoimmune as well as allergic inflammation. The emergence of these T-cell clones occurs in patients with hypomorphic mutations in recombination activating gene 1 or 2, but not in patients with deleterious mutations in these enzymes which render them inactive. Recently, OS was also identified in a growing list of other leaky SCIDs with mutations in RNA component of mitochondrial RNA processing endoribonuclease , adenosine deaminase , IL-2 receptor γ , IL-7 receptor α , ARTEMIS , and DNA ligase 4 . This new information revealed OS is a distinct inflammatory process that can be associated with genetically diverse leaky SCIDS.

  • burkitt s lymphoma in a patient with adenosine deaminase deficiency severe Combined Immunodeficiency treated with polyethylene glycol adenosine deaminase
    The Journal of Pediatrics, 2007
    Co-Authors: Maitham Husain, Eyal Grunebaum, Ahmed Naqvi, Adelle Atkinson, Boyee Ngan, Alessandro Aiuti, Chaim M. Roifman
    Abstract:

    We describe a patient with severe Combined Immunodeficiency because of aberrations in adenosine deaminase (ADA) who despite adequate replacement with polyethylene glycol-linked ADA (PEG-ADA) for 13 years developed Burkitt's lymphoma. Although treatment corrected the metabolic abnormalities caused by ADA deficiency, it failed to fully restore cellular immunity.

  • effect of cd3δ deficiency on maturation of α β and γ δ t cell lineages in severe Combined Immunodeficiency
    The New England Journal of Medicine, 2003
    Co-Authors: Harjit Dadi, Amos J Simon, Chaim M. Roifman
    Abstract:

    Three closely related infants with a form of severe Combined Immunodeficiency characterized by the absence of T cells but normal numbers of B cells were found to have an identical germ-line mutation in the CD3δ gene. The mutation prevented synthesis of the CD3δ protein and was associated with a block early in the development of thymocytes into mature T cells.

Yesim Yilmaz Demirdag - One of the best experts on this subject based on the ideXlab platform.

Alexandra F Freeman - One of the best experts on this subject based on the ideXlab platform.

  • hematopoietic stem cell transplantation in primary immunodeficiencies beyond severe Combined Immunodeficiency
    Journal of the Pediatric Infectious Diseases Society, 2018
    Co-Authors: Alexandra F Freeman
    Abstract:

    Hematopoietic stem cell transplantation (HSCT) has been the standard of care for infants with severe Combined Immunodeficiency (SCID) for several decades due to the dismal prognosis early in life without immune reconstitution. In recent years, as HSCT conditioning regimens and supportive care have greatly improved, HSCT is gaining in acceptance for more non-SCID primary immunodeficiencies (PIDs) and outside the early childhood period. In addition, potential donor options for non-SCID PIDs are expanding with increasing success for haploidentical donor transplants. In this brief report of a presentation at the PIDS-St. Jude 2018 conference, PIDs for which transplants are increasingly performed outside of early childhood will be discussed.

  • Combined Immunodeficiency associated with dock8 mutations
    The New England Journal of Medicine, 2009
    Co-Authors: Qian Zhang, Jeremiah C Davis, Ian T Lamborn, Alexandra F Freeman, Huie Jing, Amanda J Favreau, Helen F Matthews, Joie Davis, Maria L Turner, Gulbu Uzel
    Abstract:

    Background Recurrent sinopulmonary and cutaneous viral infections with elevated serum levels of IgE are features of some variants of Combined Immunodeficiency. The genetic causes of these variants are unknown. Methods We collected longitudinal clinical data on 11 patients from eight families who had recurrent sinopulmonary and cutaneous viral infections. We performed comparative genomic hybridization arrays and targeted gene sequencing. Variants with predicted loss-of-expression mutations were confirmed by means of a quantitative reverse-transcriptase–polymerase-chain-reaction assay and immunoblotting. We evaluated the number and function of lymphocytes with the use of in vitro assays and flow cytometry. Results Patients had recurrent otitis media, sinusitis, and pneumonias; recurrent Staphylococcus aureus skin infections with otitis externa; recurrent, severe herpes simplex virus or herpes zoster infections; extensive and persistent infections with molluscum contagiosum; and human papillomavirus infectio...