Publications by authors named "Celine Hanson"

32 Publications

Case Report: Secondary Hemophagocytic Lymphohistiocytosis With Disseminated Infection in Chronic Granulomatous Disease-A Serious Cause of Mortality.

Front Immunol 2020 9;11:581475. Epub 2020 Dec 9.

Division of Allergy and Immunology, Department of Pediatrics, University of South Florida, St. Petersburg, FL, United States.

Chronic granulomatous disease (CGD) is a primary immune deficiency due to defects in phagocyte respiratory burst leading to severe and life-threatening infections. Patients with CGD also suffer from disorders of inflammation and immune dysregulation including colitis and granulomatous lung disease, among others. Additionally, patients with CGD may be at increased risk of systemic inflammatory disorders such as hemophagocytic lymphohistiocytosis (HLH). The presentation of HLH often overlaps with symptoms of systemic inflammatory response syndrome (SIRS) or sepsis and therefore can be difficult to identify, especially in patients with a primary immune deficiency in which incidence of infection is increased. Thorough evaluation and empiric treatment for bacterial and fungal infections is necessary as HLH in CGD is almost always secondary to infection. Simultaneous treatment of infection with anti-microbials and inflammation with immunosuppression may be needed to blunt the hyperinflammatory response in secondary HLH. Herein, we present a series of X-linked CGD patients who developed HLH secondary to or with concurrent disseminated CGD-related infection. In two patients, CGD was a known diagnosis prior to development of HLH and in the other two CGD was diagnosed as part of the evaluation for HLH. Concurrent infection and HLH were fatal in three; one case was successfully treated, ultimately receiving hematopoietic stem cell transplantation. The current literature on presentation, diagnosis, and treatment of HLH in CGD is reviewed.
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http://dx.doi.org/10.3389/fimmu.2020.581475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756012PMC
December 2020

Disease-associated CTNNBL1 mutation impairs somatic hypermutation by decreasing nuclear AID.

J Clin Invest 2020 08;130(8):4411-4422

Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.

Patients with common variable immunodeficiency associated with autoimmune cytopenia (CVID+AIC) generate few isotype-switched B cells with severely decreased frequencies of somatic hypermutations (SHMs), but their underlying molecular defects remain poorly characterized. We identified a CVID+AIC patient who displays a rare homozygous missense M466V mutation in β-catenin-like protein 1 (CTNNBL1). Because CTNNBL1 binds activation-induced cytidine deaminase (AID) that catalyzes SHM, we tested AID interactions with the CTNNBL1 M466V variant. We found that the M466V mutation interfered with the association of CTNNBL1 with AID, resulting in decreased AID in the nuclei of patient EBV-transformed B cell lines and of CTNNBL1 466V/V Ramos B cells engineered to express only CTNNBL1 M466V using CRISPR/Cas9 technology. As a consequence, the scarce IgG+ memory B cells from the CTNNBL1 466V/V patient showed a low SHM frequency that averaged 6.7 mutations compared with about 18 mutations per clone in healthy-donor counterparts. In addition, CTNNBL1 466V/V Ramos B cells displayed a decreased incidence of SHM that was reduced by half compared with parental WT Ramos B cells, demonstrating that the CTNNBL1 M466V mutation is responsible for defective SHM induction. We conclude that CTNNBL1 plays an important role in regulating AID-dependent antibody diversification in humans.
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http://dx.doi.org/10.1172/JCI131297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410074PMC
August 2020

Outcomes after Allogeneic Transplant in Patients with Wiskott-Aldrich Syndrome.

Biol Blood Marrow Transplant 2018 03 28;24(3):537-541. Epub 2017 Nov 28.

Center for Cell and Gene Therapy, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas. Electronic address:

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by a triad of immunodeficiency, eczema, and thrombocytopenia. Currently, hematopoietic stem cell transplantation (HSCT) is the most reliable curative treatment with excellent results for patients with HLA-matched family or unrelated donors. However, even after fully myeloablative preparative regimens, mixed donor chimerism is a potential concern. We performed a retrospective chart review of 12 children who underwent allogeneic HSCT for WAS to report our experience. The median age at transplant was 10.5 months (range, 3 to 39). The median nucleated cell dose from the marrow was 4.55 × 10/kg (range, .3 to 7.9). The median times to neutrophil and platelet engraftment were 19 days (range, 13 to 27) and 18.5 days (range, 12 to 31), respectively. The rate of overall survival was 92% with median follow-up of 67 months (range, 3 to 146). Two patients developed grade IV acute graft-versus-host disease, and 1 died on day +99. Five of 12 patient's (42%) had mixed donor chimerism (range, 12% to 85%) at day +180. None of the pretransplant patient parameters was predictive of mixed chimerism. Nonetheless, of these 5 patients, 2 had normalization of the platelet count despite the mixed chimerism, 2 had full donor chimerism after receiving a second transplant with the same donor, and 1 remains transfusion dependent awaiting a second transplant. Hence, even with a significant rate of mixed chimerism, HSCT provides substantial benefit to WAS patients, with excellent overall survival.
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http://dx.doi.org/10.1016/j.bbmt.2017.11.019DOI Listing
March 2018

T-Cell Lymphopenia Detected by Newborn Screening in Two Siblings with an Xq13.1 Duplication.

Front Pediatr 2017 18;5:156. Epub 2017 Jul 18.

Center for Human Immunobiology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, United States.

Newborn screening for severe combined immunodeficiency has proven successful in identifying infants with T-cell deficiencies before they become severely ill. Additionally, the newborn screen can detect subtle early phenotypes that may become severe later in life. We present the case of siblings with features suggestive of T-cell lymphopenia identified as having low T-cell receptor excision circles counts by newborn screening. Expanded immune testing showed robust lymphocyte mitogen and antigen responses with normal vaccine responses and immunoglobulin levels for both boys over time. Genetic analysis revealed an Xq13.1 duplication in each child not found in the mother. The variant is downstream of the IL2RG gene with potential regulatory significance, suggesting a mechanism for the T-cell lymphopenia. The newborn screen provided these patients heightened surveillance and patient-specific management, including delayed live vaccines and pneumonia prophylaxis. Fortunately, the brothers have not suffered invasive or opportunistic infections and are well at ages 3 and 4 years. In this report, we illustrate the challenges of managing seemingly asymptomatic immunodeficient patients without a definitive genetic diagnosis and show how unbiased genetic analysis can expand understanding about primary immunodeficiency phenotypes.
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http://dx.doi.org/10.3389/fped.2017.00156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513981PMC
July 2017

Novel Combined Immune Deficiency and Radiation Sensitivity Blended Phenotype in an Adult with Biallelic Variations in and .

Front Immunol 2017 26;8:576. Epub 2017 May 26.

Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

With the advent of high-throughput genomic sequencing techniques, novel genetic etiologies are being uncovered for previously unexplained Mendelian phenotypes, and the underlying genetic architecture of disease is being unraveled. Although most of these "mendelizing" disease traits represent phenotypes caused by single-gene defects, a percentage of patients have blended phenotypes caused by pathogenic variants in multiple genes. We describe an adult patient with susceptibility to bacterial, herpesviral, and fungal infections. Immunologic defects included CD8 T cell lymphopenia, decreased T cell proliferative responses to mitogens, hypogammaglobulinemia, and radiation sensitivity. Whole-exome sequencing revealed compound heterozygous variants in . Biallelic mutations in are known to produce a spectrum of immune deficiency that includes the T cell abnormalities observed in this patient. Analyses for variants in genes associated with radiation sensitivity identified the presence of a homozygous variant of unknown significance. deficiency causes radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties syndrome and may account for the radiation sensitivity. Thus, the patient was found to have a novel blended phenotype associated with multilocus genomic variation: i.e., separate and distinct genetic defects. These findings further illustrate the clinical utility of applying genomic testing in patients with primary immunodeficiency diseases.
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http://dx.doi.org/10.3389/fimmu.2017.00576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445153PMC
May 2017

Linking newborn severe combined immunodeficiency screening with targeted exome sequencing: A case report.

J Allergy Clin Immunol Pract 2017 Sep - Oct;5(5):1442-1444. Epub 2017 Apr 21.

Immunology, Allergy and Rheumatology Section, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, Texas Children's Hospital, Houston, Texas; Baylor College of Medicine, Houston, Texas.

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http://dx.doi.org/10.1016/j.jaip.2017.03.004DOI Listing
June 2019

Annatto seed hypersensitivity in a pediatric patient.

Ann Allergy Asthma Immunol 2016 Sep;117(3):331-3

Department of Pediatrics, Baylor College of Medicine, Houston, Texas. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2016.07.001DOI Listing
September 2016

Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.

Authors:
Asbjørg Stray-Pedersen Hanne Sørmo Sorte Pubudu Samarakoon Tomasz Gambin Ivan K Chinn Zeynep H Coban Akdemir Hans Christian Erichsen Lisa R Forbes Shen Gu Bo Yuan Shalini N Jhangiani Donna M Muzny Olaug Kristin Rødningen Ying Sheng Sarah K Nicholas Lenora M Noroski Filiz O Seeborg Carla M Davis Debra L Canter Emily M Mace Timothy J Vece Carl E Allen Harshal A Abhyankar Philip M Boone Christine R Beck Wojciech Wiszniewski Børre Fevang Pål Aukrust Geir E Tjønnfjord Tobias Gedde-Dahl Henrik Hjorth-Hansen Ingunn Dybedal Ingvild Nordøy Silje F Jørgensen Tore G Abrahamsen Torstein Øverland Anne Grete Bechensteen Vegard Skogen Liv T N Osnes Mari Ann Kulseth Trine E Prescott Cecilie F Rustad Ketil R Heimdal John W Belmont Nicholas L Rider Javier Chinen Tram N Cao Eric A Smith Maria Soledad Caldirola Liliana Bezrodnik Saul Oswaldo Lugo Reyes Francisco J Espinosa Rosales Nina Denisse Guerrero-Cursaru Luis Alberto Pedroza Cecilia M Poli Jose L Franco Claudia M Trujillo Vargas Juan Carlos Aldave Becerra Nicola Wright Thomas B Issekutz Andrew C Issekutz Jordan Abbott Jason W Caldwell Diana K Bayer Alice Y Chan Alessandro Aiuti Caterina Cancrini Eva Holmberg Christina West Magnus Burstedt Ender Karaca Gözde Yesil Hasibe Artac Yavuz Bayram Mehmed Musa Atik Mohammad K Eldomery Mohammad S Ehlayel Stephen Jolles Berit Flatø Alison A Bertuch I Celine Hanson Victor W Zhang Lee-Jun Wong Jianhong Hu Magdalena Walkiewicz Yaping Yang Christine M Eng Eric Boerwinkle Richard A Gibbs William T Shearer Robert Lyle Jordan S Orange James R Lupski

J Allergy Clin Immunol 2017 01 16;139(1):232-245. Epub 2016 Jul 16.

Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex. Electronic address:

Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions.

Objective: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs.

Methods: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping.

Results: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays.

Conclusion: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.
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http://dx.doi.org/10.1016/j.jaci.2016.05.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5222743PMC
January 2017

Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency.

Sci Transl Med 2016 04;8(335):335ra57

Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

X-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural killer (NK) cell immunity caused by mutations inIL2RGencoding the common chain (γc) of several interleukin receptors. Gamma-retroviral (γRV) gene therapy of SCID-X1 infants without conditioning restores T cell immunity without B or NK cell correction, but similar treatment fails in older SCID-X1 children. We used a lentiviral gene therapy approach to treat five SCID-X1 patients with persistent immune dysfunction despite haploidentical hematopoietic stem cell (HSC) transplant in infancy. Follow-up data from two older patients demonstrate that lentiviral vector γc transduced autologous HSC gene therapy after nonmyeloablative busulfan conditioning achieves selective expansion of gene-marked T, NK, and B cells, which is associated with sustained restoration of humoral responses to immunization and clinical improvement at 2 to 3 years after treatment. Similar gene marking levels have been achieved in three younger patients, albeit with only 6 to 9 months of follow-up. Lentiviral gene therapy with reduced-intensity conditioning appears safe and can restore humoral immune function to posthaploidentical transplant older patients with SCID-X1.
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http://dx.doi.org/10.1126/scitranslmed.aad8856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557273PMC
April 2016

Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes.

J Allergy Clin Immunol 2016 05 24;137(5):1498-1505.e1. Epub 2016 Feb 24.

Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC; Division of Allergy and Immunology, Children's National Medical Center, Washington, DC. Electronic address:

Background: Viral infections are a leading fatal complication for patients with primary immunodeficiencies (PIDs) who require hematopoietic stem cell transplantation (HSCT). Use of virus-specific T lymphocytes (VSTs) has been successful for the treatment and prevention of viral infections after HSCT for malignant and nonmalignant conditions. Here we describe the clinical use of VSTs in patients with PIDs at 4 centers.

Objective: We sought to evaluate the safety and efficacy of VSTs for treatment of viral infections in patients with PIDs.

Methods: Patients with PIDs who have received VST therapy on previous or current protocols were reviewed in aggregate. Clinical information, including transplantation details, viral infections, and use of antiviral and immunosuppressive pharmacotherapy, were evaluated. Data regarding VST production, infusions, and adverse reactions were compared.

Results: Thirty-six patients with 12 classes of PID diagnoses received 37 VST products before or after HSCT. Twenty-six (72%) patients had received a diagnosis of infection with cytomegalovirus, EBV, adenovirus, BK virus, and/or human herpesvirus 6. Two patients were treated before HSCT because of EBV-associated lymphoproliferative disease. Partial or complete responses against targeted viruses occurred in 81% of patients overall. Time to response varied from 2 weeks to 3 months (median, 28 days). Overall survival at 6 months after therapy was 80%. Four patients had graft-versus-host disease in the 45 days after VST infusion, which in most cases was therapy responsive.

Conclusion: VSTs derived from either stem cell donors or third-party donors are likely safe and effective for the treatment of viral infections in patients with PIDs.
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http://dx.doi.org/10.1016/j.jaci.2015.12.1311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860050PMC
May 2016

Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States.

JAMA 2014 Aug;312(7):729-38

Department of Pediatrics, University of California, San Francisco, San Francisco2UCSF Benioff Children's Hospital, San Francisco, California.

Importance: Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100,000 births.

Objectives: To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia, and document early institution of effective treatments.

Design: Epidemiological and retrospective observational study.

Setting: Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data, and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3,030,083 newborns screened with a TREC test.

Main Outcomes And Measures: Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked.

Results: Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58,000 infants (95% CI, 1/46,000-1/80,000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87% (45/52), 92% (45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up practices influenced the rates of detection of non-SCID T-cell lymphopenia.

Conclusions And Relevance: Newborn screening in 11 programs in the United States identified SCID in 1 in 58,000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.
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http://dx.doi.org/10.1001/jama.2014.9132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492158PMC
August 2014

Next generation sequencing reveals skewing of the T and B cell receptor repertoires in patients with wiskott-Aldrich syndrome.

Front Immunol 2014 18;5:340. Epub 2014 Jul 18.

Department of Immunology, Boston Children's Hospital , Boston, MA , USA ; Manton Center for Orphan Disease Research, Boston Children's Hospital , Boston, MA , USA.

The Wiskott-Aldrich syndrome (WAS) is due to mutations of the WAS gene encoding for the cytoskeletal WAS protein, leading to abnormal downstream signaling from the T cell and B cell antigen receptors (TCR and BCR). We hypothesized that the impaired signaling through the TCR and BCR in WAS would subsequently lead to aberrations in the immune repertoire of WAS patients. Using next generation sequencing (NGS), the T cell receptor β and B cell immunoglobulin heavy chain (IGH) repertoires of eight patients with WAS and six controls were sequenced. Clonal expansions were identified within memory CD4(+) cells as well as in total, naïve and memory CD8(+) cells from WAS patients. In the B cell compartment, WAS patient IGH repertoires were also clonally expanded and showed skewed usage of IGHV and IGHJ genes, and increased usage of IGHG constant genes, compared with controls. To our knowledge, this is the first study that demonstrates significant abnormalities of the immune repertoire in WAS patients using NGS.
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http://dx.doi.org/10.3389/fimmu.2014.00340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102881PMC
August 2014

PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia.

Am J Hum Genet 2014 Jul 12;95(1):96-107. Epub 2014 Jun 12.

Section of Immunology, Allergy, and Rheumatology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.

Human phosphoglucomutase 3 (PGM3) catalyzes the conversion of N-acetyl-glucosamine (GlcNAc)-6-phosphate into GlcNAc-1-phosphate during the synthesis of uridine diphosphate (UDP)-GlcNAc, a sugar nucleotide critical to multiple glycosylation pathways. We identified three unrelated children with recurrent infections, congenital leukopenia including neutropenia, B and T cell lymphopenia, and progression to bone marrow failure. Whole-exome sequencing demonstrated deleterious mutations in PGM3 in all three subjects, delineating their disease to be due to an unsuspected congenital disorder of glycosylation (CDG). Functional studies of the disease-associated PGM3 variants in E. coli cells demonstrated reduced PGM3 activity for all mutants tested. Two of the three children had skeletal anomalies resembling Desbuquois dysplasia: short stature, brachydactyly, dysmorphic facial features, and intellectual disability. However, these additional features were absent in the third child, showing the clinical variability of the disease. Two children received hematopoietic stem cell transplantation of cord blood and bone marrow from matched related donors; both had successful engraftment and correction of neutropenia and lymphopenia. We define PGM3-CDG as a treatable immunodeficiency, document the power of whole-exome sequencing in gene discoveries for rare disorders, and illustrate the utility of genomic analyses in studying combined and variable phenotypes.
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http://dx.doi.org/10.1016/j.ajhg.2014.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085583PMC
July 2014

Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype.

J Allergy Clin Immunol 2014 Jun 3;133(6):1667-75. Epub 2014 May 3.

Laboratory of Host Defenses, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md. Electronic address:

Background: Autosomal recessive loss-of-function mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency characterized by atopy, recurrent infections, and cancer susceptibility. A genotype-phenotype explanation for the variable disease expression is lacking.

Objective: We investigated whether reversions contributed to the variable disease expression.

Methods: Patients followed at the National Institutes of Health's Clinical Center were studied. We performed detailed genetic analyses and intracellular flow cytometry to detect DOCK8 protein expression within lymphocyte subsets.

Results: We identified 17 of 34 DOCK8-deficient patients who had germline mutations with variable degrees of reversion caused by somatic repair. Somatic repair of the DOCK8 mutations resulted from second-site mutation, original-site mutation, gene conversion, and intragenic crossover. Higher degrees of reversion were associated with recombination-mediated repair. DOCK8 expression was restored primarily within antigen-experienced T cells or natural killer cells but less so in naive T or B cells. Several patients exhibited multiple different repair events. Patients who had reversions were older and had less severe allergic disease, although infection susceptibility persisted. No patients were cured without hematopoietic cell transplantation.

Conclusions: In patients with DOCK8 deficiency, only certain combinations of germline mutations supported secondary somatic repair. Those patients had an ameliorated disease course with longer survival but still had fatal complications or required hematopoietic cell transplantation. These observations support the concept that some DOCK8-immunodeficient patients have mutable mosaic genomes that can modulate disease phenotype over time.
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http://dx.doi.org/10.1016/j.jaci.2014.03.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132167PMC
June 2014

The natural history of children with severe combined immunodeficiency: baseline features of the first fifty patients of the primary immune deficiency treatment consortium prospective study 6901.

J Clin Immunol 2013 Oct 2;33(7):1156-64. Epub 2013 Jul 2.

Division of Pediatric Allergy, Immunology, and Bone Marrow Transplant, Benioff Children's Hospital, University of California San Francisco, 505 Parnassus Ave., M-659, San Francisco, CA, 94143-1278, USA,

The Primary Immune Deficiency Treatment Consortium (PIDTC) consists of 33 centers in North America. We hypothesized that the analysis of uniform data on patients with severe combined immunodeficiency (SCID) enrolled in a prospective protocol will identify variables that contribute to optimal outcomes following treatment. We report baseline clinical, immunologic, and genetic features of the first 50 patients enrolled, and the initial therapies administered, reflecting current practice in the diagnosis and treatment of both typical (n = 37) and atypical forms (n = 13) of SCID. From August 2010 to May 2012, patients with suspected SCID underwent evaluation and therapy per local center practices. Diagnostic information was reviewed by the PIDTC eligibility review panel, and hematopoietic cell transplantation (HCT) details were obtained from the Center for International Blood and Marrow Transplant Research. Most patients (92 %) had mutations in a known SCID gene. Half of the patients were diagnosed by newborn screening or family history, were younger than those diagnosed by clinical signs (median 15 vs. 181 days; P = <0.0001), and went to HCT at a median of 67 days vs. 214 days of life (P = <0.0001). Most patients (92 %) were treated with HCT within 1-2 months of diagnosis. Three patients were treated with gene therapy and 1 with enzyme replacement. The PIDTC plans to enroll over 250 such patients and analyze short and long-term outcomes for factors beneficial or deleterious to survival, clinical outcome, and T- and B-cell reconstitution, and which biomarkers are predictive of these outcomes.
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http://dx.doi.org/10.1007/s10875-013-9917-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784642PMC
October 2013

Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans.

Blood 2012 Nov 11;120(18):3635-46. Epub 2012 Sep 11.

Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD, USA.

We conducted a gene therapy trial in 10 patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency using 2 slightly different retroviral vectors for the transduction of patients' bone marrow CD34(+) cells. Four subjects were treated without pretransplantation cytoreduction and remained on ADA enzyme-replacement therapy (ERT) throughout the procedure. Only transient (months), low-level (< 0.01%) gene marking was observed in PBMCs of 2 older subjects (15 and 20 years of age), whereas some gene marking of PBMC has persisted for the past 9 years in 2 younger subjects (4 and 6 years). Six additional subjects were treated using the same gene transfer protocol, but after withdrawal of ERT and administration of low-dose busulfan (65-90 mg/m(2)). Three of these remain well, off ERT (5, 4, and 3 years postprocedure), with gene marking in PBMC of 1%-10%, and ADA enzyme expression in PBMC near or in the normal range. Two subjects were restarted on ERT because of poor gene marking and immune recovery, and one had a subsequent allogeneic hematopoietic stem cell transplantation. These studies directly demonstrate the importance of providing nonmyeloablative pretransplantation conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient severe combined immunodeficiency.
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http://dx.doi.org/10.1182/blood-2012-02-400937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488882PMC
November 2012

Ruling out HIV infection when testing for severe combined immunodeficiency and other T-cell deficiencies.

J Allergy Clin Immunol 2012 Mar;129(3):875-876.e5

Section of Allergy and Immunology, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.

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http://dx.doi.org/10.1016/j.jaci.2012.01.065DOI Listing
March 2012

Rare duplication or deletion of exons 6, 7 and 8 in CYBB leading to X-linked chronic granulomatous disease in two patients from different families.

J Clin Immunol 2012 Aug 2;32(4):653-62. Epub 2012 Mar 2.

Chronic Granulomatous Disease Diagnosis and Research Centre, Therex-TIMC/Imag, UMR CNRS 5525, UJF-Grenoble 1, Grenoble, 38041, France.

Chronic granulomatous disease (CGD) is a rare congenital disorder in which phagocytes cannot generate superoxide (O(2)(-)) and other microbicidal oxidants due to mutations in one of the five components of the O(2)(-)-generating NADPH oxidase complex. The most common form is caused by mutations in CYBB on the X chromosome, encoding gp91phox, the enzymatic subunit of the phagocyte NADPH oxidase. Here, we report two rare cases of male X-linked CGD patients, one caused by a 5.7-kb duplication of a region containing CYBB exons 6 to 8 and the other caused by a deletion of this same region. We found both the duplication in patient 1 and the deletion in patient 2 to be bordered by a GT repeat. Indeed, in control DNA, the 3' part of CYBB intron 5 contains a GT repeat and the 5' part of intron 8 also contains such a repeat. Duplication of exons 6, 7 and 8 in patient 1 was probably caused by a non-homologous crossing over between the two GT repeats. The deletion found in patient 2 probably arose from a similar misalignment. The results found in these patients were confirmed by multiplex ligation-dependent probe amplification. The clinical profile of XCGD is severe in both patients.
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http://dx.doi.org/10.1007/s10875-012-9667-2DOI Listing
August 2012

Myeloid dysplasia and bone marrow hypocellularity in adenosine deaminase-deficient severe combined immune deficiency.

Blood 2011 Sep 1;118(10):2688-94. Epub 2011 Jul 1.

Disorders of Immunity Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.

Genetic deficiency of adenosine deaminase (ADA) can cause profound lymphopenia and result in the clinical presentation of severe combined immune deficiency (SCID). However, because of the ubiquitous expression of ADA, ADA-deficient patients often present also with nonimmunologic clinical problems, affecting the skeletal, central nervous, endocrine, and gastrointestinal systems. We now report that myeloid dysplasia features and bone marrow hypocellularity are often found in patients with ADA-SCID. As a clinical correlate to this finding, we have observed vulnerability to antibiotic-induced myelotoxicity and prolonged neutropenia after nonmyeloablative chemotherapy. We have also noted that, in the absence of enzyme replacement therapy, absolute neutrophil counts of patients with ADA deficiency vary inversely with the accumulation of deoxynucleotides. These data have significant implications for the application of standard and investigational therapies to patients with ADA-SCID and support further studies to investigate the possibility that ADA deficiency is associated with a stem cell defect. These trials were registered at www.clinicaltrials.gov as #NCT00018018 and #NCT00006319.
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http://dx.doi.org/10.1182/blood-2011-01-329359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172788PMC
September 2011

Early versus delayed diagnosis of SCID: triumph versus tragedy.

Clin Immunol 2011 Jun 14;139(3):360-2. Epub 2011 Apr 14.

Department of Pediatrics, Baylor College of Medicine & Section of Allergy and Immunology, Texas Children's Hospital, 1102 Bates, Suite 330, Houston, TX 77030, USA.

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http://dx.doi.org/10.1016/j.clim.2011.03.010DOI Listing
June 2011

X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease.

Blood 2011 Jan 6;117(1):53-62. Epub 2010 Oct 6.

Center of Immunodeficiency, Molecular Immunology Unit, Institute of Child Health, London, United Kingdom.

X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression.
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http://dx.doi.org/10.1182/blood-2010-06-284935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3374620PMC
January 2011

Rapid genetic analysis of x-linked chronic granulomatous disease by high-resolution melting.

J Mol Diagn 2010 May 12;12(3):368-76. Epub 2010 Mar 12.

Department of Pathology, Pediatrics and Medicine, 5B114, University of Utah School of Medicine, 50 N. Medical Dr., Salt Lake City, UT 84132, USA.

High-resolution melting analysis was applied to X-linked chronic granulomatous disease, a rare disorder resulting from mutations in CYBB. Melting curves of the 13 PCR products bracketing CYBB exons were predicted by Poland's algorithm and compared with observed curves from 96 normal individuals. Primer plates were prepared robotically in batches and dried, greatly simplifying the 3- to 6-hour workflow that included DNA isolation, PCR, melting, and cycle sequencing of any positive products. Small point mutations or insertions/deletions were detected by mixing the hemizygous male DNA with normal male DNA to produce artificial heterozygotes, whereas detection of gross deletions was performed on unmixed samples. Eighteen validation samples and 22 clinical kindreds were analyzed for CYBB mutations. All blinded validation samples were correctly identified. The clinical probands were identified after screening for neutrophil oxidase activity. Nineteen different mutations were found, including seven near intron-exon boundaries predicting splicing defects, five substitutions within exons, three small deletions predicting premature termination, and four gross deletions of multiple exons. Ten novel mutations were found, including (c.) two missense (730T>A, 134T>G), one nonsense (90C>A), four splice site defects (45 + 1G>T, 674 + 4A>G, 1461 + 2delT, and 1462-2A>C), two small deletions (636delT, 1661_1662delCT), and one gross deletion of exons 6 to 8. High-resolution melting can provide timely diagnosis at low cost for effective clinical management of rare, genetic primary immunodeficiency disorders.
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http://dx.doi.org/10.2353/jmoldx.2010.090147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860474PMC
May 2010

Vaccine-acquired rotavirus in infants with severe combined immunodeficiency.

N Engl J Med 2010 Jan;362(4):314-9

Department of Pediatrics, Section of Allergy and Immunology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.

Live pentavalent human-bovine reassortant rotavirus vaccine is recommended in the United States for routine immunization of infants. We describe three infants, two with failure to thrive, who had dehydration and diarrhea within 1 month after their first or second rotavirus immunization and subsequently received a diagnosis of severe combined immunodeficiency. Rotavirus was detected, by means of reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay, in stool specimens obtained from all three infants, and gene-sequence analysis revealed the presence of vaccine rotavirus. These infections raise concerns regarding the safety of rotavirus vaccine in severely immunocompromised patients.
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http://dx.doi.org/10.1056/NEJMoa0904485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103739PMC
January 2010

Outcomes of patients with severe combined immunodeficiency treated with hematopoietic stem cell transplantation with and without preconditioning.

J Allergy Clin Immunol 2009 Nov;124(5):1062-9.e1-4

Department of Pediatrics, Section of Allergy and Immunology, Baylor College of Medicine, Texas Children's Hospital, Houston, Tex 77039, USA.

Background: The effect of pretransplantation conditioning on the long-term outcomes of patients receiving hematopoietic stem cell transplantation for severe combined immunodeficiency (SCID) has not been completely determined.

Objective: We sought to assess the outcomes of 23 mostly conditioned patients with SCID and compare their outcomes with those of 25 previously reported nonconditioned patients with SCID who underwent transplantation.

Methods: In the present study we reviewed the medical records of these 23 consecutive, mostly conditioned patients with SCID who underwent transplantation between 1998 and 2007.

Results: Eighteen patients (median age at transplantation, 10 months; range, 0.8-108 months) received haploidentical mismatched related donor, matched unrelated donor, or mismatched unrelated donor transplants, 17 of whom received pretransplantation conditioning (with 1 not conditioned); 13 (72%) patients engrafted with donor cells and survive at a median of 3.8 years (range, 1.8-9.8 year); 5 (38%) of 13 patients require intravenous immunoglobulin; and 6 of 6 age-eligible children attend school. Of 5 recipients (median age at transplantation, 7 months; range, 2-23 months) of matched related donor transplants, all 5 engrafted and survive at a median of 7.5 years (range, 1.5-9.5 year), 1 recipient requires intravenous immunoglobulin, and 3 of 3 age-eligible children attend school. Gene mutations were known in 16 cases: mutation in the common gamma chain of the IL-2 receptor (IL2RG) in 7 patients, mutation in the alpha chain of the IL-7 receptor (IL7RA) in 4 patients, mutation in the recombinase-activating gene (RAG1) in 2 patients, adenosine deaminase deficiency (ADA) in 2 patients, and adenylate kinase 2 (AK2) in 1 patient. Early outcomes and quality of life of the previous nonconditioned versus the present conditioned cohorts were not statistically different, but longer-term follow-up is necessary for confirmation.

Conclusions: Hematopoietic stem cell transplantation in patients with SCID results in engraftment, long-term survival, and a good quality of life for the majority of patients with or without pretransplantation conditioning.
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http://dx.doi.org/10.1016/j.jaci.2009.08.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271026PMC
November 2009

Mumps resurgence in the United States.

J Allergy Clin Immunol 2006 Oct 28;118(4):938-41. Epub 2006 Aug 28.

Allergy/Immunology Section, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, USA.

The recent mumps epidemic in the central United States has generated a large amount of public concern. A total of 2597 mumps cases have been reported in the United States in 11 states since January 1, 2006, representing a marked resurgence of mumps in a single year. The majority of these recent cases have occurred in college students age 18 to 25 years. Most were vaccinated with 2 doses of measles, mumps, and rubella-containing vaccines. Such outbreaks provide an opportunity for clinicians to review the clinical presentation, diagnosis, and morbidity of vaccine-preventable infections and also to review immunologic mechanisms and practice guidelines that might contribute to poor vaccine responses. A review of mumps is provided with discussion of potential mechanisms for vaccine failure.
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http://dx.doi.org/10.1016/j.jaci.2006.07.033DOI Listing
October 2006

Mechanistic actions of the risks and adverse events associated with vaccine administration.

J Allergy Clin Immunol 2004 Nov;114(5):1010-20; quiz 1021

Department of Allergy and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.

Vaccine-preventable disease levels in the United States are at or near record lows. Most parents today have never seen a case of diphtheria, measles, or other once commonly encountered infectious diseases now preventable by vaccine administration. As a result, some parents wonder why their children must receive shots for diseases that do not seem to exist. Myths and misinformation about vaccine safety abound and can confuse parents who are trying to make sound decisions about their children's health care. However, we cannot take continued high immunization coverage levels for granted. A successful vaccination program, like a successful society, depends on the cooperation of every individual to ensure the good of all. This review outlines for clinical allergists-immunologists the molecular basis for the risks and adverse events associated with vaccine administration so that they can be better informed as experts on vaccine-associated adverse reactions.
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http://dx.doi.org/10.1016/j.jaci.2004.09.007DOI Listing
November 2004

29. Immunization.

J Allergy Clin Immunol 2003 Feb;111(2 Suppl):S754-65

Department of Allergy and Immunology, Texas Children's Hospital, Baylor College of Medicine, 6621 Fannin Street (MC-FC330.01), Houston, TX 77030, USA.

The medical dictionary defines immunization as the "protection of susceptible individuals from communicable diseases by the administration of a living modified agent, a suspension of killed organisms, or an inactivated toxin." This elegant description can be expanded to include twenty-first century approaches to immunization that include recombinant technology, reassortment virus techniques, live vectors, DNA vaccines, and the expansion of the field to encompass noncommunicable diseases such as Alzheimer's disease, autoimmunity, and tumor immunogenetics. Integral to the success of immunization is our knowledge of the immune system's memory of antigens, yet our understanding of this fundamental feature remains limited. On a global scale, communicable diseases remain the number-one cause of morbidity and mortality; hence Jenner's pioneering work with its birth in 1796 still has a challenging and exciting future.
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http://dx.doi.org/10.1067/mai.2003.83DOI Listing
February 2003