Search tips
Search criteria

Results 1-23 (23)

Clipboard (0)

Select a Filter Below

Year of Publication
more »
Document Types
1.  Protecting Pediatric Oncology Patients From Influenza 
The Oncologist  2013;18(2):204-211.
This review examines evidence to support various strategies to protect pediatric oncology patients from influenza-related morbidity. Influenza vaccination should be considered standard. Additional evidence-supported measures include antiviral treatment, antiviral prophylaxis, cohorting of patients, and hospital infection control measures.
Learning Objectives
Identify optimal vaccination strategies and define the vaccine response rates among pediatric chemotherapy patients.Explain the advantage of beginning empiric antiviral therapy.Describe the need for family member vaccination, hygiene measures, and social distancing.
Influenza is a common respiratory pathogen. Its severity can be unpredictable, but people with chronic illness are at increased risk of severe infection, complications, and death from influenza. This review examines evidence to support various strategies to protect pediatric oncology patients from influenza-related morbidity. Influenza vaccination should be considered standard. Additional evidence-supported measures include antiviral treatment, antiviral prophylaxis, cohorting of patients, and hospital infection control measures. Data from other high-risk populations support the vaccination of family members, double-dose or high-dose vaccination, and the use of barrier methods. These measures have the potential to optimize patient outcomes because there will be fewer treatment interruptions for acute illness. These strategies can also protect patients from prolonged hospitalizations and morbidity related to influenza.
PMCID: PMC3579605  PMID: 23370325
Influenza; Vaccine; Chemotherapy; Chemoprophylaxis
2.  Defective actin accumulation impairs human natural killer cell function in DOCK8 deficiency 
DOCK8 mutations are responsible for a rare primary combined immunodeficiency syndrome associated with severe cutaneous viral infections, elevated IgE, autoimmunity, and malignancy. Natural killer (NK) cells are essential for tumor surveillance and defense against virally infected cells. NK cell function relies on Wiskott-Aldrich syndrome protein (WASp) for filamentous actin (F-actin) accumulation at the lytic NK cell immunologic synapse (IS). DOCK8 activates Cdc42, which, together with WASp, coordinates F-actin reorganization. While abnormalities in T and B cell function have been described in DOCK8-deficient patients, the role of NK cells in this disease is unclear.
Understand the role of DOCK8 in NK cell function in order to determine if NK cell abnormalities explain the pathogenesis of the clinical syndrome of DOCK8 deficiency.
A cohort of DOCK8-deficient patients was assembled and patient NK cells as well as NK cell lines with stably reduced DOCK8 expression were studied. NK cell cytotoxicity, F-actin content, and lytic immunological synapse formation were measured.
DOCK8-deficient patient NK cells and DOCK8 knockdown cell lines all had decreased NK cell cytotoxicity, which could not be restored after IL-2 stimulation. Importantly, DOCK8 deficiency impaired F-actin accumulation at the lytic immunological synapse without affecting overall NK cell F-actin content.
DOCK8 deficiency results in severely impaired NK cell function owing to an inability to form a mature lytic IS via targeted synaptic F-actin accumulation. This defect may underlie and explain important attributes of the DOCK8 deficiency clinical syndrome including the unusual susceptibility to viral infection and malignancy.
PMCID: PMC3646579  PMID: 23380217
DOCK8 deficiency; NK cells; actin; cytotoxicity; immunologic synapse
3.  Rituximab-Treated Patients Have a Poor Response to Influenza Vaccination* 
Journal of clinical immunology  2012;33(2):388-396.
The efficacy of influenza vaccination in patients treated with rituximab is a clinically important question. Rheumatology clinics are populated with patients receiving rituximab for a broad array of disorders. Although several studies have explored the efficacy of other vaccines in rituximab-treated populations, results have been conflicting. We wished to define influenza vaccine efficacy in a rituximab-treated cohort. We examined 17 evaluable subjects treated with rituximab for rheumatologic conditions. T cell subsets, B cells subsets, T cell function, and B cell function were evaluated at specific time points along with hemagglutinination inhibition titers after receiving the standard inactivated influenza vaccine. T cell subset counts were significantly different than controls but did not change with rituximab. B cells depleted in all patients but were in various stages of recovery at the time of vaccination. Influenza vaccine responsiveness was poor overall, with only 16% of subjects having a four-fold increase in titer. Pre-existing titers were retained throughout the study, however. The ability to respond to the influenza vaccine appeared to be related to the degree of B cell recovery at the time of vaccination. This study emphasizes that antibody responses to vaccine are impaired in subjects treated with rituximab and supports the concept that B cell recovery influences influenza vaccine responsiveness.
PMCID: PMC3565069  PMID: 23064976
Rituxmab; influenza; antibody; HAI titer; B cell
4.  Immunologic Consequences of Chemotherapy for Acute Myeloid Leukemia 
There are few data characterizing the immunologic consequences of chemotherapy for AML and almost nothing is known about the effects of chemotherapy in a pediatric AML cohort. We identified T cell subsets, B cell subsets and used ELISPOT analyses to define the function of T cells and B cells in seven pediatric patients with AML on chemotherapy. The data demonstrate that the effects of chemotherapy disproportionately target the B cell and depletion of B cells is associated with impaired responses to the inactivated influenza vaccine. Diminished T cell numbers were also observed although the magnitude of the effect was less than what was seen for B cells. Furthermore, measures of T cell function were largely intact. We conclude that humoral immunity is significantly affected by chemotherapy for AML.
PMCID: PMC3526680  PMID: 23018569
5.  Global H4 acetylation analysis by ChIP-chip in SLE monocytes 
Genes and immunity  2009;11(2):124-133.
Systemic lupus erythematosus is a polygenic disorder affecting approximately 1:1000 adults. Recent data have implicated interferons in the pathogenesis and the expression of many genes downstream of interferons are regulated at the level of histone modifications. We examined H4 acetylation and gene expression in monocytes from patients with systemic lupus erythematosus to define alterations to the epigenome. Monocytes from 14 controls and 24 SLE patients were used for analysis by chromatin immunoprecipitation for H4 acetylation and gene expression arrays. Primary monocytes treated with μ-interferon were used as a comparator. Data were analyzed for concordance of H4 acetylation and gene expression. Network analyses and transcription factor analyses were performed to identify potential pathways. H4 acetylation was significantly altered in monocytes from patients with systemic lupus erythematosus. Sixty three percent of genes with increased H4 acetylation had the potential for regulation by IRF1. IRF1 binding sites were also upstream of nearly all genes with both increased H4 acetylation and gene expression. μ-interferon was a significant contributor to both expression and H4 acetylation patterns but the greatest concordance was seen in the enrichment of certain transcription factor binding sites upstream of genes with increased H4 acetylation in SLE and genes with increased H4 acetylation after μ-interferon treatment.
PMCID: PMC2832080  PMID: 19710693
SLE; lupus; epigenetics; chromatin; interferon; IRF1
6.  Cytokine-Induced Monocyte Characteristics in SLE 
Monocytes in SLE have been described as having aberrant behavior in a number of assays. We examined gene expression and used a genome-wide approach to study the posttranslational histone mark, H4 acetylation, to examine epigenetic changes in SLE monocytes. We compared SLE monocyte gene expression and H4 acetylation with three types of cytokine-treated monocytes to understand which cytokine effects predominated in SLE monocytes. We found that γ-interferon and α-interferon both replicated a broad range of the gene expression changes seen in SLE monocytes. H4 acetylation in SLE monocytes was overall higher than in controls and there was less correlation of H4ac with cytokine-treated cells than when gene expression was compared. A set of chemokine genes had downregulated expression and H4ac. Therefore, there are significant clusters of aberrantly expressed genes in SLE which are strongly associated with altered H4ac, suggesting that these cells have experienced durable changes to their epigenome.
PMCID: PMC2896681  PMID: 20625490
7.  Novel Mutation in Syntaxin-Binding Protein 2 (STXBP2) Prevents IL-2-induced Natural Killer Cell Cytotoxicity 
Capsule Summary
We have identified dizygotic twins with a novel syntaxin-binding protein 2 (STXBP2) mutation, where cytotoxicity cannot be restored with IL-2. This defines STXBP2 as an absolute requirement for NK cell cytotoxic function.
PMCID: PMC3646578  PMID: 22336081
Familial hemophagocytic lymphohistiocytosis (FHL); syntaxin-binding protein 2 (STXBP2); Munc18-2; syntaxin-11
8.  The TNFα locus is Altered in Monocytes from Patients with Systemic Lupus Erythematosus 
In systemic lupus erythematosus, TNFα is elevated in the serum and correlates with disease activity and triglyceride levels. The stimuli that drive TNFα in this setting are incompletely understood. This study was designed to evaluate monocyte chromatin at the TNFα locus to identify semi-permanent changes that might play a role in altered expression of TNFα. SLE patients with relatively quiescent disease (mean Physician Global Assessment=0.6) and healthy controls were recruited for this study. TNFα expression was measured by intracellular cytokine staining of different monocyte subsets in patients (n=24) and controls (n=12). Histone acetylation at the TNFα locus was measured by chromatin immunoprecipitation using a normalized quantitative PCR in patients (n=46) and controls (n=24). There were no differences in the overall fractions of cells expressing CD14 in SLE patients compared to controls, however, the fraction of DR+/CD16+ cells expressing CD14 was slightly higher as was true in the monocyte subset defined by DR+/CD11b+. Within the monocyte population defined by physical characteristics and DR+/CD14+, TNFα expressing cells were more frequent in SLE patients compared to controls. Both the fraction of positive cells and the mean fluorescence intensity were higher in patients than controls. Consistent with this was the finding that monocytes from patients had increased TNFα transcripts and more highly acetylated histones at the TNFα locus compared to controls. Furthermore, patients with the highest levels of TNFα histone acetylation were more likely to have had consistently elevated erythrocyte sedimentation rates, and to have required cytotoxic use. Histone acetylation, associated with increased transcriptional competence of TNFα, may play a role in certain inflammatory aspects of the disease.
PMCID: PMC1905860  PMID: 17276734
lupus; epigenetics; histone; TNFalpha
9.  Genome-Wide Analysis of Interferon Regulatory Factor I Binding in Primary Human Monocytes 
Gene  2011;487(1):21-28.
IRF1 is a transcription factor that participates in interferon signaling. Previous studies of IRF1 binding have utilized in vitro assays. We used ChIP-seq in human monocytes to better define the recognition motif for IRF1. The newly identified 18bp motif (RAAASNGAAAGTGAAASY) is a refinement of the 13bp IRF1 motif commonly used. We utilized the 18bp consensus motif and identified 345 potential target genes. To compare the 18bp motif with the 13bp motif, we compared putative gene targets. Only 56 potential gene targets were defined by both consensus motifs. To compare biological effects of interferon on the 13bp and the 18bp consensus targets, we mined expression data from cells exposed to interferons or transfected with IRF1. In all cases, the 18bp consensus motif was more strongly associated with transcriptional responses than the 13bp motif. Therefore, the new 18bp consensus motif appears to have a greater association with biological activities of IRF1.
PMCID: PMC3167955  PMID: 21803131
IRF1; IRF-E; chromatin immunoprecipitation; inflammation; lupus; interferon
10.  Leucine-Rich Repeat (in Flightless I) Interacting Protein-1 Regulates a Rapid Type I Interferon Response 
The cell autonomous response to viral infection is carefully regulated to induce type I interferons (IFNs), which in turn induce the establishment of an antiviral state. Leucine-rich repeat (in Flightless I) interacting protein-1 (LRRFIP1) and LRRFIP2 are 2 related proteins that have been identified as interacting with MyD88 and Flightless I homolog, a leucine-rich repeat protein. LRRFIP2 positively regulates NFκB and macrophage cytokine production after lipopolysaccharide, but less is known about LRRFIP1. We hypothesized that LRRFIP1 could be more important in antiviral responses, as overexpression led to type I IFN production in a pilot study. The induction of type I IFNs occurred even in the absence of virus, but was enhanced by the presence of virus. Conversely, knockdown of LRRFIP1 compromised IFN expression. We found that LRRFIP1 was rapidly recruited to influenza-containing early endosomes in a p38-dependent fashion. This was specific for virus-containing endosomes as there was almost no colocalization of LRRFIP1 with early endosomes in the absence of virus. Further, LRRFIP1 was recruited to RNA-containing vesicles. Taken together, these data suggest that LRRFIP1 participates in cell responses to virus at early time points and is important for type I IFN induction.
PMCID: PMC2992405  PMID: 20586614
11.  Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome 
We hypothesized that sirolimus, an mTOR inhibitor, may be effective in patients with autoimmune lymphoproliferative syndrome (ALPS) and treated patients who were intolerant to or failed other therapies. Four patients were treated for autoimmune cytopenias; all had a rapid complete or near complete response. Two patients were treated for autoimmune arthritis and colitis, demonstrating marked improvement. Three patients had complete resolution of lymphadenopathy and splenomegaly and all patients had a reduction in double negative T cells, a population hallmark of the disease. Based on these significant responses, we recommend that sirolimus be considered as second-line therapy for patients with steroid-refractory disease.
PMCID: PMC2819393  PMID: 19208097
mTOR; autoimmunity; signal transduction; rapamycin
12.  Association of the BANK 1 R61H variant with systemic lupus erythematosus in Americans of European and African ancestry 
Recently an association was demonstrated between the single nucleotide polymorphism (SNP), rs10516487, within the B-cell gene BANK1 and systemic lupus erythematosus (SLE) as a consequence of a genome wide association study of this disease in European and Argentinean populations. In a bid for replication, we examined the effects of the R61H non-synonymous variant with respect to SLE in our genotyped American cohorts of European and African ancestry. Utilizing data from our ongoing genome-wide association study in our cohort of 178 Caucasian SLE cases and 1808 Caucasian population-based controls plus 148 African American (AA) SLE cases and 1894 AA population-based controls we investigated the association of the previously described non-synonymous SNP at the BANK1 locus with the disease in the two ethnicities separately. Using a Fisher’s exact test, the minor allele frequency (MAF) of rs10516487 in the Caucasian cases was 22.6% while it was 31.2% in Caucasian controls, yielding a protective odds ratio (OR) of 0.64 (95% CI 0.49-0.85; one-sided p = 7.07 × 10−4). Furthermore, the MAF of rs10516487 in the AA cases was 18.7% while it was 23.3% in AA controls, yielding a protective OR of 0.75 (95% CI 0.55–1.034; one-sided p = 0.039). The OR of the BANK1 variant in our study cohorts is highly comparable with that reported previously in a South American/European SLE case-control cohort (OR = 0.72). As such, R61H in the BANK1 gene confers a similar magnitude of SLE protection, not only in European Americans, but also in African Americans.
PMCID: PMC3681036  PMID: 23776345
systemic lupus erythematosus; African Americans; European Americans; BANK1 gene
13.  GCF2/LRRFIP1 Represses Tumor Necrosis Factor Alpha Expression 
Molecular and Cellular Biology  2005;25(20):9073-9081.
Tumor necrosis factor alpha (TNF-α) is an important mediator of inflammation, apoptosis, and the development of secondary lymphoid structures. Multiple polymorphic microsatellites have been identified in and around the gene, and there are also multiple single-base pair biallelic polymorphisms in the introns and promoter. The TNF-α −308 promoter polymorphism is a G-to-A transition which has been statistically associated with various autoimmune disorders. Some studies have found that it may directly mediate the increased transcription of TNF-α in some circumstances. This study characterizes proteins interacting at the polymorphic promoter site. Affinity purification of binding proteins and confirmatory chromatin immunoprecipitation assays were used to identify the proteins. Electrophoretic mobility shift analyses and surface plasmon resonance were used to define binding characteristics. Proteins interacting at this site include GCF2/LRRFIP1 and Ets-1. GCF2/LRRFIP1 appears to act as a repressor and occupies the −308 site in cells that do not make TNF-α. Cells competent to produce TNF-α have Ets-1 bound to the −308 promoter site. Active transcription is accompanied by NF-κB and c-Jun binding to the proximal promoter. Thus, dynamic changes on the TNF-α promoter, particularly at the −308 site, accompany the transition from repressed to active transcription. GCF2/LRRFIP1 is the first TNF-α repressor identified.
PMCID: PMC1265793  PMID: 16199883
14.  Infections in Patients with Inherited Defects in Phagocytic Function 
Clinical Microbiology Reviews  2003;16(4):597-621.
Patients with defects in phagocytic function are predisposed to intracellular microorganisms and typically have early dissemination of the infection. Recognition of the underlying disorder and aggressive antimicrobial therapy has been beneficial for the patients. Improved understanding of the pathophysiology has also affected patient management by allowing specific, targeted immunomodulatory intervention. The disorders described in this review are not common but have had a significant impact on our understanding of the role of phagocytic cells in host defense. Conversely, understanding the role of the neutrophil and macrophage in infection has benefited not just the patients described in this review but also other patients with similar disease processes.
PMCID: PMC207096  PMID: 14557288
15.  TH1 and TH2 Cytokine mRNA and Protein Levels in Human Immunodeficiency Virus (HIV)-Seropositive and HIV-Seronegative Youths 
The roles of cytokines in the progression of human immunodeficiency virus (HIV)-associated disease are controversial. The patterns of innate cytokine production have been postulated to shift from TH1- to TH2-type cytokines with the progression of HIV-associated disease. Although there have been studies of cytokines in children and adults, no data are available on cytokine production in healthy or HIV-infected adolescents. We analyzed and characterized cytokine mRNA and protein levels for gamma interferon, interleukin 2 (IL-2), IL-4, and tumor necrosis factor alpha and protein levels of IL-6 in both stimulated and unstimulated peripheral blood mononuclear cells obtained from a large longitudinal, observational cohort study of HIV-seropositive and -seronegative adolescents. We correlated cytokine results with viral load and CD4+-T-cell counts as critical markers of disease progression in HIV-infected adolescents. These data were used to examine hypotheses related to the TH1-to-TH2 cytokine shift in a sample of HIV-infected adolescents. Five hundred twenty subjects participating in the REACH (Reaching for Excellence in Adolescent Care and Health) Project of the Adolescent Medicine HIV/AIDS Research Network contributed blood samples. Samples selected for the cross-sectional data set analyzed had to meet selection criteria developed to minimize the potential confounding effects of acute intercurrent illnesses or infections, recent vaccination for hepatitis, and altered hormone status and to optimize congruence of cytokine measurements with assays of viral load and CD4+-T-cell counts. Group differences in the proportions of subjects with detectable levels of each cytokine marker were compared. In the subset of subjects with detectable cytokine values, differences in detected values were compared across subgroups defined by HIV serostatus and among HIV-seropositive subjects by three viral load classifications. The study sample was 65% HIV seropositive, 71% African-American, and 75% female with a mean age of 17.4 years. HIV-seropositive subjects were relatively healthy with mean and median CD4+-T-cell counts of 534 and 499 cells/mm3, respectively. Only 8.1% of subjects had CD4+-T-cell counts below 200 cells/mm3, and 25% had viral loads that were below the threshold of detection (<400 copies/ml). Detailed analyses of these data indicate that there were no differences in cytokines detected in HIV-seropositive and HIV-seronegative adolescents, and there was no apparent relationship between the cytokine measurements and the viral load or CD4+-T-cell categorization, the parameters selected as markers of HIV-associated disease status. These adolescents, including the HIV-seropositive subjects, were relatively healthy, and the HIV-infected subjects were at an early stage in the course of their HIV-associated disease. On the basis of our data, we conclude that, early in the course of HIV-associated disease in adolescents, there are no detectable shifts from TH1 to TH2 cytokine production.
PMCID: PMC154958  PMID: 12738638
16.  CD4+ CD25+ T-Cell Production in Healthy Humans and in Patients with Thymic Hypoplasia 
Regulatory T cells are found primarily in the CD4+ CD25+ fraction of T cells and play an important role in the prevention of autoimmunity. We examined CD4+ CD25+ T cells in 33 healthy children and adults and compared them to a population with an inherited form of thymic hypoplasia and a predisposition to autoimmune disease. Absolute numbers of CD4+ CD25+ T cells were markedly higher in healthy infants than in infants with chromosome 22q11.2 deletion syndrome.
PMCID: PMC120063  PMID: 12204972
17.  Gamma Interferon and Lipopolysaccharide Interact at the Level of Transcription To Induce Tumor Necrosis Factor Alpha Expression 
Infection and Immunity  2001;69(5):2847-2852.
Lipopolysaccharide (LPS) is a very potent inducer of tumor necrosis factor alpha (TNF-α) expression from monocytes and macrophages. Another inflammatory cytokine, gamma interferon (IFN-γ), can potentiate the effects of LPS, but the mechanism is not thoroughly understood. Previous reports emphasized the ability of IFN-γ to upregulate CD14 expression (the receptor for LPS), and nearly all studies have utilized sequential stimulation with IFN-γ followed by LPS to exploit this phenomenon. This study demonstrates that IFN-γ can upregulate the effect of LPS at the level of transcription. Human monoblastic Mono-Mac-6 cells produced up to threefold-greater levels of TNF-α when simultaneously stimulated with LPS and IFN-γ compared to treatment with LPS alone. RNase protection studies showed a similar increase in RNA beginning as early as within 30 min. The synthesis of TNF-α mRNA in IFN-γ- and LPS-treated Mono-Mac-6 cells was also temporally prolonged even though the message turnover rate was identical to that seen in LPS stimulated cells. The modulatory effect of IFN-γ may be mediated by Jak2.
PMCID: PMC98233  PMID: 11292697
18.  Measurement of Cytokine Secretion, Intracellular Protein Expression, and mRNA in Resting and Stimulated Peripheral Blood Mononuclear Cells 
Quantitation of cytokine production is a valuable adjunct to standard immunologic assays in defining several pathologic processes. Nevertheless, there is little agreement about which tissues should be assayed, which type of assay should be performed, and which stimulation protocol should be used. As these types of assays enter the clinical arena, there is need for standardization. There is also a need to maximize the amount of information which may be derived from a single sample. We compared secreted interleukin 4 (IL-4), IL-2, IL-6, tumor necrosis factor alpha (TNF-α), and gamma interferon proteins as measured by enzyme-linked immunosorbent assay with intracellular cytokine production (IL-2 and gamma interferon) as detected by flow cytometry and quantitative competitive PCR for IL-2, IL-4, TNF-α, and gamma interferon mRNA and cDNA. Results from unstimulated cells and cells stimulated with phorbol myristate acetate, phytohemagglutinin, and phorbol myristate acetate plus phytohemagglutin were compared. All three methodologies detected significant stimulation of cytokine production. The combination of phytohemagglutinin and phorbol myristate acetate was overall the most-potent stimulus.
PMCID: PMC95986  PMID: 11063499
19.  Longitudinal Analysis of Lymphocyte Function and Numbers in the First Year of Life in Chromosome 22q11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial Syndrome)† 
Chromosome 22q11.2 deletion syndrome is a common syndrome typically consisting of variable cardiac defects, hypoparathyroidism, developmental delay, and immunodeficiency. The hemizygous deletion has variable effects on the immune system even within the same kindred, and the extent of the immunodeficiency is difficult to predict. Some patients have shown improvement over time; however, this is the first prospective longitudinal study of the dynamic nature of the immunodeficiency. Nineteen patients were studied prospectively between 1994 and 1997. The results of the newborn immunologic studies in the chromosome 22q11.2 deletion group were significantly different from those of a group of newborns with cardiac disease due to other causes. Peripheral blood T-cell numbers were decreased in the chromosome 22q11.2 deletion group, although T-cell function was largely preserved. The group as a whole demonstrated few changes in the first year of life, but a subset of patients with markedly diminished T-cell numbers did demonstrate improvement. Therefore, improvement in peripheral blood T-cell counts is variable in chromosome 22q11.2 deletion syndrome. The patients with the lowest T-cell counts improved the most in the first year of life.
PMCID: PMC95796  PMID: 10548584
20.  Increased Prevalence of Immunoglobulin A Deficiency in Patients with the Chromosome 22q11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial Syndrome) 
We wished to determine the prevalence of immunoglobulin A (IgA) deficiency in patients with the chromosome 22q11.2 deletion syndrome. A total of 32 patients with the chromosome 22q11.2 deletion were examined for IgA deficiency. We report a 13% (n = 4) prevalence of IgA deficiency in patients with this syndrome. The odds ratio of IgA deficiency in this population is 14.20 (P < 0.0001). This confirms the occurrence of significant humoral deficits in this predominantly cellular immunodeficiency.
PMCID: PMC104536  PMID: 9606003
21.  Adenosine Deaminase Deficiency and Purine Nucleoside Phosphorylase Deficiency in Common Variable Immunodeficiency 
The clinical presentations of adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency are widely variable and include clinical and immunologic findings compatible with common variable immunodeficiency. The screening of 44 patients with common variable immunodeficiency failed to identify any individuals with deficiencies of these enzymes.
PMCID: PMC104530  PMID: 9605997
22.  Allogeneic Hematopoietic Cell Transplantation for Primary Immune Deficiency Diseases Current Status and Critical Needs 
Allogeneic hematopoietic cell transplantation (HCT) has been employed for 40 years to ameliorate or cure primary immune deficiency (PID) diseases, including severe combined immune deficiency (SCID) and non-SCID PID. There is a critical need for evaluation of the North American experience of different HCT approaches for these diseases, in order to identify best practices and plan future investigative clinical trials. A conference of experts in HCT treatment of PID has recommended: (1) a comprehensive cross-sectional and retrospective analysis of HCT survivors with SCID; (2) a prospective study of SCID patients receiving HCT, with comparable baseline and follow-up testing across participating centers; (3) a pilot study of newborn screening for SCID to identify affected infants prior to compromise by infection; and (4) for the non-SCID diseases, Wiskott-Aldrich syndrome and Chronic Granulomatous Disease, studies of the natural history of disease in patients who do or do not receive HCT. To accomplish these goals, collaboration by a consortium of institutions in North America is proposed. Participation of immunologists and HCT physicians having interest in PID and experts in laboratory methods, clinical outcomes assessment, databases and analysis will be required for the success of these studies.
PMCID: PMC3357108  PMID: 18992926
Allogeneic hematopoietic cell transplantation; primary immunodeficiency; clinical trial
23.  Hemizygous mutations in SNAP29 unmask autosomal recessive conditions and contribute to atypical findings in patients with 22q11.2DS 
Journal of Medical Genetics  2012;50(2):80-90.
22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder, affecting an estimated 1 : 2000–4000 live births. Patients with 22q11.2DS have a broad spectrum of phenotypic abnormalities which generally includes congenital cardiac abnormalities, palatal anomalies, and immunodeficiency. Additional findings, such as skeletal anomalies and autoimmune disorders, can confer significant morbidity in a subset of patients. 22q11.2DS is a contiguous gene DS and over 40 genes are deleted in patients; thus deletion of several genes within this region contributes to the clinical features. Mutations outside or on the remaining 22q11.2 allele are also known to modify the phenotype.
We utilised whole exome, targeted exome and/or Sanger sequencing to examine the genome of 17 patients with 22q11.2 deletions and phenotypic features found in <10% of affected individuals.
Results and conclusions
In four unrelated patients, we identified three novel mutations in SNAP29, the gene implicated in the autosomal recessive condition cerebral dysgenesis, neuropathy, ichthyosis and keratoderma (CEDNIK). SNAP29 maps to 22q11.2 and encodes a soluble SNARE protein that is predicted to mediate vesicle fusion at the endoplasmic reticulum or Golgi membranes. This work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to mutations on the non-deleted chromosome, which leads to unmasking of autosomal recessive conditions such as CEDNIK, Kousseff, and a potentially autosomal recessive form of Opitz G/BBB syndrome. Furthermore, our work implicates SNAP29 as a major modifier of variable expressivity in 22q11.2 DS patients.
PMCID: PMC3585484  PMID: 23231787
22q11.2DS; SNAP29; CEDNIK; Kousseff; Exome Sequencing

Results 1-23 (23)