Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Engelhardt, K. R., McGhee, S., Winkler, S., Sassi, A., Woellner, C., Lopez-Herrera, G., Chen, A., Kim, H. S., Lloret, M. G., Schulze, I., Ehl, S., Thiel, J., Pfeifer, D., Veelken, H., Niehues, T., Siepermann, K., Weinspach, S., Reisli, I., Keles, S., Genel, F., Kutuculer, N., Camcioglu, Y., Somer, A., Karakoc-Aydiner, E., Barlan, I., Gennery, A., Metin, A., Degerliyurt, A., Pietrogrande, M. C., Yeganeh, M., Baz, Z., Al-Tamemi, S., Klein, C., Puck, J. M., Holland, S. M., McCabe, E. R., Grimbacher, B., Chatila, T. A.
2009; 124 (6): 1289-1302
Abstract
The genetic etiologies of the hyper-IgE syndromes are diverse. Approximately 60% to 70% of patients with hyper-IgE syndrome have dominant mutations in STAT3, and a single patient was reported to have a homozygous TYK2 mutation. In the remaining patients with hyper-IgE syndrome, the genetic etiology has not yet been identified.We aimed to identify a gene that is mutated or deleted in autosomal recessive hyper-IgE syndrome.We performed genome-wide single nucleotide polymorphism analysis for 9 patients with autosomal-recessive hyper-IgE syndrome to locate copy number variations and homozygous haplotypes. Homozygosity mapping was performed with 12 patients from 7 additional families. The candidate gene was analyzed by genomic and cDNA sequencing to identify causative alleles in a total of 27 patients with autosomal-recessive hyper-IgE syndrome.Subtelomeric biallelic microdeletions were identified in 5 patients at the terminus of chromosome 9p. In all 5 patients, the deleted interval involved dedicator of cytokinesis 8 (DOCK8), encoding a protein implicated in the regulation of the actin cytoskeleton. Sequencing of patients without large deletions revealed 16 patients from 9 unrelated families with distinct homozygous mutations in DOCK8 causing premature termination, frameshift, splice site disruption, and single exon deletions and microdeletions. DOCK8 deficiency was associated with impaired activation of CD4+ and CD8+T cells.Autosomal-recessive mutations in DOCK8 are responsible for many, although not all, cases of autosomal-recessive hyper-IgE syndrome. DOCK8 disruption is associated with a phenotype of severe cellular immunodeficiency characterized by susceptibility to viral infections, atopic eczema, defective T-cell activation and T(h)17 cell differentiation, and impaired eosinophil homeostasis and dysregulation of IgE.
View details for DOI 10.1016/j.jaci.2009.10.038
View details for Web of Science ID 000273071500022
View details for PubMedID 20004785
Abstract
Assay of T-cell receptor excision circles (TRECs) in dried blood spots obtained at birth permits population-based newborn screening (NBS) for severe combined immunodeficiency (SCID).We sought to report the first 2 years of TREC NBS in California.Since August 2010, California has conducted SCID NBS. A high-throughput TREC quantitative PCR assay with DNA isolated from routine dried blood spots was developed. Samples with initial low TREC numbers had repeat DNA isolation with quantitative PCR for TRECs and a genomic control, and immunophenotyping was performed within the screening program for infants with incomplete or abnormal results. Outcomes were tracked.Of 993,724 infants screened, 50 (1/19,900 [0.005%]) had significant T-cell lymphopenia. Fifteen (1/66,250) required hematopoietic cell or thymus transplantation or gene therapy; these infants had typical SCID (n = 11), leaky SCID or Omenn syndrome (n = 3), or complete DiGeorge syndrome (n = 1). Survival to date in this group is 93%. Other T-cell lymphopenic infants had variant SCID or combined immunodeficiency (n = 6), genetic syndromes associated with T-cell impairment (n = 12), secondary T-cell lymphopenia (n = 9), or preterm birth (n = 8). All T-cell lymphopenic infants avoided live vaccines and received appropriate interventions to prevent infections. TREC test specificity was excellent: only 0.08% of infants required a second test, and 0.016% required lymphocyte phenotyping by using flow cytometry.TREC NBS in California has achieved early diagnosis of SCID and other conditions with T-cell lymphopenia, facilitating management and optimizing outcomes. Furthermore, NBS has revealed the incidence, causes, and follow-up of T-cell lymphopenia in a large diverse population.
View details for DOI 10.1016/j.jaci.2013.04.024
View details for Web of Science ID 000321052300019
View details for PubMedID 23810098
Abstract
A major diagnostic intervention in the consideration of many patients suspected to have primary immunodeficiency diseases (PIDDs) is the application and interpretation of vaccination. Specifically, the antibody response to antigenic challenge with vaccines can provide substantive insight into the status of human immune function. There are numerous vaccines that are commonly used in healthy individuals, as well as others that are available for specialized applications. Both can potentially be used to facilitate consideration of PIDD. However, the application of vaccines and interpretation of antibody responses in this context are complex. These rely on consideration of numerous existing specific studies, interpolation of data from healthy populations, current diagnostic guidelines, and expert subspecialist practice. This document represents an attempt of a working group of the American Academy of Allergy, Asthma & Immunology to provide further guidance and synthesis in this use of vaccination for diagnostic purposes in consideration of PIDD, as well as to identify key areas for further research.
View details for DOI 10.1016/j.jaci.2012.07.002
View details for Web of Science ID 000308464300001
View details for PubMedID 22935624
Abstract
Personalized medicine seeks to stratify therapies according to individual characteristics, and by so doing improve effectiveness and reduce complications. However, there are not many models of care that is highly stratified within a single diagnosis in this manner. One potential model is the practice of allergy, in which care is tailored to specific allergens for individual patients within the broader context of care for rhinitis or asthma. Allergists have already confronted many of the same regulatory issues anticipated for personalized medicine. The history of allergy practice also anticipates some of the patient safety concerns that may arise from tracking and using highly personalized medical information. Finally, the therapy of allergy and asthma has been at the forefront of attempts to incorporate pharmacogenomics information into patient care. Individualized therapy has always been central to the practice of allergy, and so provides a useful proving ground for personalized medicine as a concept of care.
View details for DOI 10.1016/j.ymgme.2011.07.017
View details for Web of Science ID 000295151300002
View details for PubMedID 21810545
Abstract
DOCK8 deficiency is a newly described primary immune deficiency resulting in profound susceptibility to cutaneous viral infections, elevated IgE levels, and eosinophilia, but lacking in the skeletal manifestations commonly seen in hyper IgE syndrome, which it otherwise resembles. Although little is known about the DOCK8 protein, it resembles other atypical guanine exchange factors in the DOCK family, and is known to bind to CDC42. This suggests that a likely role for DOCK8 is in modulating signals that trigger cytoskeletal reorganization. As a result, DOCK8 may also be related to other immune deficiencies that involve the cytoskeleton and Rho GTPase signaling pathways, such as Wiskott-Aldrich syndrome and Rac2 deficiency.
View details for DOI 10.3233/DMA-2010-0740
View details for Web of Science ID 000285458400005
View details for PubMedID 21178274
Abstract
Adoptive transfer of mature T cells (ATMTC) through bone marrow (BM) transplantation, first attempted over 20 years ago, has recently emerged as a successful therapy for complete 22q deletion syndrome (22qDS). This provides a potential option to thymic transplantation (TT) for immune reconstitution in 22qDS. Compared to thymic transplant, ATMTC is an easier procedure to accomplish and is available at more centers. However, there are differences in the nature of the T-cell reconstitution that results. Predictably, more naïve T cells and recent thymic emigrants are present in patients treated with thymus transplant. There are no significant differences in mortality between the two procedures, but the number of patients is too limited to conclude that the procedures are equally effective. Adoptive transfer should be pursued as a reasonable treatment for 22qDS patients requiring immune reconstitution when thymus transplant is not available.
View details for DOI 10.1007/s12026-009-8108-7
View details for Web of Science ID 000269904000004
View details for PubMedID 19238335
Abstract
The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE, and diminished inflammatory responses. It exists as autosomal-dominant and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)-3 and impaired T(H)17 differentiation.To elucidate mechanisms underlying different forms of HIES.A cohort of 25 Turkish children diagnosed with HIES were examined for STAT3 mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-alpha was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. T(H)17 and T(H)1 cell differentiation was assessed by measuring the production of IL-17 and IFN-gamma, respectively.Six subjects had STAT3 mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired T(H)17 responses, but whereas STAT3 mutations abrogated early steps in T(H)17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps.In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired T(H)17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome.
View details for DOI 10.1016/j.jaci.2009.05.004
View details for Web of Science ID 000268860400023
View details for PubMedID 19577286
Abstract
The benefit of immunoglobulin (IG) replacement in primary antibody deficiencies is unquestionable. Many of these congenital disorders present early in life and this therapy is often first implemented in the young. This article focuses on the indications of IG replacement in children, with an emphasis on the specific diagnostic problems encountered in this population. Also presented is an overview of the practical aspects of IG administration in the pediatric setting, including the recognition and management of adverse reactions. Finally, the advent of subcutaneous IG, a therapeutic IG modality with the potential to have a great impact on the quality of life of children with antibody deficiencies and their families, is discussed.
View details for DOI 10.1016/j.iac.2008.07.001
View details for Web of Science ID 000261161800010
View details for PubMedID 18940577
Abstract
DiGeorge (del22q11.2) syndrome is estimated to occur in 1:4,000 births, is the most common contiguous-gene deletion syndrome in humans, and is caused by autosomal dominant deletions in the 22q11.2 DiGeorge syndrome critical region (DGCR). Multiple microarray methods have been developed recently for analyzing such copy number changes, but data analysis and accurate deletion detection remains challenging. Clinical use of these microarray methods would have many advantages, particularly when the possibility of a chromosomal disorder cannot be determined simply on the basis of history and physical examination data alone. We investigated the use of the microarray technique, representational oligonucleotide microarray analysis (ROMA), in the detection of del22q11.2 syndrome. Genomic DNA was isolated from three well-characterized cell lines with 22q11.2 DGCR deletions and from the blood of a patient suspected of having del22q11.2 syndrome, and analyzed using both the binning and change-point model algorithms. Though the 22q11.2 deletion was easily identified with either method, change-point models provide clearer identification of deleted regions, with the potential for fewer false-positive results. For circumstances in which a clear, a priori, copy-number change hypothesis is not present, such as in many clinical samples, change-point methods of analysis may be easier to interpret.
View details for DOI 10.1002/humu.20593
View details for Web of Science ID 000252143300024
View details for PubMedID 17694540
Abstract
Therapeutic options for DiGeorge syndrome (DGS) with profound T-cell deficiency are very limited. Thymic transplantation has shown promising results but is not easily available. Hematopoietic cell transplantation (HCT) has been successful in restoring immune competence in the short term.Present the long-term follow-up of 2 patients with complete DGS who received bone marrow transplants in the neonatal period from HLA-matched siblings, and perform a multicenter survey to document the status of other patients with DGS who have undergone HCT.Immune function assessment by immunophenotyping, lymphocyte proliferation, T-cell receptor excision circles, single nucleotide polymorphism mapping arrays, spectratyping, cytogenetics, and fluorescence in situ hybridization were used.Among reported patients with DGS receiving HCT, survival is greater than 75%. Our patients are in their 20s and in good health. Their hematopoietic compartment shows continuous engraftment with mixed chimerism, normal T-cell function, and humoral immunity. Circulating T cells exhibit a memory phenotype with a restricted repertoire and are devoid of T-cell receptor excision circles.These features suggest that T-cell reconstitution has occurred predominantly through expansion of the donors' mature T-cell pool. Although restricted, their immune systems are capable of providing substantial protection to infection and respond to vaccines. We conclude that bone marrow transplant achieves long-lived reconstitution of immune function in complete DGS and is a good alternative to thymic transplantation in patients with a suitable donor.Bone marrow transplant in complete DGS using an HLA-matched sibling donor provides long-lasting immunity and is a suitable and more available alternative to thymic transplantation.
View details for DOI 10.1016/j.jaci.2007.08.048
View details for Web of Science ID 000250157700027
View details for PubMedID 17931564
Abstract
Outcomes for infants with severe combined immunodeficiency (SCID) would be improved by universal newborn screening, but there are not yet screening tests of sufficient accuracy for the disorder. In a pilot study, we assessed the ability of a two-tiered strategy to improve accuracy. Dried blood samples from patients were assessed with two tests for lymphopenia: interleukin-7, a T-cell growth cytokine, and TRECs, a byproduct of T-cell receptor recombination. IL-7 screening has a specificity of 96.1% and TRECs have a specificity of 92.3%. Combining these tests in a two-tiered strategy increases specificity to 100% (97-100% CI). Sensitivity was 85% for IL-7 screening and 100% for TREC screening. A two-tiered strategy may be of sufficient accuracy to enable universal SCID screening, and should be assessed in a prospective trial.
View details for DOI 10.1016/j.ymgme.2005.09.005
View details for Web of Science ID 000234282500002
View details for PubMedID 16260163
Abstract
Severe combined immunodeficiency (SCID) is a rare, treatable disorder of the immune system. The incidence is unknown but may be more common than published estimates because infants frequently die of infection before diagnosis. SCID is a candidate for universal newborn screening, so there is a need to determine under which circumstances screening would be cost-effective.We assumed a screening program for SCID would use T-cell lymphopenia as the screening criterion and performed a cost-utility analysis comparing universal screening with screening only those with a family history of SCID.Assuming society is willing to pay $50,000 for every quality-adjusted life-year saved, a SCID screening test that cost less than $5 with a false-negative rate of 0.9% and a false-positive rate of 0.4% would be considered cost-effective. A nationwide screening program would cost an additional $23.9 million per year for screening costs but would result in 760 years of life saved per year of screening. The cost to detect 1 case of SCID would be $485,000.SCID screening could result in a large benefit to detected individuals, making screening relatively cost-effective in spite of the low incidence of the disease. However, an adequate test is critical to cost-effectiveness.
View details for DOI 10.1016/j.jpeds.2005.06.001
View details for Web of Science ID 000233500000012
View details for PubMedID 16291349
Abstract
We report a 16-year-old boy with no evidence of immunodeficiency who had a 2-year history of chronic fatigue, low grade fever and slapped-cheek rash associated with chronic parvovirus B19 viremia. Prolonged intravenous immunoglobulin therapy resulted in resolution of his symptoms and viremia. Intravenous immunoglobulin may be useful in the resolution of parvovirus viremia regardless of immune status.
View details for DOI 10.1097/01.inf.0000155194.66797.20
View details for Web of Science ID 000227567700017
View details for PubMedID 15750469
Abstract
The authors report on the level of posttraumatic stress disorder (PTSD) experienced by fourth-grade children 6 months after Hurricane Floyd and describe the children's efforts to cope with their stress. All of the children they studied were directly affected by the hurricane, secondary to the destruction of their school by floodwaters. The homes of 37% of these children were also flooded. Ninety-five percent of the children experienced at least mild symptoms of PTSD, and 71% had symptoms that were moderate to very severe. Children who reported that their homes were flooded were 3 times more likely to report symptoms than those whose homes were not flooded, and the girls were twice as likely as the boys to report symptoms. The high PTSD prevalence rates are comparable to findings from other studies involving violence in which 94% of the victims reported experiencing symptoms. For further analyses, the authors used symptom clusters of hyperarousal, numbing/avoidance, and reexperiencing symptoms.
View details for Web of Science ID 000180870600003
View details for PubMedID 12613287
Abstract
Nonspecific cross-reacting antigen (NCA) is the name of a family of highly glycosylated bacterial-binding receptors found on human granulocytes and other tissues. These glycoproteins are members of the immunoglobulin supergene family and are related structurally to carcinoembryonic antigen. In this study, we demonstrate that ligation of granulocyte NCA results in the activation of the cells, as measured by degranulation and the flux of intracellular calcium. These studies further the proposition that NCA has a function in the immune response of granulocytes against bacterial infections.
View details for Web of Science ID A1996VP42800024
View details for PubMedID 8890209
Abstract
The organic solvent octane has been used routinely to permeabilize the hydrophobic vitelline membrane surrounding the Drosophila embryo, thereby allowing the movement of small molecules into the egg. We present evidence that hexane is a more effective permeabilizing agent than octane and compare the effects of these solvents on uniformity of permeabilization and embryonic viability. The ability of each solvent to make the embryo accessible to a range of biological stains was compared. The effect of octane versus hexane permeabilization on subsequent embryonic viability was measured at seven different stages during early embryogenesis. We found that although hexane is a superior solvent for permeabilizing the vitelline membrane, it decreases the viability of embryos exposed between 0 and 3 hr of age. Older embryos treated with either hexane or octane are usually viable. We also showed that molecules with a molecular mass of 984 Daltons or more did not diffuse into the embryo following treatment with either hexane or octane. Results presented here challenge a phase-partition model that has been proposed previously to explain the molecular basis of permeabilization of the Drosophila egg. An alternative model is described as well as an optimized protocol for permeabilizing and staining Drosophila embryos at any stage during early embryogenesis while maintaining viability for subsequent culture.
View details for Web of Science ID A1994MU12300004
View details for PubMedID 7511938
