Manish Butte

Evidence for a pre-malignant cell line in a skin biopsy from a patient with Nijmegen breakage syndrome.

Mol Cytogenet. 2018;11:17

Authors: Habib R, Neitzel H, Ernst A, Wong JKL, Goryluk-Kozakiewicz B, Gerlach A, Demuth I, Sperling K, Chrzanowska K

Abstract
Background: Nijmegen breakage syndrome is an autosomal recessive disorder characterized by microcephaly, immunodeficiency, hypersensitivity to X-irradiation, and a high predisposition to cancer. Nibrin, the product of the NBN gene, is part of the MRE11/RAD50 (MRN) complex that is involved in the repair of DNA double strand breaks (DSBs), and plays a critical role in the processing of DSBs in immune gene rearrangements, telomere maintenance, and meiotic recombination. NBS skin fibroblasts grow slowly in culture and enter early into senescence.
Case presentation: Here we present an incidental finding. Skin fibroblasts, derived from a 9 year old NBS patient, showed a mosaic of normal diploid cells (46,XY) and those with a complex, unbalanced translocation. The aberrant karyotype was analysed by G-banding, comparative genomic hybridization, and whole chromosome painting. The exact breakpoints of the derivative chromosome were mapped by whole genome sequencing: 45,XY,der(6)(6pter → 6q11.1::13q11 → 13q21.33::20q11.22 → 20qter),-13. The deleted region of chromosomes 6 harbors almost 1.400 and that of chromosome 13 more than 500 genes, the duplicated region of chromosome 20 contains about 700 genes. Such unbalanced translocations are regularly incompatible with cellular survival, except in malignant cells. The aberrant cells, however, showed a high proliferation potential and could even be clonally expanded. Telomere length was significantly reduced, hTERT was not expressed. The cells underwent about 50 population doublings until they entered into senescence. The chromosomal preparation performed shortly before senescence showed telomere fusions, premature centromere divisions, endoreduplications and tetraploid cells, isochromatid breaks and a variety of marker chromosomes. Inspection of the site of skin biopsy 18 years later, presented no evidence for abnormal growth.
Conclusions: The aberrant cells had a significant selective advantage in vitro. It is therefore tempting to speculate that this highly unbalanced translocation could be a primary driver of cancer cell growth.

PMID: 29445421 [PubMed]

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Clinical Implications of Digenic Inheritance and Epistasis in Primary Immunodeficiency Disorders.

Front Immunol. 2017;8:1965

Authors: Ameratunga R, Woon ST, Bryant VL, Steele R, Slade C, Leung EY, Lehnert K

Abstract
The existence of epistasis in humans was first predicted by Bateson in 1909. Epistasis describes the non-linear, synergistic interaction of two or more genetic loci, which can substantially modify disease severity or result in entirely new phenotypes. The concept has remained controversial in human genetics because of the lack of well-characterized examples. In humans, it is only possible to demonstrate epistasis if two or more genes are mutated. In most cases of epistasis, the mutated gene products are likely to be constituents of the same physiological pathway leading to severe disruption of a cellular function such as antibody production. We have recently described a digenic family, who carry mutations of TNFRSF13B/TACI as well as TCF3 genes. Both genes lie in tandem along the immunoglobulin isotype switching and secretion pathway. We have shown they interact in an epistatic way causing severe immunodeficiency and autoimmunity in the digenic proband. With the advent of next generation sequencing, it is likely other families with digenic inheritance will be identified. Since digenic inheritance does not always cause epistasis, we propose an epistasis index which may help quantify the effects of the two mutations. We also discuss the clinical implications of digenic inheritance and epistasis in humans with primary immunodeficiency disorders.

PMID: 29434582 [PubMed]

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PSTPIP1 controls immune synapse stability in human T-cells.

J Allergy Clin Immunol. 2018 Feb 09;:

Authors: Janssen WJM, Grobarova V, Leleux J, Jongeneel CH, van Gijn M, van Montfrans JM, Boes M

Abstract
BACKGROUND: PSTPIP1 is a cytosolic adaptor protein involved with T-cell activation, differentiation, and migration. Upon cognate T-cell contact, PSTPIP1 is recruited to surface-expressed CD2, where it regulates f-actin remodeling. An immune synapse (IS) is thereby rapidly formed, consisting of TCR clusters surrounded by a ring of adhesion molecules including CD2.
OBJECTIVE: From genetic screening of primary immunodeficiency patients, we identified two mutations in PSTPIP1, R228C and T274M which we further characterized in primary patient T-cells.
METHODS: F-actin dynamics were assessed in patient and healthy control primary T-cells by use of FACS. HEK293T and Jurkat cells were transfected with R228C, T274M and WT PSTPIP1 in order to visualize f-actin in immune synapse formation. CD2-PSTPIP1 association was quantified through immunoprecipitation assays.
RESULTS: The patients presented with immunodeficiency without signs of auto-inflammation. The R228C patient had expansion of mostly naive phenotype T-cells and few memory T-cells; the T274M patient had 75% reduction in CD4 T-cells that were predominantly of memory subset.We observed f-actin polymerization defects in both PSTPIP1 patient T-cells, most notably T274M. Capping of CD2-containing membrane microdomains was disrupted. Analysis of IS formation using Jurkat T-cell transfectants revealed a reduction in f-actin accumulation at the IS, again especially in T274M PSTPIP1 cells. Patient T274M T-cells migrated spontaneously at increased speed as assessed in a 3D collagen matrix, while TCR crosslinking induced a significantly diminished calcium flux.
CONCLUSIONS: We propose that PSTPIP1 T-cell differentiation defects are caused by defective control of f-actin polymerization. A pre-activated polymerized f-actin status, as seen in PSTPIP1-T274M T-cells, appears particularly damaging. PSTPIP1 controls IS formation and cell adhesion, through its function as orchestrator of the f-actin cytoskeleton.

PMID: 29432774 [PubMed – as supplied by publisher]

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The anti-osteosarcoma cell activity by a mTORC1/2 dual inhibitor RES-529.

Biochem Biophys Res Commun. 2018 Feb 09;:

Authors: Hu X, Wang Z, Chen M, Chen X, Liang W

Abstract
mTOR over-activation is important for human osteosarcoma (OS) tumorigenesis and progression. RES-529 is a mTORC1/2 dual inhibitor. Here, our results show that RES-529 inhibited viability, cell cycle progression and proliferation of the established (U2OS line) and primary human OS cells. RES-529 induced apoptosis activation in OS cells. It was yet non-cytotoxic to OB-6 osteoblastic cells and the primary human osteoblasts. RES-529 disrupted assembling of mTORC1 (mTOR-Raptor association) and mTORC2 (mTOR-Rictor-mLST8 association) in human OS cells, blocking mTORC1/2 activation. Significantly, RES-529 induced reactive oxygen species (ROS) production and mitochondrial depolarization in U2OS cells as well. RES-529-induced anti-OS cell activity was more potent than other known Akt-mTOR inhibitors. In vivo, RES-529 intraperitoneal injection significantly inhibited U2OS xenograft tumor growth in severe combined immunodeficiency (SCID) mice. mTORC1/2 activation in RES-529-treated tumor tissues was largely inhibited. Collectively, the mTOR inhibitor RES-529 efficiently inhibits human OS cell growth in vitro and in vivo.

PMID: 29432734 [PubMed – as supplied by publisher]

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[Burkholderia cepacia infection in children: a clinical analysis of 16 cases].

Zhongguo Dang Dai Er Ke Za Zhi. 2018 Feb;20(2):112-115

Authors: Peng F, Zhong LL, Lin XJ, Chen M, Zhou M

Abstract
OBJECTIVE: To investigate the distribution characteristics and clinical features of Burkholderia cepacia infection in children.
METHODS: A retrospective analysis was performed for the clinical data of 16 children with Burkholderia cepacia infection who were hospitalized between June 2012 and September 2017.
RESULTS: All 16 children with Burkholderia cepacia infection were sporadic cases. A total of 16 strains of Burkholderia cepacia were isolated, among which 8 were detected by sputum culture, 5 were detected by blood culture, 2 were detected by tracheal intubation tip culture, and 1 was detected by lung biopsy culture. Of the 16 children, there were 11 boys and 5 girls, with an age of 5 days to 6 years, and the children aged <1 year accounted for 69%. As for department distribution, 10 children were in the PICU/NICU and 6 were in the general wards. As for clinical manifestations, one child had disseminated intravascular coagulation, and the other 15 children had pulmonary infection, among who 11 had severe pneumonia (8 of them underwent mechanical ventilation during treatment). As for underlying diseases, 2 had severe congenital heart disease, 4 had primary immunodeficiency, 3 were highly suspected of immunodeficiency or inherited metabolic diseases, 1 had tracheal stenosis, 1 had Kawasaki disease, 1 was a preterm infant with bronchopulmonary dysplasia, 1 had severe cleft lip and palate, and 3 had no definite underlying diseases. Of all the children, 7 also had infections with adenovirus and Mycoplasma. The average length of hospital stay was 20.3 days for all children, and 12 were improved and 4 died after treatment. All 16 strains of Burkholderia cepacia had a drug resistance rate of 100% to amikacin and gentamicin and ≥80% to ampicillin/sulbactam and ticarcillin/clavulanic acid, as well as the lowest drug resistance rate to levofloxacin.
CONCLUSIONS: Burkholderia cepacia is an opportunistic pathogen often found in immunocompromised children and can produce drug resistance. The presence or absence of underlying diseases should be considered during anti-infective therapy. The children with Burkholderia cepacia infection often have a poor prognosis, and an understanding of the disease spectrum of Burkholderia cepacia infection helps with clinical diagnosis and treatment.

PMID: 29429458 [PubMed – in process]

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Vaccination in immunocompromised host: Recommendations of Italian Primary Immunodeficiency Network Centers (IPINET).

Vaccine. 2018 Feb 06;:

Authors: Martire B, Azzari C, Badolato R, Canessa C, Cirillo E, Gallo V, Graziani S, Lorenzini T, Milito C, Panza R, Moschese V, with Italian Network for Primary Immunodeficiencies (IPINET)

Abstract
Infectious complications are a major cause of morbidity and mortality in patients with primary or secondary immunodeficiency. Prevention of infectious diseases by vaccines is among the most effective healthcare measures mainly for these subjects. However immunocompromised people vary in their degree of immunosuppression and susceptibility to infection and, therefore, represent a heterogeneous population with regard to immunization. To date there is no well- established evidence for use of vaccines in immunodeficient patients, and indications are not clearly defined even in high-quality reviews and in most of the guidelines prepared to provide recommendations for the active vaccination of immunocompromised hosts. The aim of this document is to issue recommendations based on published literature and the collective experience of the Italian primary immunodeficiency centers, about how and when vaccines can be used in immunocompromised patients, in order to facilitate physician decisions and to ensure the best immune protection with the lowest risk to the health of the patient.

PMID: 29426658 [PubMed – as supplied by publisher]

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Clinical and Genetic Features of the Patients with X-Linked Agammaglobulinemia from Turkey: Single Center Experience.

Scand J Immunol. 2018 Feb 09;:

Authors: Esenboga S, Çagdas D, Ozgur TT, Gur Çetinkaya P, Turkdemir LM, Sanal O, VanDer Burg M, Tezcan İ

Abstract
INTRODUCTION: X-linked agammaglobulinemia is a primary immunodeficiency disorder resulting from BTK gene mutations. There are many studies in the literature suggesting contradictory ideas about phenotype- genotype correlation.
OBJECTIVE: The aim of this study was to identify the mutations and clinical findings of patients with XLA in Turkey, to determine long-term complications related to the disease and to analyze the phenotype-genotype correlation.
MATERIALS AND METHODS: Thirty-two patients with XLA diagnosed between 1985-2016 in Pediatric Immunology Department of Hacettepe University Ihsan Dogramaci Children’s Hospital were investigated. A clinical survey including clinical features of the patients was completed and the patients were classified according to the type of genetic defect, namely, those having mutations leading to aminoacid substitution, or protein truncation, and according to the affected domain.
RESULTS: Thirty-two patients from 26 different families were included in the study. We did not observe any significant correlation between genotype and severity of the disease. There was no significant difference regarding age at the onset of symptoms, age at diagnosis, time for diagnosis from disease onset, median IgG levels in the first/ last year of IVIg replacement, IgA, IgG and IgM levels at first visit, severity of disease in groups with different defects.
DISCUSSION: Getting early diagnosis and regular assessment with imaging techniques seems to be the most important issues for improving the health status of the patients with XLA. Early molecular analysis gives chance for definitive diagnosis and genetic counseling, but not for predicting the clinical severity and prognosis. This article is protected by copyright. All rights reserved.

PMID: 29424453 [PubMed – as supplied by publisher]

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Prescribing Immunoglobulin Replacement Therapy for Patients with Non-classical and Secondary Antibody Deficiency: an Analysis of the Practice of Clinical Immunologists in the UK and Republic of Ireland.

J Clin Immunol. 2018 Feb 08;:

Authors: Edgar JDM, Richter AG, Huissoon AP, Kumararatne DS, Baxendale HE, Bethune CA, Garcez T, Misbah SA, Sorensen RU, United Kingdom Primary Immunodeficiency Network (UKPIN) Immunoglobulin Decision to Treat Study Group

Abstract
BACKGROUND: Immunologists are increasingly being asked to assess patients with non-classical and secondary antibody deficiency to determine their potential need for immunoglobulin replacement therapy (IGRT). Immunoglobulin is a limited, expensive resource and no clear guidance exists for this broad patient group. The purpose of this survey is to establish what factors influence the decision to commence IGRT in adult patients, when diagnostic criteria for primary antibody deficiency are not fulfilled.
METHODS: Under the auspices of the United Kingdom Primary Immunodeficiency Network (UKPIN), a study group was established which circulated an online questionnaire to the consultant body across the UK and Ireland. Results provided a snapshot of the current clinical practice of 71% of consultant immunologists, from 30 centers.
RESULTS: In order of importance, factors which influence the decision to commence IGRT include number of hospital admissions with infection, serum IgG level, bronchiectasis, radiologically proven pneumonia, number of positive sputum cultures, number of antibiotic courses, and results of immunization studies. The commonest test vaccine used was Pneumovax 23 with measurement of serotype-specific responses at 4 weeks, with a threshold of 0.35 μg/ml in 2/3 of serotypes measured. Eighty-six percent of patients are treated with a trial of prophylactic antibiotics prior to consideration of IGRT. Efficacy of IGRT trial is assessed at between 6 and 12 months.
CONCLUSIONS: There was consistency in clinical practice using a combination of clinical history, evidence of infections, and vaccination testing for diagnosis. However, there was some variation in the implementation of this practice, particularly in vaccine choice and assessment of response to vaccination.

PMID: 29423883 [PubMed – as supplied by publisher]

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Neurologic Involvement in Primary Immunodeficiency Disorders.

J Child Neurol. 2018 Jan 01;:883073817754176

Authors: Yildirim M, Ayvaz DC, Konuskan B, Gocmen R, Tezcan I, Topcu M, Topaloglu H, Anlar B

Abstract
The nervous system may be affected in primary immune deficiency (PID) syndromes through infectious, autoimmune, neoplastic mechanisms, or as a primary feature of the syndrome. However certain neurologic problems do not conform to these etiopathogenetic groups. We retrospectively examined PID patients seen in neurology consultation between 2014 and 2017 in order to determine the spectrum of nervous system involvement. Among patients with confirmed neurologic problems (n = 35), common manifestations were encephalopathy and global developmental/cognitive delay. In 13 (37%) instances, the neurologic signs had no apparent relation with a treatment-related, infectious, or vascular complication and were considered as primary findings: acquired microcephaly, central nervous system malformation, or peripheral neuropathy. The diagnosis of PID was made after, and based on, the neurologic manifestation in 6 of 35 (17%) patients. Neurologic presentation may constitute the initial manifestation in some types of primary immune deficiency.

PMID: 29421957 [PubMed – as supplied by publisher]

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Autosomal recessive hyper-IgE syndrome in two brothers of a Chinese family with a novel mutation in DOCK8 gene.

J Eur Acad Dermatol Venereol. 2018 Feb 08;:

Authors: Wang S, Mou W, Xu Z, Gui J, Ma L

Abstract
The hyper-IgE syndromes (HIES) are complex primary immunodeficiency disorders, including autosomal dominant form (AD-HIES) and recessive form (AR-HIES). Here we describe two boys with AR-HIES in a Chinese family and a novel mutation of DOCK8 gene was identified.The index patient was an 8-year-old boy. He presented with recurrent flexural skin lesions (similar with atopic dermatitis (AD)) for more than 5 years (Fig. 1a,b), and a 6-months history of severe molluscum contagiosum(Fig. 1c) and verruca plana(Fig. 1d). He had repeated respiratory tract infection, nasosinusitis and otitis media every year, with a history of asthma and peanut allergy. This article is protected by copyright. All rights reserved.

PMID: 29419892 [PubMed – as supplied by publisher]

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