Manish Butte

Epidermodysplasia Verruciformis: Inborn Errors of Immunity to Human Beta-Papillomaviruses.

Front Microbiol. 2018;9:1222

Authors: de Jong SJ, Imahorn E, Itin P, Uitto J, Orth G, Jouanguy E, Casanova JL, Burger B

Abstract
Epidermodysplasia verruciformis (EV) is an autosomal recessive skin disorder with a phenotype conditional on human beta-papillomavirus (beta-HPV) infection. Such infections are common and asymptomatic in the general population, but in individuals with EV, they lead to the development of plane wart-like and red or brownish papules or pityriasis versicolor-like skin lesions, from childhood onwards. Most patients develop non-melanoma skin cancer (NMSC), mostly on areas of UV-exposed skin, from the twenties or thirties onwards. At least half of the cases of typical EV are caused by biallelic loss-of-function mutations of TMC6/EVER1 or TMC8/EVER2. The cellular and molecular basis of disease in TMC/EVER-deficient patients is unknown, but a defect of keratinocyte-intrinsic immunity to beta-HPV is suspected. Indeed, these patients are not susceptible to other infectious diseases and have apparently normal leukocyte development. In contrast, patients with an atypical form of EV due to inborn errors of T-cell immunity invariably develop clinical symptoms of EV in the context of other infectious diseases. The features of the typical and atypical forms of EV thus suggest that the control of beta-HPV infections requires both EVER1/EVER2-dependent keratinocyte-intrinsic immunity and T cell-dependent adaptive immunity.

PMID: 29946305 [PubMed]

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Analysis of differences between total IgG and sum of the IgG subclasses in children with suspected immunodeficiency – indication of determinants.

BMC Immunol. 2018 Jun 27;19(1):22

Authors: Pasternak G, Lewandowicz-Uszyńska A, Pentoś K

Abstract
BACKGROUND: Deficits in disorders of humoral immunity associated with a deficit of antibodies are the most common primary immunodeficiency. Total IgG and IgG subclasses measurements are used to diagnose, differentiate and control in patients with primary and secondary immunodeficiencies.
METHODS: The purpose of the study was to analyze the structure patients group according to difference between total IgG and sum of the IgG subclasses and to determine factors affecting the level of this difference. This study was based on data collected from 670 children referred to the Department of Clinical Immunology and Pediatrics in order to diagnose the immune disorders. For all children the level of the total of immunoglobulins IgG and of the IgG subclasses (IgG1, IgG2, IgG3, IgG4) were determined. The group of children was divided into subgroups according to gender, age (under 6 years of age, 6.5-12 years, and 12-18 years), and IgG abnormality (below the normal range, normal and above the normal range). In the patients group, the total IgG values were on average higher than sum of the IgG subclasses.
RESULTS: Statistical analysis shown the all parameters under study (age, gender and IgG abnormality) influence statistically significant on the discrepancy between the sum of the IgG subclasses and total IgG. Assessment of IgG and IgG subclasses levels is based on different methods what causes the discrepancy between the sum of the IgG subclasses and total IgG.
CONCLUSIONS: Standardization in that regard is crucial. In addition, we have shown the reliability of the results obtained. Despite the determination in two different laboratories and on different analyzers, as well as the freezing process does not affect the test results.

PMID: 29945547 [PubMed – in process]

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Newborn screening using TREC/KREC assay for severe T and B cell lymphopenia in Iran.

Scand J Immunol. 2018 Jun 26;:e12699

Authors: Nourizadeh M, Shakerian L, Borte S, Fazlollahi M, Badalzadeh M, Houshmand M, Alizadeh Z, Dalili H, Rashidi-Nezhad A, Kazemnejad A, Moin M, Hammarström L, Pourpak Z

Abstract
T-cell receptor excision circles (TRECs) and κ-deleting recombination excision circles (KRECs) are recently used for detection of T or B cell lymphopenia in neonates based on region-specific cutoff levels. Here, we report cutoffs for TREC and KREC copies useful for newborn screening and/or diagnosis of primary immunodeficiency diseases (PID) in Iran. DNA was extracted from a single 3.2 mm punch of dried blood spots collected from 2160 anonymized newborns referred to two major referral health centers between 2014 and 2016. For refinement of the cutoffs, 51 patients with a definite diagnosis of severe combined immunodeficiency, X-linked agammaglobulinaemia and combined immunodeficiency, including ataxia telangiectasia, human phosphoglucomutase 3 and Janus kinase-3 deficiency, as well as 47 healthy controls were included. Samples from patients with an X-linked hyper-IgM-syndrome, Wiskott-Aldrich syndrome and DNA ligase 4 deficiency were considered as disease controls. Triplex-quantitative real-time PCR was used. Cutoffs were calculated as TRECs < 11 and KRECs < 6 copies with an ACTB > 700 copies with sensitivity of 100% for TREC and 97% for KREC. Among thirty anonymized newborn samples (1.5%) with abnormal results for TREC and/or KREC, only twenty one available cases were retested and shown to be in the normal range except for three samples (0.15%). All of the patients with a definitive diagnosis were correctly identified based on our established TREC/KREC copy numbers. Determining cutoffs for TREC/KREC is essential for correctly identifying children with PID in newborn screening. Early diagnosis of PID patients enables appropriate measures and therapies like stem cell transplantation. This article is protected by copyright. All rights reserved.

PMID: 29943473 [PubMed – as supplied by publisher]

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Novel IL2RG Mutation Causes Leaky TLOWB+NK+ SCID With Nodular Regenerative Hyperplasia and Normal IL-15 STAT5 Phosphorylation.

J Pediatr Hematol Oncol. 2018 Jun 22;:

Authors: Neves JF, Martins C, Cordeiro AI, Neves C, Plagnol V, Curtis J, Fabre M, Bibi S, Borrego LM, Moshous D, Nejentsev S, Gilmour K

Abstract
X-linked severe combined immunodeficiency disease (SCID) is caused by mutations in the interleukin (IL)-2 receptor γ (IL2RG) gene and patients usually present with a TBNK SCID phenotype. Nevertheless, a minority of these patients present with a TBNK phenotype, similar to the IL-7R-deficient patients. We report a patient with a novel missense p.Glu297Gly mutation in the IL2RG gene presenting with a leaky TBNK SCID with delayed onset, moderate susceptibility to infections, and nodular regenerative hyperplasia. He presents with preserved STAT5 tyrosine phosphorylation in response to IL-15 stimulation but not in response to IL-2 and IL-7, resulting in the NK phenotype.

PMID: 29939941 [PubMed – as supplied by publisher]

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Identification of CD24 as a marker for tumorigenesis of melanoma.

Onco Targets Ther. 2018;11:3401-3406

Authors: Tang MR, Guo JY, Wang D, Xu N

Abstract
Objective: Cutaneous melanoma (CM) is a common skin cancer. Surgery is still the primary treatment for CM, as melanoma is resistant to chemotherapy. In the recent years, it has been found that cancer stem-like cells (CSCs) are responsible for this drug resistance. CD24 is a widely used marker to isolate CSCs. In this study, we aimed to analyze the properties of CD24+ and CD24- subpopulation of melanoma cells.
Materials and methods: We isolated CD24+ cells CSCs using magnetic-activated cell sorting system. We extracted total RNA and carried out reverse transcription polymerase chain reaction analysis. We counted the cell colonies using soft agar assay and assessed the cell invasion using cell migration assay. We implanted CD24+ or CD24- cells into the flank of non-obese diabetic severe combined immunodeficiency mice, and measured the tumor volumes every 5 days until the end of the experiment. We carried out immunohistochemical analysis to study the tissue sections.
Results: We demonstrated that the CD24+ subpopulation has self-renewal properties in vitro and in vivo by using soft agar assay and xenograft tumor model. Furthermore, we confirmed that CD24 expression is accompanied by activation of Notch1 signaling pathway.
Conclusion: This study provides new knowledge on the role of CD24 in the tumorigenic ability of melanoma.

PMID: 29928131 [PubMed]

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Genetic immune and inflammatory markers associated with diabetes in solid organ transplant recipients.

Am J Transplant. 2018 Jun 19;:

Authors: Quteineh L, Wójtowicz A, Bochud PY, Crettol S, Vandenberghe F, Venetz JP, Manuel O, Golshayan D, Lehmann R, Mueller NJ, Binet I, van Delden C, Steiger J, Mohacsi P, Dufour JF, Soccal PM, Kutalik Z, Marques-Vidal P, Vollenweider P, Recher M, Hess C, Pascual M, Eap CB, Swiss Transplant Cohort Study

Abstract
New-onset diabetes after transplantation (NODAT) is a complication following solid organ transplantation (SOT) and may be related to immune or inflammatory responses. We investigated whether single nucleotide polymorphisms (SNPs) within 158 immune- or inflammation-related genes contribute to NODAT in SOT recipients. The association between 263 SNPs and NODAT were investigated in a discovery sample of SOT recipients from the Swiss Transplant Cohort Study (STCS, n1 =696). Positive results were tested in a first STCS replication sample (n2 =489) and SNPs remaining significant after multiple test corrections were tested in a second SOT replication sample (n3 =156). Associations with diabetic traits were further tested in several large general population-based samples (n>480’000). Only SP110 rs2114592C>T remained associated with NODAT in the STCS replication sample. Carriers of rs2114592-TT had 9.9 times (95%C.I.:3.22-30.5, p=0.00006) higher risk for NODAT in the combined STCS samples (n=1184). rs2114592C>T was further associated with NODAT in the second SOT sample (OR:4.8, 95%C.I.:1.55-14.6, p=0.006). On the other hand, SP110 rs2114592C>T was not associated with diabetic traits in population-based samples, suggesting a specific gene-environment interaction, possibly due to the use of specific medications (i.e. immunosuppressants) in transplant patients and/or to the illness that may unmask the gene effect. This article is protected by copyright. All rights reserved.

PMID: 29920932 [PubMed – as supplied by publisher]

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“Experiences of the burden of treatment” – patient-reports of facilitated subcutaneous immunoglobulin treatment in adults with immunodeficiency.

J Clin Nurs. 2018 Jun 19;:

Authors: Petersson C, Fust R, Hagstedt C, Vågström P, Nilsdotter-Augustinsson Å

Abstract
AIMS AND OBJECTIVES: To evaluate patient-reported experiences of facilitated subcutaneous immunoglobulin treatment in adults with primary or secondary immunodeficiency.
BACKGROUND: Decreased levels of circulating antibodies (humoral immunodeficiency) are often associated with higher infection rates which cause problems in daily living, for example symptoms of severe and recurrent bacterial infections that may cause chronic lung diseases. For some diagnoses, treatment with immunoglobulin becomes critical and life-long. The acceptability of administration forms is important to achieve adherence to treatment, and to increase quality of life for these patients.
DESIGN: Convergent mixed method approach.
METHODS: A structured telephone interview with nine questions evaluated on a score scale about treatment experience, satisfaction, and ancillary supplies was used, followed by open-ended questions for each item.
RESULTS: Prohibiting factors were revealed, exemplified by problems due to technical issues and ancillary supply issues. Promoting factors was shown by high a satisfaction when combining treatment with daily life as well as increased wellbeing. Facilitated subcutaneous immunoglobulin treatment led to fewer treatment sessions, with a time-saving aspect also described by high scores in the item concerning longer treatment interval.
CONCLUSIONS: The opportunity to be given the best possible treatment plan adjusted for each patients’ situation is central. Healthcare professionals should discuss the different aspects that can promote and inhibit the outcomes of treatment.
RELEVANCE TO CLINICAL PRACTICE: The results can help professionals to understand different factors that may impinge on the patients’ everyday life when they are forced into a lifelong treatment regimen. This knowledge is also important for nurses who have a responsibility to promote health concerning patients with long-term conditions in general. This article is protected by copyright. All rights reserved.

PMID: 29917296 [PubMed – as supplied by publisher]

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Chronic subcutaneous infection due to Lichtheimia ramosa.

J Eur Acad Dermatol Venereol. 2018 Jun 17;:

Authors: Geng C, Lv X, Li J, Jiang Q, Yang R, Zhan P

Abstract
Lichtheimia (formerly Absidia), is a genus of saprotrophic zygomycetous fungi which causes invasive mucormycosis in immunocompromised human hosts, e.g, patient with haematological malignancy, neutropenia, diabetes mellitus and organ transplantations, as well as long period of corticosteroid and immunosuppressant application. There has been an increase of Lichtheimia infections worldwide and the most common agents are reported to be Lichtheimia corymbifera. Primary cutaneous and subcutaneous infection is usually associated with immunodeficiency or trauma and presents as locally invasive, very rapid aggressive lesions due to this fungi’s ability of angioinvasion. This article is protected by copyright. All rights reserved.

PMID: 29911306 [PubMed – as supplied by publisher]

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Crucial genes of inflammatory bowel diseases explored by gene expression profiling analysis.

Scand J Gastroenterol. 2018 Jun 16;:1-7

Authors: Xie D, Zhang Y, Qu H

Abstract
OBJECTIVES: This study aimed to uncover new potential genes associated with the inflammatory bowel diseases (IBDs).
MATERIALS AND METHODS: The datasets GSE36807 and GSE9686 were obtained from Gene Expression Omnibus (GEO). Totally, 24 Crohn’s disease (CD) samples, 20 ulcerative colitis (UC) samples and 15 healthy controls in the two datasets were used for our analysis. The differentially expressed genes (DEGs) were identified by limma package. Then, co-expression network was constructed by weighted gene correlation network analysis (WGCNA) package, and co-expression network modules were obtained via clustering method. The top 100 genes with the highest connectivity degrees were selected to construct a new co-expression network (CEN). Besides, pathway enrichment analysis for the genes in identified modules was conducted with the clusterProfiler package in R.
RESULTS: Totally, 302 and 2276 DEGs were respectively identified in CD and UC samples, and 291 ones were both differentially expressed in the two subtypes. Five modules were identified from the CEN. In the new CEN consisted of the top 100 genes with the highest connectivity degrees, the up-regulated DEGs all belonged to module 5, and the down-regulated ones all belonged to module 1. Furthermore, pathway enrichment analysis showed that some DEGs were related to primary immunodeficiency (e.g., CD4, CD3D and CD40LG), complement and coagulation cascades (e.g., C2, C1QB and C7) and nitrogen metabolism (e.g., CA1, CA12 and CA2).
CONCLUSION: The DEGs correlated with primary immunodeficiency, complement and coagulation cascades and nitrogen metabolism might be important for the development of IBD.

PMID: 29909694 [PubMed – as supplied by publisher]

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ZNF341 controls STAT3 expression and thereby immunocompetence.

Sci Immunol. 2018 Jun 15;3(24):

Authors: Frey-Jakobs S, Hartberger JM, Fliegauf M, Bossen C, Wehmeyer ML, Neubauer JC, Bulashevska A, Proietti M, Fröbel P, Nöltner C, Yang L, Rojas-Restrepo J, Langer N, Winzer S, Engelhardt KR, Glocker C, Pfeifer D, Klein A, Schäffer AA, Lagovsky I, Lachover-Roth I, Béziat V, Puel A, Casanova JL, Fleckenstein B, Weidinger S, Kilic SS, Garty BZ, Etzioni A, Grimbacher B

Abstract
Signal transducer and activator of transcription 3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled, and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-immunoglobulin E (IgE) syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished T helper 17 cell numbers, in absence of STAT3 mutations. We identified two distinct homozygous nonsense mutations in ZNF341, which encodes a zinc finger transcription factor. Wild-type ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindreds. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.

PMID: 29907690 [PubMed – in process]

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