Research

New insights into physiopathology of immunodeficiency-associated vaccine-derived poliovirus infection; systematic review of over 5 decades of data.

Vaccine. 2018 Feb 22;:

Authors: Shaghaghi M, Soleyman-Jahi S, Abolhassani H, Yazdani R, Azizi G, Rezaei N, Barbouche MR, McKinlay MA, Aghamohammadi A

Abstract
Widespread administration of oral poliovirus vaccine (OPV) has decreased global incidence of poliomyelitis by ≈99.9%. However, the emergence of vaccine-derived polioviruses (VDPVs) is threatening polio-eradication program. Primary immunodeficiency (PID) patients are at higher risks of vaccine-associated paralytic poliomyelitis (VAPP) and prolonged excretion of immunodeficiency-associated VDPV (iVDPV). We searched Embase, Medline, Science direct, Scopus, Web of Science, and CDC and WHO databases by 30 September 2016, for all reports of iVDPV cases. Patient-level data were extracted form eligible studies. Data on immunization coverage and income-level of countries were extracted from WHO/UNICEF and the WORLD BANK databases, respectively. We assessed bivariate associations between immunological, clinical, and virological parameters, and exploited multivariable modeling to identify independent determinants of poliovirus evolution and patients’ outcomes. Study protocol was registered with PROSPERO (CRD42016052931). 4329 duplicate-removed titles were screened. A total of 107 iVDPV cases were identified from 68 eligible articles. The majority of cases were from higher income countries with high polio-immunization coverage. 74 (69.81%) patients developed VAPP. Combined immunodeficiency patients showed lower rates of VAPP (p < .001) and infection clearance (p = .02), compared to humoral immunodeficiency patients. The rate of poliovirus genomic evolution was higher at early stages of replication, decreasing over time until reaching a steady state. Independent of replication duration, higher extent (p = .04) and rates (p = .03) of genome divergence contributed to a less likelihood of virus clearance. PID type (p < .001), VAPP occurrence (p = .008), and income-level of country (p = .04) independently influenced patients' survival. With the use of OPV, new iVDPVs will emerge independent of the rate of immunization coverage. Inherent features of PIDs contribute to the clinical course of iVDPV infection and virus evolution. This finding could shed further light on poliomyelitis pathogenesis and iVDPV evolution pattern. It also has implications for public health, the polio eradication effort and the development of effective antiviral interventions.

PMID: 29478755 [PubMed – as supplied by publisher]

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The Brain-Lung-Thyroid syndrome (BLTS): A novel deletion in chromosome 14q13.2-q21.1 expands the phenotype to humoral immunodeficiency.

Eur J Med Genet. 2018 Feb 22;:

Authors: Villafuerte B, Benito DN, González A, Mori MA, Palomares M, Nevado J, García-Miñaur S, Lapunzina P, González-Granado LI, Allende LM, Moreno JC

Abstract
Genetic defects of NKX2-1 are classically associated with hypothyroidism, benign chorea and neonatal respiratory distress. The purpose of this study was to identify the genetic pathogenesis of the “NKX2-1 triad” in a 10 year-old female presenting additional features barely described in the disorder. In the neonatal period, she presented with generalized hypotonia and respiratory distress, with later episodes of frequent wheezing. At 3 month-age developmental dysplasia of the hip was diagnosed and at 10 months, primary hypothyroidism was detected and treated. Subsequently, delayed achievement of developmental milestones and then subtle choreic movements of extremities were identified at 2 years of age. Furthermore, delayed teeth eruption and agenesis of some dental pieces, short stature and joint hyperlaxity were also noticed. At 10 years, a poor immune response to polysaccharide antigens and hypogammaglobulinemia, including all IgG subclasses were detected. Surprisingly, no mutations were identified in the complete coding region of NKX2-1 by PCR and Sanger sequencing. MLPA showed a de novo loss of gene dosage in all 3 probes located in NKX2-1 exons. A CGH-array identified a deletion of 3.32 Mb in chromosome 14q13.2-q21.1 containing 20 genes, including NKX2-1, PAX9 and two candidate genes (NFKB1A and PPP2R3C) involved in immune response. The Brain-Lung-Thyroid syndrome (OMIM#610978; ORPHA:209905) associated with other clinical phenotypes should suggest monoallelic deletions of chromosome 14 causing haploinsufficiency of NKX2-1, and other contiguous genes like PAX9 (hypodontia) or other dosage-sensitive genes in the chromosomal vicinity that emerge as candidates for hypogammaglobulinemia, mainly NFKBIA.

PMID: 29477862 [PubMed – as supplied by publisher]

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Prevalence and clinical challenges among adult primary immunodeficiency patients with RAG deficiency.

J Allergy Clin Immunol. 2018 Feb 22;:

Authors: Lawless D, Geier CB, Farmer JR, Lango HA, Thwaites D, Atschekzei F, Brown M, Buchbinder D, Burns SO, Butte MJ, Csomos K, Deevi SVV, Egner W, Ehl S, Eibl MM, Fadugba O, Foldvari Z, Green DM, Henrickson SE, Holland SM, John T, Klemann C, Kuijpers TW, Moreira F, Piller A, Rayner-Matthews P, Romberg ND, Sargur R, Schmidt RE, Schröder C, Schuetz C, Sharapova SO, Smith KGC, Sogkas G, Speckmann C, Stirrups K, Thrasher AJ, Wolf HM, Notarangelo LD, Anwar R, Boyes J, Ujhazi B, NIHR BioResource – Rare Diseases Consortium, Thaventhiran J, Walter JE, Savic S

PMID: 29477728 [PubMed – as supplied by publisher]

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Loss of function NFKB1 variants are the most common monogenic cause of CVID in Europeans.

J Allergy Clin Immunol. 2018 Feb 22;:

Authors: Tuijnenburg P, Lango Allen H, Burns SO, Greene D, Jansen MH, Staples E, Stephens J, Carss KJ, Biasci D, Baxendale H, Thomas M, Chandra A, Kiani-Alikhan S, Longhurst HJ, Seneviratne SL, Oksenhendler E, Simeoni I, de Bree GJ, Tool ATJ, van Leeuwen EMM, Ebberink EHTM, Meijer AB, Tuna S, Whitehorn D, Brown M, Turro E, Thrasher AJ, Smith KGC, Thaventhiran JE, Kuijpers TW, NIHR-BioResource – Rare Diseases Consortium

Abstract
BACKGROUND: The genetic etiology of primary immunodeficiency disease (PID) carries prognostic information.
OBJECTIVE: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR-BioResource – Rare Disease cohort.
METHODS: In the predominantly European study population of principally sporadic unrelated PID cases (n=846), a novel Bayesian method identified NFKB1 as one most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n=390) in the cohort. Amino-acid substitutions predicted to be pathogenic were assessed by analysis of structural protein data. Immunophenotyping, immunoblotting and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype co-segregation analyses.
RESULTS: Both sporadic and familial cases demonstrated evidence of the non-infective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%) and autoimmune disease (48%), features prior studies correlate with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B lymphocyte differentiation. Detailed assessment of B lymphocyte numbers, phenotype and function identifies the presence of a raised CD21low B cell population: combined with identification of the disease-causing variant, this distinguishes between healthy individuals, asymptomatic carriers and clinically affected cases.
CONCLUSION: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID that results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.

PMID: 29477724 [PubMed – as supplied by publisher]

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Fifteen-minute consultation: The child with an incidental finding of low IgA.

Arch Dis Child Educ Pract Ed. 2018 Feb 23;:

Authors: Sullivan A, Bland RM, Hague R

Abstract
Low or absent immunoglobulin A (IgA) levels are frequently found in children in whom immunodeficiency is not suspected. IgA deficiency is the most common primary immunodeficiency disorder in the UK affecting approximately 1 in 600 people. Isolated IgA deficiency is often identified coincidentally when investigating a child for conditions such as coeliac disease. The aim of this article is to provide a structured approach to the history, investigation and management of an isolated IgA deficiency.

PMID: 29475900 [PubMed – as supplied by publisher]

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Diagnostic Tools for Inborn Errors of Human Immunity (Primary Immunodeficiencies and Immune Dysregulatory Diseases).

Curr Allergy Asthma Rep. 2018 Feb 22;18(3):19

Authors: Richardson AM, Moyer AM, Hasadsri L, Abraham RS

Abstract
PURPOSE OF REVIEW: The purpose of this review is to provide an overview of diagnostic testing in primary immunodeficiency and immune dysregulatory disorders (PIDDs), particularly focusing on flow cytometry and genetic techniques, utilizing specific examples of PIDDs.
RECENT FINDINGS: Flow cytometry remains a vital tool in the diagnosis and monitoring of immunological diseases. Its utility ranges from cellular analysis and specific protein quantitation to functional assays and signaling pathway analysis. Mass cytometry combines flow cytometry and mass spectrometry to dramatically increase the throughput of multivariate single-cell analysis. Next-generation sequencing in combination with other molecular techniques and processing algorithms has become more widely available and identified the diverse and heterogeneous genetic underpinnings of these disorders. As the spectrum of disease is further clarified by increasing immunological, genetic, and epigenetic knowledge, the careful application of these diagnostic tools and bioinformatics will assist not only in our understanding of these complex disorders, but also enable the implementation of personalized therapeutic approaches for disease management.

PMID: 29470720 [PubMed – in process]

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Oncogenic JAK2V617F causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms.

Sci Transl Med. 2018 Feb 21;10(429):

Authors: Prestipino A, Emhardt AJ, Aumann K, O’Sullivan D, Gorantla SP, Duquesne S, Melchinger W, Braun L, Vuckovic S, Boerries M, Busch H, Halbach S, Pennisi S, Poggio T, Apostolova P, Veratti P, Hettich M, Niedermann G, Bartholomä M, Shoumariyeh K, Jutzi JS, Wehrle J, Dierks C, Becker H, Schmitt-Graeff A, Follo M, Pfeifer D, Rohr J, Fuchs S, Ehl S, Hartl FA, Minguet S, Miething C, Heidel FH, Kröger N, Triviai I, Brummer T, Finke J, Illert AL, Ruggiero E, Bonini C, Duyster J, Pahl HL, Lane SW, Hill GR, Blazar BR, von Bubnoff N, Pearce EL, Zeiser R

Abstract
Recent evidence has revealed that oncogenic mutations may confer immune escape. A better understanding of how an oncogenic mutation affects immunosuppressive programmed death ligand 1 (PD-L1) expression may help in developing new therapeutic strategies. We show that oncogenic JAK2 (Janus kinase 2) activity caused STAT3 (signal transducer and activator of transcription 3) and STAT5 phosphorylation, which enhanced PD-L1 promoter activity and PD-L1 protein expression in JAK2V617F-mutant cells, whereas blockade of JAK2 reduced PD-L1 expression in myeloid JAK2V617F-mutant cells. PD-L1 expression was higher on primary cells isolated from patients with JAK2V617F-myeloproliferative neoplasms (MPNs) compared to healthy individuals and declined upon JAK2 inhibition. JAK2V617F mutational burden, pSTAT3, and PD-L1 expression were highest in primary MPN patient-derived monocytes, megakaryocytes, and platelets. PD-1 (programmed death receptor 1) inhibition prolonged survival in human MPN xenograft and primary murine MPN models. This effect was dependent on T cells. Mechanistically, PD-L1 surface expression in JAK2V617F-mutant cells affected metabolism and cell cycle progression of T cells. In summary, we report that in MPN, constitutive JAK2/STAT3/STAT5 activation, mainly in monocytes, megakaryocytes, and platelets, caused PD-L1-mediated immune escape by reducing T cell activation, metabolic activity, and cell cycle progression. The susceptibility of JAK2V617F-mutant MPN to PD-1 targeting paves the way for immunomodulatory approaches relying on PD-1 inhibition.

PMID: 29467301 [PubMed – in process]

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Peripheral whole blood lncRNA expression analysis in patients with eosinophilic asthma.

Medicine (Baltimore). 2018 Feb;97(8):e9817

Authors: Zhu YJ, Mao D, Gao W, Hu H

Abstract
Long noncoding RNA (lncRNA) plays roles in many diseases including asthma. Several lncRNAs function in the early differentiation of T-helper cells. lncRNA controls gene transcription, protein expression, and epigenetic regulation. Of the 4 asthma phenotypes, eosinophilic asthma (EA) is the most common. However, the lncRNAs associated with eosinophilic asthma have yet to be identified.We designed a study to identify the circulating lncRNA signature in EA samples. We tested whether significant differences in lncRNA expression were observed between blood samples from patients with EA and healthy individuals (control). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for the lncRNA-mRNA (messenger RNA) co-expression network. lncRNA expression was measured using quantitative real-time PCR (polymerase chain reaction).A total of 41 dysregulated lncRNAs and 762 dysregulated mRNAs (difference ≥ 2-fold) were found in EA compared to control samples. GO terms and KEGG pathway annotation data revealed that several lncRNAs are significantly associated with EA. KEGG pathway annotation indicated that the pathways most enriched in EA were measles, T cell receptor signaling pathway, peroxisome proliferator activated-receptors (PPAR) signaling pathway, Fc gamma R-mediated phagocytosis, NF (nuclear factor) kappa B signaling pathway, chemokine signaling pathway, and primary immunodeficiency. Using qRT-PCR, lncRNA was confirmed to differ significantly between EA and control samples.The results presented here show that several lncRNAs may take part in the immune regulation of EA. Whether these lncRNAs can be used as biomarkers needs further study.

PMID: 29465565 [PubMed – in process]

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Diagnostic utility of telomere length testing in a hospital-based setting.

Proc Natl Acad Sci U S A. 2018 Feb 20;:

Authors: Alder JK, Hanumanthu VS, Strong MA, DeZern AE, Stanley SE, Takemoto CM, Danilova L, Applegate CD, Bolton SG, Mohr DW, Brodsky RA, Casella JF, Greider CW, Jackson JB, Armanios M

Abstract
Telomere length (TL) predicts the onset of cellular senescence in vitro but the diagnostic utility of TL measurement in clinical settings is not fully known. We tested the value of TL measurement by flow cytometry and FISH (flowFISH) in patients with mutations in telomerase and telomere maintenance genes. TL had a discrete and reproducible normal range with definable upper and lower boundaries. While TL above the 50th age-adjusted percentile had a 100% negative predictive value for clinically relevant mutations, the lower threshold in mutation carriers was age-dependent, and adult mutation carriers often overlapped with the lowest decile of controls. The extent of telomere shortening correlated with the age at diagnosis as well as the short telomere syndrome phenotype. Extremely short TL caused bone marrow failure and immunodeficiency in children and young adults, while milder defects manifested as pulmonary fibrosis-emphysema in adults. We prospectively examined whether TL altered treatment decisions for newly diagnosed idiopathic bone marrow failure patients and found abnormally short TL enriched for patients with mutations in some inherited bone marrow failure genes, such as RUNX1, in addition to telomerase and telomere maintenance genes. The result was actionable, altering the choice of treatment regimen and/or hematopoietic stem cell donor in one-fourth of the cases (9 of 38, 24%). We conclude that TL measurement by flowFISH, when used for targeted clinical indications and in limited settings, can influence treatment decisions in ways that improve outcome.

PMID: 29463756 [PubMed – as supplied by publisher]

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B-cell Deficiency: A De Novo IKZF1 Patient and Review of the Literature.

J Investig Allergol Clin Immunol. 2018;28(1):53-56

Authors: Chen QY, Wang XC, Wang WJ, Zhou QH, Liu DR, Wang Y

PMID: 29461212 [PubMed – in process]

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