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Prospective neonatal screening for severe T- and B- lymphocyte deficiencies in Seville.

Pediatr Allergy Immunol. 2015 Oct 25;

Authors: de Felipe B, Olbrich P, Lucenas JM, Delgado-Pecellin C, Pavon-Delgado A, Marquez J, Salamanca C, Soler-Palacin P, Gonzalez-Granado LI, Antolin LF, Borte S, Neth O

Abstract
BACKGROUND: Early diagnosis of primary immunodeficiency such as severe combined immunodeficiency (SCID) and X-linked agammaglobulinemia (XLA) improves outcome of affected children. T-cell-receptor-excision circles (TRECs) and kappa-deleting-recombination-excision circles (KRECs) determination from dried blood spots (DBS) identify neonates with severe T- and/or B-lymphopenia. No prospective data exist of the impact of gestational age (GA) and birth weight (BW) on TRECs and KRECs values.
METHODS: TRECs and KRECs determination using triplex RT-PCR (TRECS-KRECS-β-actin-Assay) from prospectively collected DBS between 02/2014 and 02/2015 in three hospitals in Seville, Spain. Cut-off levels were TRECs<6/punch, KRECs<4/punch and -β-actin>700/punch. Internal (SCID, XLA, ataxia telangiectasia) and external controls (NBS quality assurance program, CDC) were included.
RESULTS: A total of 5160 DBS were tested. Re-punch was needed in 77 samples (1.5%) due to insufficient β-actin (<700 copies/punch). Preterm neonates (GA<37 weeks) and neonates with a BW<2500g showed significantly lower TRECs and KRECs levels (p<0.001). Due to repeat positive results five neonates were re-called (<0.1%): Fatal chromosomopathy (n=1; TRECs 1/KRECs 4); extreme prematurity (n=2; TRECs 0/KRECs 0 and TRECs 1/KRECs 20 copies/punch); neonates born to mothers receiving azathioprine during pregnancy (n=2; TRECs 92/KRECs 1 and TRECs 154/KRECs 3 copies/punch). All internal and external controls were correctly identified.
CONCLUSIONS: TRECS-KRECS-β-actin-Assay correctly identifies T- and B-cell lymphopenias. Prematurity and low BW is associated with lower TREC and KREC levels. Extreme prematurity and maternal immune suppressive therapy may be a cause for false positive results of TRECs and KRECs values, respectively. To reduce the rate of insufficient samples, DBS extraction and storage need to be improved. This article is protected by copyright. All rights reserved.

PMID: 26498110 [PubMed – as supplied by publisher]

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Managing patients with side effects and adverse events to immunoglobulin therapy.

Expert Rev Clin Pharmacol. 2015 Oct 23;:1-12

Authors: Azizi G, Abolhassani H, Asgardoon MH, Shaghaghi S, Negahdari B, Mohammadi J, Rezaei N, Aghamohammadi A

Abstract
Immunoglobulin therapy has not only served as a lifesaving approach for the prevention and treatment of infections in primary and secondary immunodeficiency diseases, but has also been used as an immunomodulatory agent for autoimmune and inflammatory disorders and to provide passive immunity for some infectious diseases. Most of the adverse effects associated with immunoglobulin therapy are mild, transient and self-limiting. However, serious side effects also occur. Therefore, to minimize the adverse events of immunoglobulin therapy, specialist review of patient clinical status and immunoglobulin products, in addition to selection of appropriate treatment strategy for the management of patients with associated side effects and adverse events, are crucial.

PMID: 26496172 [PubMed – as supplied by publisher]

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Patterns of Allergic Sensitization in High IgE Syndromes.

Curr Allergy Asthma Rep. 2015 Dec;15(12):70

Authors: Lawrence MG

Abstract
Dramatic elevations in the serum IgE level are seen both in polygenic allergic diseases such as atopic dermatitis and food allergy, and in a growing list of monogenic primary immune deficiencies (PIDs). Although the IgE produced in patients with PID has generally been considered to be driven by dysregulated IL-4 production and thus lack antigen specificity, in fact allergen-specific IgE can be detected by skin and serum testing in many of these patients. However, perhaps not surprisingly given the distinct immunologic pathways involved, the patterns of allergic disease and atopic sensitization vary widely between syndromes, leading to strikingly different clinical phenotypes.

PMID: 26492876 [PubMed – as supplied by publisher]

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T lymphocytes and fractalkine contribute to myocardial ischemia/reperfusion injury in patients.

J Clin Invest. 2015 Aug 3;125(8):3063-76

Authors: Boag SE, Das R, Shmeleva EV, Bagnall A, Egred M, Howard N, Bennaceur K, Zaman A, Keavney B, Spyridopoulos I

Abstract
BACKGROUND: Lymphocytes contribute to ischemia/reperfusion (I/R) injury in several organ systems, but their relevance in ST elevation myocardial infarction (STEMI) is unknown. Our goal was to characterize lymphocyte dynamics in individuals after primary percutaneous coronary intervention (PPCI), assess the prognostic relevance of these cells, and explore mechanisms of lymphocyte-associated injury.
METHODS: Lymphocyte counts were retrospectively analyzed in 1,377 STEMI patients, and the prognostic relevance of post-PPCI lymphopenia was assessed by Cox proportional hazards regression. Blood from 59 prospectively recruited STEMI patients undergoing PPCI was sampled, and leukocyte subpopulations were quantified. Microvascular obstruction (MVO), a component of I/R injury, was assessed using MRI.
RESULTS: In the retrospective cohort, lymphopenia was associated with a lower rate of survival at 3 years (82.8% vs. 96.3%, lowest vs. highest tertile; hazard ratio 2.42). In the prospective cohort, lymphocyte counts fell 90 minutes after reperfusion, primarily due to loss of T cells. CD8+ T cells decreased more than CD4+ T cells, and effector subsets exhibited the largest decline. The early decrease in effector T cell levels was greater in individuals that developed substantial MVO. The drop in T cell subsets correlated with expression of the fractalkine receptor CX3CR1 (r2 = 0.99, P = 0.006). Serum fractalkine concentration peaked at 90 minutes after reperfusion, coinciding with the T cell count nadir.
CONCLUSIONS: Lymphopenia following PPCI is associated with poor prognosis. Our data suggest that fractalkine contributes to lymphocyte shifts, which may influence development of MVO through the action of effector T cells.
TRIAL REGISTRATION: Not applicable.
FUNDING: British Heart Foundation (FS/12/31/29533) and National Institute of Health Research (NIHR) Newcastle Biomedical Research Centre.

PMID: 26168217 [PubMed – indexed for MEDLINE]

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An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes.

Nat Cell Biol. 2015 Aug;17(8):1074-87

Authors: Wheway G, Schmidts M, Mans DA, Szymanska K, Nguyen TM, Racher H, Phelps IG, Toedt G, Kennedy J, Wunderlich KA, Sorusch N, Abdelhamed ZA, Natarajan S, Herridge W, van Reeuwijk J, Horn N, Boldt K, Parry DA, Letteboer SJ, Roosing S, Adams M, Bell SM, Bond J, Higgins J, Morrison EE, Tomlinson DC, Slaats GG, van Dam TJ, Huang L, Kessler K, Giessl A, Logan CV, Boyle EA, Shendure J, Anazi S, Aldahmesh M, Al Hazzaa S, Hegele RA, Ober C, Frosk P, Mhanni AA, Chodirker BN, Chudley AE, Lamont R, Bernier FP, Beaulieu CL, Gordon P, Pon RT, Donahue C, Barkovich AJ, Wolf L, Toomes C, Thiel CT, Boycott KM, McKibbin M, Inglehearn CF, UK10K Consortium, University of Washington Center for Mendelian Genomics, Stewart F, Omran H, Huynen MA, Sergouniotis PI, Alkuraya FS, Parboosingh JS, Innes AM, Willoughby CE, Giles RH, Webster AR, Ueffing M, Blacque O, Gleeson JG, Wolfrum U, Beales PL, Gibson T, Doherty D, Mitchison HM, Roepman R, Johnson CA

Abstract
Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and 3 pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localize to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequencing data identified recessive mutations in PIBF1, also known as CEP90, and C21orf2, also known as LRRC76, as causes of the ciliopathies Joubert and Jeune syndromes. Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2 variants. Our global, unbiased approaches provide insights into ciliogenesis complexity and identify roles for unanticipated pathways in human genetic disease.

PMID: 26167768 [PubMed – indexed for MEDLINE]

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A novel mutation in ORAI1 presenting with combined immunodeficiency and residual T-cell function.

J Allergy Clin Immunol. 2015 Aug;136(2):479-82.e1

Authors: Chou J, Badran YR, Yee CS, Bainter W, Ohsumi TK, Al-Hammadi S, Pai SY, Feske S, Geha RS

PMID: 26070885 [PubMed – indexed for MEDLINE]

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Hypogammaglobulinemia in sub-Saharan Africa: a case report and review of the literature.

Afr Health Sci. 2015 Mar;15(1):299-301

Authors: Hsu J, Opoka R, Lund TC

Abstract
UNLABELLED: Patients with hypogammaglobulinemia are susceptible to recurrent bacterial, viral, fungal, and parasitic infections. The most common clinical manifestation includes recurrent severe infections caused by encapsulated bacteria, in which antibody opsonization is the primary defense mechanism. To our knowledge, this is the first case report of hypogammaglobulinemia in a Ugandan child in Sub-Saharan Africa. The case emphasizes the importance of including hypogammaglobulinemia in the differential diagnosis for children presenting with a history of recurrent infections.
AIM: To raise the index of clinical suspicion of hypogammaglobulinemia in an African child and allow for prompt recognition and management of hypogammaglobulinemia.

PMID: 25834564 [PubMed – indexed for MEDLINE]

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The autoimmune conundrum in common variable immunodeficiency disorders.

Curr Opin Allergy Clin Immunol. 2015 Oct 17;

Authors: van de Ven AA, Warnatz K

Abstract
PURPOSE OF REVIEW: Autoimmune and inflammatory manifestations are the biggest clinical challenge in the care of patients with common variable immunodeficiency (CVID). The increasing pathogenic knowledge and potential therapeutic implications require a new evaluation of the status quo.
RECENT FINDINGS: The conundrum of the simultaneous manifestation of primary immunodeficiency and autoimmune disease (AID) is increasingly elucidated by newly discovered genetic defects. Thus, cytotoxic T lymphocyte-associated antigen 4 or caspase-9 deficiency presenting with CVID-like phenotypes reiterate concepts of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome and autoimmune lymphoproliferative syndrome. Activating signaling defects downstream of antigen or cytokine receptors are often associated with loss-of-tolerance in the affected patients. Increasingly, forms of combined immunodeficiency are discovered among CVID-like patients. Although different autoimmune manifestations often coincide in the same patient their immunopathology varies. Treatment of AID in CVID remains a challenge, but based on a better definition of the immunopathology first attempts of targeted treatment have been made.
SUMMARY: The increasing comprehension of immunological concepts promoting AID in CVID will allow better and in some cases possibly even targeted treatment. A genetic diagnosis therefore becomes important information in this group of patients, especially in light of the fact that some patients might require hematopoietic stem cell transplantation because of their underlying immunodeficiency.

PMID: 26485099 [PubMed – as supplied by publisher]

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Evans Syndrome in Children: Long-Term Outcome in a Prospective French National Observational Cohort.

Front Pediatr. 2015;3:79

Authors: Aladjidi N, Fernandes H, Leblanc T, Vareliette A, Rieux-Laucat F, Bertrand Y, Chambost H, Pasquet M, Mazingue F, Guitton C, Pellier I, Roqueplan-Bellmann F, Armari-Alla C, Thomas C, Marie-Cardine A, Lejars O, Fouyssac F, Bayart S, Lutz P, Piguet C, Jeziorski E, Rohrlich P, Lemoine P, Bodet D, Paillard C, Couillault G, Millot F, Fischer A, Pérel Y, Leverger G

Abstract
Evans syndrome (ES) is a rare autoimmune disorder whose long-term outcome is not well known. In France, a collaborative pediatric network set up via the National Rare Disease Plan now provides comprehensive clinical data in children with this disease. Patients aged less than 18 years at the initial presentation of autoimmune cytopenia have been prospectively included into a national observational cohort since 2004. The definition of ES was restricted to the simultaneous or sequential association of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP). Cases were deemed secondary if associated with a primitive immunodeficiency or systemic lupus erythematosus. In December 2014, we analyzed the data pertaining to 156 children from 26 centers with ES whose diagnosis was made between 1981 and 2014. Median age (range) at the onset of cytopenia was 5.4 years (0.2-17.2). In 85 sequential cases, the time lapse between the first episodes of AIHA and ITP was 2.4 years (0.1-16.3). The follow-up period as from ES diagnosis was 6.5 years (0.1-28.8). ES was secondary, revealing another underlying disease, in 10% of cases; various associated immune manifestations (mainly lymphoproliferation, other autoimmune diseases, and hypogammaglobulinemia) were observed in 60% of cases; and ES remained primary in 30% of cases. Five-year ITP and AIHA relapse-free survival were 25 and 61%, respectively. Overall, 69% of children required one or more second-line immune treatments, and 15 patients (10%) died at the age of 14.3 years (1.7-28.1). To our knowledge, this is the first consistent long-term clinical description of this rare syndrome. It underscores the high rate of associated immune manifestations and the burden of long-term complications and treatment toxicity. Future challenges include (1) the identification of the underlying genetic defects inducing immune dysregulation and (2) the need to better characterize patient subgroups and second-line treatment strategies.

PMID: 26484337 [PubMed]

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Susceptibility to infections, without concomitant hyper-IgE, reported in 1976, is caused by hypomorphic mutations in the phosphoglucomutase 3 (PGM3) gene.

Clin Immunol. 2015 Oct 16;

Authors: Lundin KE, Hamasy A, Backe PH, Moens LN, Falk-Sörqvist E, Elgstøen KB, Mørkrid L, Bjørås M, Granert C, Norlin AC, Nilsson M, Christensson B, Stenmark S, Smith CI

PMID: 26482871 [PubMed – as supplied by publisher]

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