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B-cell subpopulations in children: National reference values.

Immun Inflamm Dis. 2014 Nov;2(3):131-40

Authors: Duchamp M, Sterlin D, Diabate A, Uring-Lambert B, Guérin-El Khourouj V, Le Mauff B, Monnier D, Malcus C, Labalette M, Picard C

Abstract
Peripheral B-lymphocytes undergo a series of changes during the first few years of life. Encounters with foreign antigens lead to maturation and differentiation. Several primary antibody deficiencies (PADs) affecting B-cell development are associated with abnormalities in the composition and/or differentiation of B-cell compartments. The most recent international classifications of primary immunodeficiencies (PIDs) and common variable immunodeficiencies (CVID) have highlighted the importance of B-cell immunophenotyping and age-specific reference intervals for diagnostic purposes. We established national reference values for memory B-cell subpopulations, on the basis of CD27 and surface IgD expression in the peripheral blood of 242 healthy children. We report here the absolute counts and percentages of naive, switched and non-switched memory B-cells for seven age groups, from neonates to adults. We found that the naive B-cells percentage declined between the ages of 6 months and 8 years, after which it remained stable at about 70-80%. Memory B-cells are already present at birth and their numbers increase throughout childhood, stabilizing between the ages of 12 and 18 years. The definition of reference intervals for pediatric B-cell levels should facilitate the screening and diagnosis of various B-cell immunodeficiencies. This multicenter study, providing national reference values, should thus facilitate immunological diagnosis in children.

PMID: 25505547 [PubMed]

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Identification of a Novel Mutation in MAGT1 and Progressive Multifocal Leucoencephalopathy in a 58-Year-Old Man with XMEN Disease.

J Clin Immunol. 2014 Dec 13;

Authors: Dhalla F, Murray S, Sadler R, Chaigne-Delalande B, Sadaoka T, Soilleux E, Uzel G, Miller J, Collins GP, Hatton CS, Bhole M, Ferry B, Chapel HM, Cohen JI, Patel SY

Abstract
XMEN disease (X-linked immunodeficiency with Magnesium defect, Epstein-Barr virus infection and Neoplasia) is a novel primary immune deficiency caused by mutations in MAGT1 and characterised by chronic infection with Epstein-Barr virus (EBV), EBV-driven lymphoma, CD4 T-cell lymphopenia, and dysgammaglobulinemia [1]. Functional studies have demonstrated roles for magnesium as a second messenger in T-cell receptor signalling [1], and for NKG2D expression and consequently NK- and CD8 T-cell cytotoxicity [2]. 7 patients have been described in the literature; the oldest died at 45 years and was diagnosed posthumously [1-3]. We present the case of a 58-year-old Caucasian gentleman with a novel mutation in MAGT1 with the aim of adding to the phenotype of this newly described disease by detailing his clinical course over more than 20 years.

PMID: 25504528 [PubMed – as supplied by publisher]

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[Histoplasmosis of the central nervous system in an immunocompetent patient].

Biomedica. 2014 Dec;34(4):506-13

Authors: Osorio N, López Y, Jaramillo JC

Abstract
Histoplasmosis is a multifaceted condition caused by the dimorphic fungi Histoplasma capsulatum whose infective spores are inhaled and reach the lungs, the primary organ of infection. The meningeal form, considered one of the most serious manifestations of this mycosis, is usually seen in individuals with impaired cellular immunity such as patients with acquired immunodeficiency syndrome, systemic lupus erythematous or solid organ transplantation, and infants given their immunological immaturity. The most common presentation is self-limited and occurs in immunocompetent individuals who have been exposed to high concentrations of conidia and mycelia fragments of the fungi. In those people, the condition is manifested by pulmonary disorders and late dissemination to other organs and systems. We report a case of central nervous system histoplasmosis in an immunocompetent child.

PMID: 25504238 [PubMed – in process]

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Diagnostics of Primary Immunodeficiency Diseases: A Sequencing Capture Approach.

PLoS One. 2014;9(12):e114901

Authors: Moens LN, Falk-Sörqvist E, Asplund AC, Bernatowska E, Smith CI, Nilsson M

Abstract
Primary Immunodeficiencies (PID) are genetically inherited disorders characterized by defects of the immune system, leading to increased susceptibility to infection. Due to the variety of clinical symptoms and the complexity of current diagnostic procedures, accurate diagnosis of PID is often difficult in daily clinical practice. Thanks to the advent of “next generation” sequencing technologies and target enrichment methods, the development of multiplex diagnostic assays is now possible. In this study, we applied a selector-based target enrichment assay to detect disease-causing mutations in 179 known PID genes. The usefulness of this assay for molecular diagnosis of PID was investigated by sequencing DNA from 33 patients, 18 of which had at least one known causal mutation at the onset of the experiment. We were able to identify the disease causing mutations in 60% of the investigated patients, indicating that the majority of PID cases could be resolved using a targeted sequencing approach. Causal mutations identified in the unknown patient samples were located in STAT3, IGLL1, RNF168 and PGM3. Based on our results, we propose a stepwise approach for PID diagnostics, involving targeted resequencing, followed by whole transcriptome and/or whole genome sequencing if causative variants are not found in the targeted exons.

PMID: 25502423 [PubMed – as supplied by publisher]

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Specific antibody deficiency with normal immunoglobulin concentration in children with recurrent respiratory infections.

Allergol Immunopathol (Madr). 2014 Dec 10;

Authors: Quezada A, Norambuena X, Inostroza J, Rodríguez J

Abstract
BACKGROUND: Response to polysaccharide antigens is a test to evaluate the immunological competence of children with recurrent respiratory infections (RRI) of unknown cause and no other immune system abnormality. In order to detect specific antibody deficiency (SAD), a group of children with RRI without other immunodeficiency were prospectively studied.
METHODS: We included 20 children (12 male), age range 3-14 years, with six or more annual episodes of respiratory infections (RI); one or more monthly episodes of RI during the winter months; or three or more annual episodes of lower RI. The children were immunised with 23-valent polysaccharide anti-pneumococcal vaccine, and ELISA was used to measure anti-polysaccharide IgG antibody levels for 10 pneumococcal serotypes at baseline (T0), and 45 days (T1) and one year post-immunisation (T2). Post-immunisation response above 1.3μg/ml for more than 50% of the serotypes was considered normal for children 2-5 years, and for more than 70% of the serotypes in children older than 5 years.
RESULTS: At T1 19/20 children showed a normal response for their age, and only one patient showed a deficient response, suggestive of classic moderate SAD. At T2, 8/20 patients showed deficient responses, suggestive of impaired persistence of specific antibodies. There was a noteworthy association between deficient response and asthma and allergic rhinitis.
CONCLUSIONS: We propose first ruling out local or systemic causes, then performing serum immunoglobulin IgM, IgG, IgA, IgE and IgG subclass levels, and finally measuring response to polysaccharide pneumococcal antigens for detection of SAD.

PMID: 25498324 [PubMed – as supplied by publisher]

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Is there evidence for recommending specific intravenous immunoglobulin formulations? A systematic review of head-to-head randomized controlled trials.

Eur J Pharmacol. 2014 Dec 10;

Authors: Buehler AM, Flato UP, Ferri CP, Fernandes JG

Abstract
Intravenous immunoglobulins (IVIG) have been used for several licensed and off-label indications. Each IVIG product is a unique formulation of IgG and excipients, making them distinct products. How these differences impact on individual IVIG product efficacy and safety are not well established but can be investigated by head-to-head randomized controlled trials (RCT). A systematic review of head-to-head RCT comparing different formulations of IVIG, regardless of the target condition and outcomes investigated. Two reviewers screened 4,084 citations retrieved from MEDLINE, Embase, Cochrane and LILACS, and 23 citations were fully-text evaluated. Eight trials were included. The clinical conditions, outcomes and risk of bias were assessed. Of the eight trials included only two investigated products that are currently on the market. One evaluated two Grifols brands used in patients with primary immunodeficiency and another evaluated two Baxter brands used in patients with chronic inflammatory demyelinating polyradiculoneuropathy. There were no differences between the formulations for the outcomes evaluated. In the other trials, either the manufacturers were acquired by other companies or the formulation was withdrawn from the market. As consequence, evidence concerning these products could not be considered. The quality of the studies was low, showing high risk of bias. Direct evidence about the different IVIGs is scarce and, at present, there is no scientific evidence that can be applied for a specific brand or formulation. Further comparative effectiveness studies are highly desirable for a better understanding of the differences in safety and efficacy of IVIGs.

PMID: 25496751 [PubMed – as supplied by publisher]

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Related Articles

A coding IRAK2 protein variant compromises Toll-like receptor (TLR) signaling and is associated with colorectal cancer survival.

J Biol Chem. 2014 Aug 15;289(33):23123-31

Authors: Wang H, Flannery SM, Dickhöfer S, Huhn S, George J, Kubarenko AV, Lascorz J, Bevier M, Willemsen J, Pichulik T, Schafmayer C, Binder M, Manoury B, Paludan SR, Alarcon-Riquelme M, Bowie AG, Försti A, Weber AN

Abstract
Within innate immune signaling pathways, interleukin-1 receptor-associated kinases (IRAKs) fulfill key roles downstream of multiple Toll-like receptors and the interleukin-1 receptor. Although human IRAK4 deficiency was shown to lead to severe immunodeficiency in response to pyogenic bacterial infection during childhood, little is known about the role of human IRAK2. We here identified a non-synonymous IRAK2 variant, rs35060588 (coding R214G), as hypofunctional in terms of NF-κB signaling and Toll-like receptor-mediated cytokine induction. This was due to reduced ubiquitination of TRAF6, a key step in signal transduction. IRAK2 rs35060588 occurs in 3-9% of individuals in different ethnic groups, and our studies suggested a genetic association of rs35060588 with colorectal cancer survival. This for the first time implicates human IRAK2 in a human disease and highlights the R214G IRAK2 variant as a potential novel and broadly applicable biomarker for disease or as a therapeutic intervention point.

PMID: 24973222 [PubMed – indexed for MEDLINE]

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Related Articles

Secondary antibody deficiency.

Expert Rev Clin Immunol. 2014 May;10(5):583-91

Authors: Duraisingham SS, Buckland MS, Grigoriadou S, Longhurst HJ

Abstract
Secondary antibody deficiencies are defined by a quantitative or qualitative decrease in antibodies that occur most commonly as a consequence of renal or gastrointestinal immunoglobulin loss, hematological malignancies and corticosteroid, immunosuppressive or anticonvulsant medications. Patients with hematological malignancies or requiring immunosuppressive medications are known to be at increased risk of infection, but few studies directly address this relationship in the context of antibody deficiency. Immunoglobulin replacement therapy has been shown to be effective in reducing infections in primary and some secondary antibody deficiencies. The commonly encountered causes of secondary antibody deficiencies and their association with infection-related morbidity and mortality are discussed. Recommendations are made for screening and clinical management of those at risk.

PMID: 24684706 [PubMed – indexed for MEDLINE]

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Related Articles

Role of dendritic cells in innate and adaptive immune response in human aging.

Exp Gerontol. 2014 Jun;54:47-52

Authors: Gupta S

Abstract
Aging is associated with a progressive decline in T cell function, chronic inflammation, hyperimmunoglobulinemia, autoimmunity, poor response to vaccines, and increased susceptibility to infection as well as diseases associated with chronic inflammation. DCs in aging appear to be functionally impaired with regard to response to uptake of antigens, phagocytosis of apoptotic cells, migration, priming of CD4+ and CD8+ T cells, and production of IFN-I and IFN-III. In this review I have discussed various mechanisms, which may be responsible for impaired functions of DCs.

PMID: 24370374 [PubMed – indexed for MEDLINE]

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