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IRAK-4 deficiency as a cause for familial fatal invasive infection by steptococcus pneumoniae.

Clin Immunol. 2015 Dec 14;

Authors: Grazioli S, Hamilton SJ, McKinnon ML, Del Bel KL, Hoang L, Cook VE, Hildebrand KJ, Junker AK, Turvey SE

Abstract
In this Letter to the Editor we report the case of two siblings with fatal pneumococcal meningitis as the initial manifestation of IRAK-4 deficiency caused by previously undescribed mutations in IRAK4. The letter also highlights the importance of invasive pneumococcal infection as a critical ‘red flag’ warning of the potential for an underlying primary immunodeficiency and identifies some of the challenges in making the clinical diagnosis of IRAK-4 deficiency.

PMID: 26698383 [PubMed – as supplied by publisher]

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Efficacy and safety of Gammaplex® 5% in children and adolescents with primary immunodeficiency diseases.

Clin Exp Immunol. 2015 Dec 22;

Authors: Melamed IR, Gupta S, Bobbitt MS, Hyland N, Moy JN

Abstract
This open-label multicentre study evaluated Gammaplex(®) 5%, a human intravenous immunoglobulin (IVIG) 5% liquid, in 25 children and adolescent patients (aged 3-16 years) with primary immunodeficiency diseases (PIDs). Subjects received Gammplex 5% (at doses of 300-800 mg/kg/infusion) for 12 months, with a 3-month follow up. The primary efficacy endpoint was the incidence of serious acute bacterial infections (SABIs) during the 12-month treatment period. Secondary objectives assessed safety and tolerability. Nineteen males and 6 females were treated using the same infusion schedule as their prior IVIG treatment (14 and 11 subjects on 21- and 28-day dosing schedules, respectively). Two SABIs of pneumonia were reported, resulting in an annual SABI event rate of 0·09 (upper one-sided 99% CI, 0·36). Twenty-one subjects (84%) experienced ≥1 infection during the study, with a median infective episode per subject/year of 3·08 (range, 0-10·4). Sixteen subjects (64%) missed ≥1 day of nursery or school because of infection or other illness. All trough immunoglobulin G levels exceeded 7·00 g/L after 15 weeks (mean, 9·69 g/L; range, 7·04-15·35 g/L). Product-related adverse events occurred in 14 subjects (56%); none were serious. Of 368 total infusions, 97 (26%) were temporally associated with an adverse event (≤72 hours after infusion), regardless of causality. Laboratory test results and adverse-reaction data showed no evidence of product-related haemolysis or thromboembolic events. These data demonstrate that Gammplex 5% is effective in preventing SABIs and well-tolerated in children and adolescents with PID. This article is protected by copyright. All rights reserved.

PMID: 26696596 [PubMed – as supplied by publisher]

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[Severe atopic dermatitis caused by rare immunodeficiency in childhood].

Ugeskr Laeger. 2015 Dec 14;177(51)

Authors: Wolsk HM, Marquart HV, Laub B, Gniadecki R, Nysom K, Ifversen M

Abstract
Two children are presented with autosomal recessive hyper IgE syndrome caused by a mutation in the dedicator of cytokinesis 8 gene (DOCK8). The manifestations are typically severe atopic dermatitis, food allergies, elevated serum IgE concentration, viral skin infections and risk of malignancies. DOCK8 deficiency was first reported in 2009, following the death of the oldest sibling. The youngest sibling was cured after allogenic stem cell transplantation. This case report illustrates the need of awareness of primary immunodeficiency in children with atypical manifestation of atopic dermatitis in combination with recurrent infections.

PMID: 26692033 [PubMed – as supplied by publisher]

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Three faces of recombination activating gene 1 (RAG1) mutations.

Acta Microbiol Immunol Hung. 2015 Dec;62(4):393-401

Authors: Patiroglu T, Akar HH, Van Der Burg M

Abstract
Severe combined immune deficiency (SCID) is a group of genetic disorder associated with development of T- and/or B-lymphocytes. Recombination-activating genes (RAG1/2) play a critical role on VDJ recombination process that leads to the production of a broad T-cell receptor (TCR) and B-cell receptor (BCR) repertoire in the development of T and B cells. RAG1/2 genes mutations result in various forms of primary immunodeficiency, ranging from classic SCID to Omenn syndrome (OS) to atypical SCID with such as granuloma formation and autoimmunity. Herein, we reported 4 patients with RAG1 deficiency: classic SCID was seen in two patients who presented with recurrent pneumonia and chronic diarrhoea, and failure to thrive. OS was observed in one patient who presented with chronic diarrhoea, skin rash, recurrent lower respiratory infections, and atypical SCID was seen in one patient who presented with Pyoderma gangrenosum (PG) and had novel RAG1 mutation.

PMID: 26689875 [PubMed – in process]

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Long-term subcutaneous immunoglobulin use in inflammatory myopathies: A retrospective review of 19 cases.

Autoimmun Rev. 2015 Dec 11;

Authors: Cherin P, Belizna C, Odile C, Lascu-Dubos G, de Jaeger C, Delain JC, Crave JC, Hachulla E

Abstract
Subcutaneous immunoglobulin (SCIg) therapy is indicated in primary and secondary immunodeficiency diseases. Its use in practice is being extended to autoimmune diseases. Few studies investigated the feasibility and safety of SCIg in these rare conditions. The aim was to describe the use of SCIg in inflammatory myopathies including polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM), in real-life settings. This case series was based upon a retrospective data collection. The primary objective was to assess the feasibility of the SCIg injections for the treatment of autoimmune diseases and adherence to high doses. Secondary objectives included safety and efficacy. Nineteen cases were identified: 7 patients were diagnosed with PM, 7 with IBM, 2 with DM, and 3 with myositis associated with connective tissue disease. Patients were treated and followed-up for a mean duration of 18.8months (range 4.5-42). They received a median of 64 SCIg infusions and a total of 1215 infusions. Out of 14 patients, 10 showed an improvement in muscle strength, and 7 out of 11 showed an improvement in muscle disability scale. Two patients were lost to follow-up. Few slight adverse reactions were reported including mainly mild headaches and local skin reactions. Any serious adverse event was reported. These results suggest that the use of high-dose SCIg is feasible, beneficial and safe in patients with inflammatory myopathies. SCIg could be an alternative of IVIg in patients with difficult venous access or with insufficient response, and in patients preferring home care setting.

PMID: 26688441 [PubMed – as supplied by publisher]

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Cd4+Cd25+Foxp3+ T regulatory cells, Th1 (Ccr5, Il-2, Ifn-Γ) and Th2 (Ccr4, Il-4, Il-13) type chemokine receptors and intracellular cytokines in children with common variable immunodeficiency.

Int J Immunopathol Pharmacol. 2015 Dec 18;

Authors: Kutukculer N, Azarsiz E, Aksu G, Karaca NE

Abstract
Common variable immunodeficiency (CVID) is a heterogeneous group of primary antibody deficiencies characterized by decreased serum immunoglobulin G along with a decrease in serum IgA and/or IgM, defective specific antibody production, and recurrent bacterial infections. Abnormal lymphocyte trafficking, dysregulated cellular responses to chemokines, and uncontrolled T cell polarization may be involved in the pathogenesis and may help to understand the clinical complications. We evaluated T helper cell subsets (chemokine receptors CCR4, CCR5, and CCR7), expressions on T lymphocytes, intracellular cytokines – IL-2, IL-4, IL-13, IFN- γ-on CD4(+) T cells, and expression of CD4(+)CD25(+)Foxp3(+) regulatory T cells of 20 CVID patients and 26 healthy controls. Autoimmune clinical findings and other complications were also determined. Percentages and absolute numbers of CD4(+)CD25(+) Foxp3(+) cells did not show any significant difference between CVID cases and healthy controls nor between severe and moderate disease patients. The only significant difference regarding Th1 and Th2 type intracellular cytokines was the decreased absolute numbers of CD3(+)CD4(+)IL4(+) cells in CVID cases. There were some findings about T helper cell type dominance in CVID patients such as positive correlation between hepatomegaly and high IL-2 and IFN-γ in CD3(+)CD4(+) cells and very high expression of CCR5 (Th1) on CD3(+)CD4(+) cells in patients with granuloma. Th1 (CCR5) and Th2 (CCR4) type chemokine receptors did not show any dominance in CVID cases. However, frequencies of CCR7 expressing CD3(+) T cells, CD3(+)CD4(+) T helper cells and CD3(+)CD8(+) T cytotoxic cells were significantly lower in severe CVID patients. In addition, presence of autoimmune clinical findings was negatively correlated with CCR7(+) cells. As CCR7 is a key mediator balancing immunity and tolerance in the immune system, the abnormality of this mediator may contribute to the profound immune dysregulation seen in CVID. In addition, Th1 cells seem to be more involved in the disease pathogenesis than Th2 cells.

PMID: 26684629 [PubMed – as supplied by publisher]

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ANNALS EXPRESS: Low IgA levels detected via the tissue transglutaminase assay can reveal previously undetected monoclonal proteins.

Ann Clin Biochem. 2015 Dec 17;

Authors: Wallage M, Dutton D, Lock RJ

Abstract
Increased awareness of coeliac disease and the 2009 NICE guidance has led to an increase in patients being screened for IgA deficiency. We have shown previously that this provides an opportunity for the early identification of other underlying primary immunodeficiency, e.g. common variable immunodeficiency (CVID). In this context the underlying gastrointestinal problem appears to be related to bacterial overgrowth. Here we demonstrate that in addition this also provides an opportunity to reveal underlying secondary immunodeficiency due to other causes in patients with gastrointestinal presentation, notably lymphoproliferative disorders. In one three month period, of 60 cases reviewed for low IgA, we found four new paraproteins through this testing route ; one symptomatic multiple myeloma (MM), one asymptomatic MM, one MGUS and one in a known CLL patient.

PMID: 26684021 [PubMed – as supplied by publisher]

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Th17 Cell Pathway in Human Immunity: Lessons from Genetics and Therapeutic Interventions.

Immunity. 2015 Dec 15;43(6):1040-51

Authors: Patel DD, Kuchroo VK

Abstract
The T helper 17 (Th17) cell pathway has been linked by genome-wide association studies to multiple autoimmune diseases. Identification of the genetic causes of primary immunodeficiency diseases revealed that Th17 cells are also critical in host immunity to mucocutaneous candida infections and Staphylococcus aureus. Therapeutic interventions with inhibitors of the different components of the pathway such as interleukin-12 (IL-12), IL-23, IL-17A, and IL-17RA have variably beneficial effects in psoriasis, Crohn’s disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-infectious uveitis, and multiple sclerosis. Thus, whereas Th17 cells are protective against Candida albicans and to a lesser degree Staphylococcus aureus, they are pathogenic in many autoimmune diseases. Here, we compare and contrast the effects of human genetic mutations of and therapeutic interventions targeted at Th17 cell molecules. We discuss that although there are similarities when Th17 cell pathway molecules are modulated, each molecule has unique non-Th17 cell features that lead to different functional outcomes.

PMID: 26682981 [PubMed – in process]

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Impulse oscillometry identifies peripheral airway dysfunction in children with adenosine deaminase deficiency.

Orphanet J Rare Dis. 2015;10(1):159

Authors: Komarow HD, Sokolic R, Hershfield MS, Kohn DB, Young M, Metcalfe DD, Candotti F

Abstract
Adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) is characterized by impaired T-, B- and NK-cell function. Affected children, in addition to early onset of infections, manifest non-immunologic symptoms including pulmonary dysfunction likely attributable to elevated systemic adenosine levels. Lung disease assessment has primarily employed repetitive radiography and effort-dependent functional studies. Through impulse oscillometry (IOS), which is effort-independent, we prospectively obtained objective measures of lung dysfunction in 10 children with ADA-SCID. These results support the use of IOS in the identification and monitoring of lung function abnormalities in children with primary immunodeficiencies.

PMID: 26682746 [PubMed – as supplied by publisher]

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Chronic Granulomatous Disease: clinical, molecular and therapeutic aspects.

Pediatr Allergy Immunol. 2015 Dec 17;

Authors: Chiriaco M, Salfa I, Matteo GD, Rossi P, Finocchi A

Abstract
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by defects in the genes encoding any of the NADPH oxidase components responsible for the respiratory burst of phagocytic leukocytes. CGD is a genetically heterogeneous disease with an X-linked recessive (XR-CGD) form caused by mutations in the CYBB gene encoding the gp91(phox) protein, and an autosomal recessive (AR-CGD) form caused by mutations in the CYBA, NCF1, NCF2 or NCF4 genes encoding p22(phox) , p47(phox) , p67(phox) and p40(phox) , respectively. Patients suffering from this disease are susceptible to severe life-threatening bacterial and fungal infections and excessive inflammation characterized by granuloma formation in any organ, for instance the gastrointestinal and genitourinary tract. An early diagnosis and prompt treatment of these conditions is crucial for an optimal outcome of affected patients. In order to prevent infections, CGD patients should receive lifelong antibiotics and antifungal prophylaxis. These two measures, as well as newer more effective antimicrobials, have significantly modified the natural history of CGD, resulting in a remarkable change in overall survival, which is now around 90%, reaching well into adulthood. At present, hematopoietic stem cell transplantation (HSCT) is the only definitive treatment that can cure CGD and reverse organ dysfunction. Timing, donor selection and conditioning regimens remain the key points of this therapy. In recent years, gene therapy (GT) for XR-CGD has been proposed as an alternative to HSCT for CGD patients without a matched donor. After the failure of the first trials performed with retroviral vectors, some groups have proposed the use of regulated SIN-lentiviral vectors targeting gp91(phox) expression in myeloid cells to increase the safety and efficacy of the GT-protocols. This article is protected by copyright. All rights reserved.

PMID: 26680691 [PubMed – as supplied by publisher]

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