Research

[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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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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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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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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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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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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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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Hypomorphic function and somatic reversion of DOCK8 cause combined immunodeficiency without hyper-IgE.

Clin Immunol. 2015 Dec 8;

Authors: Kienzler AK, van Schouwenburg PA, Taylor J, Marwah I, Sharma RU, Noakes C, Thomson K, Sadler R, Segal S, Ferry B, Taylor JC, Blair E, Chapel H, Patel SY

Abstract
Loss-of-function mutations in DOCK8 are linked to hyper-IgE syndrome. Patients typically present with recurrent sinopulmonary infections, severe cutaneous viral infections, food allergies and elevated serum IgE. Although patients may present with a spectrum of disease-related symptoms, molecular mechanisms explaining phenotypic variability in patients are poorly defined. Here we characterized a novel compound heterozygous mutation in DOCK8 in a patient diagnosed with primary combined immunodeficiency which was not typical of classical DOCK8 deficiency. In contrast to previously identified mutations in DOCK8 which result in complete loss of function, the newly identified single nucleotide insertion results in expression of a truncated DOCK8 protein. Functional evaluation of the truncated DOCK8 protein revealed its hypomorphic function. In addition we found somatic reversion of DOCK8 predominantly in T cells. The combination of somatic reversion and hypomorphic DOCK8 function explains the milder and atypical phenotype of the patient and further broadens the spectrum of DOCK8-associated disease.

PMID: 26680607 [PubMed – as supplied by publisher]

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Related Articles

Lag times between lymphoproliferative disorder and clinical diagnosis of chronic lymphocytic leukemia: a prospective analysis using plasma soluble CD23.

Cancer Epidemiol Biomarkers Prev. 2015 Mar;24(3):538-45

Authors: Kaaks R, Sookthai D, Łuczyńska A, Oakes CC, Becker S, Johnson T, Johansson A, Melin B, Sjöberg K, Trichopoulos D, Trichopoulou A, Lagiou P, Mattiello A, Tumino R, Masala G, Agnoli C, Boeing H, Aleksandrova K, Brennan P, Franceschi S, Roulland S, Casabonne D, de Sanjose S, Sánchez MJ, Huerta JM, Ardanaz E, Sala N, Overvad K, Tjønneland A, Halkjær J, Weiderpass E, Bueno-de-Mesquita HB, Vermeulen R, Peeters PH, Vineis P, Kelly RS, Khaw KT, Travis RC, Key TJ, Riboli E, Nieters A

Abstract
BACKGROUND: Chronic lymphocytic leukemia (CLL) is a chronic disease that often progresses slowly from a precursor stage, monoclonal B-cell lymphocytosis (MBL), and that can remain undiagnosed for a long time.
METHODS: Within the European Prospective Investigation into Cancer cohort, we measured prediagnostic plasma sCD23 for 179 individuals who eventually were diagnosed with CLL and an equal number of matched control subjects who remained free of cancer.
RESULTS: In a very large proportion of CLL patients’ plasma sCD23 was clearly elevated 7 or more years before diagnosis. Considering sCD23 as a disease predictor, the area under the ROC curve (AUROC) was 0.95 [95% confidence interval (CI), 0.90-1.00] for CLL diagnosed within 0.1 to 2.7 years after blood measurement, 0.90 (95% CI, 0.86-0.95) for diagnosis within 2.8 to 7.3 years, and 0.76 (95% CI, 0.65-0.86) for CLL diagnosed between 7.4 and 12.5 years. Even at a 7.4-year and longer time interval, elevated plasma sCD23 could predict a later clinical diagnosis of CLL with 100% specificity at >45% sensitivity.
CONCLUSIONS: Our findings provide unique documentation for the very long latency times during which measurable B-cell lymphoproliferative disorder exists before the clinical manifestation of CLL.
IMPACT: Our findings have relevance for the interpretation of prospective epidemiologic studies on the causes of CLL in terms of reverse causation bias. The lag times indicate a time frame within which an early detection of CLL would be theoretically possible. Cancer Epidemiol Biomarkers Prev; 24(3); 538-45. ©2014 AACR.

PMID: 25542829 [PubMed – indexed for MEDLINE]

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Incidence and risk factors associated with iron deficiency anaemia among hospitalised Lebanese infants.

Int J Pharm Pract. 2015 Dec 16;

Authors: Mhanna RG, Rahal M, Iskandarani M, Hammoudi D

Abstract
OBJECTIVES: The primary objective of this study was to determine the prevalence of iron deficiency anaemia (IDA) in hospitalised 6- to 24-month-old infants in rural versus urban settings. The secondary objective was to determine associated risk factors in rural versus urban settings.
METHODS: A 6-month prospective multicentre cross-sectional study was conducted in paediatrics departments of three Lebanese hospitals. Preterm to term infants aged 6-24 months were included. Infants with blood disorders, chronic infections, congenital immunodeficiency and mental or congenital growth retardation were excluded. Incidence of IDA was assessed using haematologic laboratory values, while risk factors were assessed using questionnaires addressed to infants’ caregivers. For data analysis, P values, chi-squared and logistic regression were used.
KEY FINDINGS: Among 520 screened infants, a total of 100 patients were selected. Thirty-seven per cent of patients were anaemic with haemoglobin levels <11 g/dl. Significant risk factors included: exclusive breastfeeding for more than 6 months (95% CI, 1.03 to 8.9; P = 0.043), low family income (95% CI, 0.19 to 0.98; P = 0.045), residing in rural areas (95% CI, 0.064 to 0.0509; P < 0.001), inadequate maternal iron supply (95% CI, 1.01 to 8.26; P = 0.05), low maternal education level (95% CI, 0.07 to 0.88; P = 0.03) and lack of infant iron supply (95% CI, 1.39 to 8.41; P = 0.007).
CONCLUSION: Incidence of IDA among Lebanese infants is moderate and multifactorial. High maternal education level, urban residence, giving iron supplements to exclusively breastfed infants starting from 6 months of age, adequate family income and iron supplementation in both mother and infant are significant protective factors against anaemia in this population.

PMID: 26671320 [PubMed – as supplied by publisher]

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