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A conserved sugar bridge connected to the WSXWS motif has an important role for transport of IL-21R to the plasma membrane.

June 5, 2015 By Manish Butte

A conserved sugar bridge connected to the WSXWS motif has an important role for transport of IL-21R to the plasma membrane.

Genes Immun. 2015 Jun 4;

Authors: Siupka P, Hamming OT, Kang L, Gad HH, Hartmann R

Abstract
Interleukin-21 (IL-21) is a class I cytokine that belongs to the γc-subfamily of cytokines and regulates immune responses. It signals through a heterodimeric receptor complex composed of the IL-21R1 and γc-receptor chains. A characteristic feature of class I cytokine receptors is the presence of a consensus motif WSXWS (WS motif) in the membrane proximal fibronectin type III domain (FNIII) of these receptors. We recently described the structure of the IL-21R:IL-21 complex and showed that the first tryptophan of the WS motif of IL-21R is mannosylated and involved in formation of a sugar bridge that connects the two FNIII domains of the receptor. Furthermore, a mutation within the WS motif of IL-21R was recently shown to cause a novel kind of primary immunodeficiency syndrome (PID). Here, we report the structure of IL-21R alone, which shows that the sugar bridge forms independently of whether IL-21R binds IL-21 or not, and we furthermore investigate the role of this bridge in the export of IL-21R and γC to the plasma membrane. Thus, we provide a molecular explanation for how mutations in the WS motif may cause PIDs.Genes and Immunity advance online publication, 4 June 2015; doi:10.1038/gene.2015.22.

PMID: 26043171 [PubMed – as supplied by publisher]

Functional and molecular defects of hiPSC-derived neurons from patients with ATM deficiency.

June 5, 2015 By Manish Butte

Functional and molecular defects of hiPSC-derived neurons from patients with ATM deficiency.

Cell Death Dis. 2014;5:e1342

Authors: Carlessi L, Fusar Poli E, Bechi G, Mantegazza M, Pascucci B, Narciso L, Dogliotti E, Sala C, Verpelli C, Lecis D, Delia D

Abstract
Loss of ataxia telangiectasia mutated (ATM) kinase, a key factor of the DNA damage response (DDR) pathway, causes the cancer predisposing and neurodegenerative syndrome ataxia-telangiectasia (A-T). To investigate the mechanisms of neurodegeneration, we have reprogrammed fibroblasts from ATM-null A-T patients and normal controls to pluripotency (human-induced pluripotent stem cells), and derived from these neural precursor cells able to terminally differentiate into post-mitotic neurons positive to >90% for β-tubulin III+/microtubule-associated protein 2+. We show that A-T neurons display similar voltage-gated potassium and sodium currents and discharges of action potentials as control neurons, but defective expression of the maturation and synaptic markers SCG10, SYP and PSD95 (postsynaptic density protein 95). A-T neurons exhibited defective repair of DNA double-strand breaks (DSBs) and repressed phosphorylation of ATM substrates (e.g., γH2AX, Smc1-S966, Kap1-S824, Chk2-T68, p53-S15), but normal repair of single-strand breaks, and normal short- and long-patch base excision repair activities. Moreover, A-T neurons were resistant to apoptosis induced by the genotoxic agents camptothecin and trabectedin, but as sensitive as controls to the oxidative agents. Most notably, A-T neurons exhibited abnormal accumulation of topoisomerase 1-DNA covalent complexes (Top1-ccs). These findings reveal that ATM deficiency impairs neuronal maturation, suppresses the response and repair of DNA DSBs, and enhances Top1-cc accumulation. Top1-cc could be a risk factor for neurodegeneration as they may interfere with transcription elongation and promote transcriptional decline.

PMID: 25032865 [PubMed – indexed for MEDLINE]

Influence of chronic illnesses and underlying risk conditions on the incidence of pneumococcal pneumonia in older adults.

June 4, 2015 By Manish Butte

Influence of chronic illnesses and underlying risk conditions on the incidence of pneumococcal pneumonia in older adults.

Infection. 2015 Jun 3;

Authors: Vila-Corcoles A, Aguirre-Chavarria C, Ochoa-Gondar O, de Diego C, Rodriguez-Blanco T, Gomez F, Raga X, Barnes L, Magarolas R, Esteban L

Abstract
OBJECTIVE: To investigate hospitalizations from pneumococcal pneumonia in older adults with specific underlying chronic conditions, evaluating the influence of these conditions in developing pneumonia.
METHODS: Population-based cohort study involving 27,204 individuals ≥60 years old in Southern Catalonia, Spain. All cases of hospitalization from pneumococcal pneumonia (bacteremic and nonbacteremic) were collected since 01/12/2008 until 30/11/2011. Cox regression was used to calculate hazards ratio (HR) and estimate the association between baseline conditions and the risk of developing pneumococcal pneumonia.
RESULTS: Maximum incidences (per 1000 person-years) appeared among patients with history of prior pneumonia (14.6), nursing home residents (12.8), persons with immunodeficiency/asplenia (7.7) and patients with chronic pulmonary disease (7.6). In multivariable analysis, age (HR: 1.05), nursing home residence (HR: 4.59), history of prior pneumonia (HR: 3.58), stroke (HR: 2.50), chronic heart disease (HR: 1.53), chronic pulmonary disease (HR: 4.09), diabetes mellitus (HR: 1.66), smoking (HR: 1.69) and immunosuppressive medication (HR: 1.87) appeared significantly associated with an increased risk of pneumococcal pneumonia.
CONCLUSION: Our data support that nursing home residence, chronic pulmonary disease and immunocompromising conditions are the underlying conditions most strongly associated with an increasing risk of pneumococcal pneumonia in older adults. This data underline the need for better prevention strategies among these persons.

PMID: 26037386 [PubMed – as supplied by publisher]

Comorbidities and Assessment of Severity of Pediatric Acute Respiratory Distress Syndrome: Proceedings From the Pediatric Acute Lung Injury Consensus Conference.

June 3, 2015 By Manish Butte

Comorbidities and Assessment of Severity of Pediatric Acute Respiratory Distress Syndrome: Proceedings From the Pediatric Acute Lung Injury Consensus Conference.

Pediatr Crit Care Med. 2015 Jun;16(5_suppl Suppl 1):S41-S50

Authors: Flori H, Dahmer MK, Sapru A, Quasney MW, Pediatric Acute Lung Injury Consensus Conference Group

Abstract
OBJECTIVES: To determine the impact of patient-specific and disease-related characteristics on the severity of illness and on outcome in pediatric patients with acute respiratory distress syndrome with the intent of guiding current medical practice and identifying important areas for future research.
DESIGN: Electronic searches of PubMed, EMBASE, Web of Science, Cochrane, and Scopus were conducted. References were reviewed for relevance and features included in the following section.
SETTINGS: Not applicable.
SUBJECTS: PICU patients with evidence of acute lung injury, acute hypoxemic respiratory failure, and acute respiratory distress syndrome.
INTERVENTIONS: Not applicable.
MEASUREMENTS AND MAIN RESULTS: The comorbidities associated with outcome in pediatric acute respiratory distress syndrome can be divided into 1) patient-specific factors and 2) factors inherent to the disease process. The primary comorbidity associated with poor outcome is preexisting congenital or acquired immunodeficiency. Severity of disease is often described by factors identifiable at admission to the ICU. Many measures that are predictive are influenced by the underlying disease process itself, but may also be influenced by nutritional status, chronic comorbidities, or underlying genetic predisposition. Of the measures available at the bedside, both PaO2/FIO2 ratio and oxygenation index are fairly consistent and robust predictors of disease severity and outcomes. Multiple organ system dysfunction is the single most important independent clinical risk factor for mortality in children at the onset of acute respiratory distress syndrome.
CONCLUSIONS: The assessment of oxygenation and ventilation indices simultaneously with genetic and biomarker measurements holds the most promise for improved risk stratification for pediatric acute respiratory distress syndrome patients in the very near future. The next phases of pediatric acute respiratory distress syndrome pathophysiology and outcomes research will be enhanced if 1) age group differences are examined, 2) standardized datasets with adequately explicit definitions are used, 3) data are obtained at standardized times after pediatric acute respiratory distress syndrome onset, and 4) nonpulmonary organ failure scores are created and implemented.

PMID: 26035363 [PubMed – as supplied by publisher]

New Insights Into Multicenter PICU Mortality Among Pediatric Hematopoietic Stem Cell Transplant Patients.

June 3, 2015 By Manish Butte

New Insights Into Multicenter PICU Mortality Among Pediatric Hematopoietic Stem Cell Transplant Patients.

Crit Care Med. 2015 May 29;

Authors: Zinter MS, Dvorak CC, Spicer A, Cowan MJ, Sapru A

Abstract
OBJECTIVES: Over 2,500 children undergo hematopoietic stem cell transplantation in the United States each year, and up to 35% require PICU support for life-threatening complications. PICU mortality has dropped from 85% to 44%, but interpretation is confounded by significant cohort heterogeneity. Reports conflict regarding outcomes for patients with different underlying -hematopoietic stem cell transplantation indications, and the burden of infectious complications for these patients has not been evaluated. We aim to describe infections, critical care interventions, and mortality for pediatric hematopoietic stem cell transplantation patients requiring PICU admission.
DESIGN: A retrospective multicenter cohort analysis.
SETTING: One hundred twelve centers in the Virtual PICU Systems database, January 1, 2009, to June 30, 2012.
PATIENTS: A total of 1,782 admissions for patients who are 21 years old or younger with prior hematopoietic stem cell transplantation.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Pediatric Index of Mortality-2, Pediatric Risk of Mortality-3, transplant indication, infections, interventions, and mortality were recorded from admission through PICU death or discharge. Pediatric hematopoietic stem cell transplantation patients comprised 0.7% of all PICU admissions (1,782/246,346), which resulted in 16.2% mortality compared with 2.4% mortality for non-hematopoietic stem cell transplantation admissions (odds ratio, 7.8; 95% CI, 6.8-8.8; p < 0.001). Mortality for admissions with underlying hematologic malignancy (22.7%) was similar to that of admissions with primary immunodeficiency (19.4%; p = 0.41) but significantly greater than admissions with underlying nonmalignant non-primary immunodeficiency hematologic disease (15.4%; p = 0.020), metabolic disorder (8.1%; p < 0.001), or solid malignancy (5.7%; p < 0.001). Infection was documented in 45.7% of admissions with 22.2% mortality; viral and fungal mortality were 28.5% and 33.7%, respectively. Invasive positive pressure ventilation and renal replacement therapy were used in only 34.6% and 11.9% of admissions, with mortality of 42.5% and 51.9%, respectively.
CONCLUSIONS: PICU mortality for pediatric hematopoietic stem cell transplantation patients may be as low as 16.2% but higher for those receiving intubation (42.5%) or replacement therapy (51.9%). Hematologic malignancy and primary immunodeficiency had greater risk for mortality than other transplant indications. Greater understanding of other risk factors affecting mortality and the need for critical care support is needed.

PMID: 26035280 [PubMed – as supplied by publisher]

[Is familial screening useful in selective immunoglobulin A deficiency?]

June 3, 2015 By Manish Butte

[Is familial screening useful in selective immunoglobulin A deficiency?]

An Pediatr (Barc). 2015 May 29;

Authors: Soler-Palacín P, Cobos-Carrascosa E, Martín-Nalda A, Caracseghi F, Hernández M, Figueras-Nadal C

Abstract
INTRODUCTION: Selective immunoglobulin A deficiency (SIgAD), the most common primary immunodeficiency, is often asymptomatic. High rates of familial clustering have been described in SIgAD, but the causative genetic defect and mechanism of inheritance are unknown.
OBJECTIVES: To determine whether familial SIgAD cases show more severe clinical and immunological characteristics than sporadic ones; to investigate the utility of screening first-degree relatives (FDRs) of these patients, and to determine whether symptoms in affected family members are important enough to justify screening.
PATIENTS AND METHODS: Descriptive, cross-sectional study (October 2010-September 2011) of all patients with SIgAD and followed up in our center. Demographic, clinical, and analytical data were reviewed. A familial case was defined as an SIgAD patient with at least one affected FDR.
RESULTS: Of the 130 participants, 42 were SIgAD patients and 88 FDR. There were 13 (31%) familial cases and and 14 (16%) affected FDRs. Six family members had to be analyzed in order to detect one affected one. There were no clinical differences between familial and sporadic SIgAD cases. The percentages of intestinal disease (p=001, OR=9.57, 95%CI 2.59-35.3), hospitalizations (p=045, OR=4.01; 95%CI 1.10-14.67], and need for chronic treatment (p=006, OR=5.5; 95%CI 1.57-19.54) were higher in affected FDRs than in unaffected ones.
CONCLUSIONS: The symptoms were not more severe in familial than sporadic SIgAD cases. Nonetheless, the elevated prevalence of affected FDRs with significant morbidity may justify routine screening of close family members of these patients.

PMID: 26033741 [PubMed – as supplied by publisher]

The Swiss National Registry for Primary Immunodeficiencies: Report on the first 6 years' activity 2008-2014.

June 3, 2015 By Manish Butte

The Swiss National Registry for Primary Immunodeficiencies: Report on the first 6 years’ activity 2008-2014.

Clin Exp Immunol. 2015 Jun 1;

Authors: Marschall K, Hoernes M, Bitzenhofer-Grüber M, Jandus P, Duppenthaler A, Wuillemin WA, Rischewski J, Boyman O, Heininger U, Hauser T, Steiner U, Posfay-Barbe K, Seebach J, Recher M, Hess C, Helbling A, Reichenbach J, Swiss PID Registry Working Group

Abstract
The Swiss National Registry for Primary Immunodeficiency Disorders (PID) was established in 2008, constituting a nationwide network of paediatric and adult departments involved in the care for patients with PID at university medical centres, affiliated teaching hospitals and medical institutions. The registry collects anonymised clinical and genetic information on PID patients and is set up within the framework of the European database for PID, run by the European Society of Immunodeficiency Diseases. To date, a total of n=348 patients are registered in Switzerland indicating an estimated minimal prevalence of 4.2 patients per 100,000 inhabitants. Distribution of different PID categories, age and gender are similar to the European cohort of currently 19,091 registered patients: “Predominantly Antibody Disorders” are the most common diseases observed (n=217/348, 62%), followed by “Phagocytic Disorders” (n=31/348, 9%). As expected “Predominantly Antibody Disorders” are more prevalent in adults than in children (78% vs. 31%). Within this category “Common Variable Immunodeficiency Disorder” (CVID) is the most prevalent PID (n=98/217, 45%), followed by “Other Hypogammaglobulinemias” (i.e. a group of non-classified Hypogammaglobulinemias) (n=54/217, 25%). Amongst “Phagocytic Disorders”, “Chronic Granulomatous Disease” is the most prevalent PID (n=27/31, 87%). The diagnostic delay between onset of symptoms and diagnosis is high with a median of 6 years for CVID and more than 3 years for “Other Hypogammaglobulinemias”. This article is protected by copyright. All rights reserved.

PMID: 26031847 [PubMed – as supplied by publisher]

Immunoglobulins and their use in children.

June 3, 2015 By Manish Butte

Immunoglobulins and their use in children.

Adv Clin Exp Med. 2015 Jan-Feb;24(1):153-9

Authors: Łaguna P, Gołębiowska-Staroszczyk S, Trzaska M, Grabarczyk M, Matysiak M

Abstract
Immunoglobulin preparations are one of the products of the human plasma fractionation, where the plasma is obtained, in accordance with WHO guidelines from at least 1,000 donors. These preparations contain all IgG subclasses with various antigen characteristics. In clinical practice these drugs are used as replacement therapy in patients with primary and secondary immunodeficiencies as well as immunomodulatory therapy in many autoimmune diseases and systemic inflammatory diseases. Here we present characteristics of i.v. polyvalent, human immunoglobulin preparations available on the Polish market and the possibilities of their use in clinical practice, in children with hematological diseases. Considering the very low consumption of immunoglobulin preparations in our country as compared to other European countries, we would like to draw the attention of medical professionals, especially pediatricians and haematologists, to the benefits that stem from the use of these drugs in the therapy of children with haematological diseases. Our work will also facilitate the choice of an optimal polyvalent human immunoglobulin preparation for a particular patient.

PMID: 25923100 [PubMed – indexed for MEDLINE]

The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis.

May 30, 2015 By Manish Butte

The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis.

Haematologica. 2015 May 28;

Authors: Bode SF, Ammann S, Al-Herz W, Bataneant M, Dvorak CC, Gehring S, Gennery A, Gilmour KC, Gonzalez-Granado LI, GroB-Wieltsch U, Ifversen M, Lingman-Framme J, Matthes-Martin S, Mesters R, Meyts I, van Montfrans JM, Pachlopnik Schmid J, Pai SY, Soler-Palacin P, Schuermann U, Schuster V, Seidel MG, Speckmann C, Stepensky P, Sykora KW, Tesi B, Vraetz T, Waruiru C, Bryceson YT, Moshous D, Lehmberg K, Jordan MB, Ehl S

Abstract
Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. This includes patients with primary immunodeficiencies, in whom pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with <100/ml T-cells, 18 had partial T-cell deficiencies; episodes of hemophagocytic lymphohistiocytosis were mostly associated with viral infections. Twenty-two patients had chronic granulomatous disease with hemophagocytic episodes mainly associated with bacterial infections. Compared to patients with cytotoxicity defects, patients with T-cell deficiencies had lower soluble CD25 and higher ferritin. Other criteria for hemophagocytoc lymphohistiocytosis were not discriminative. Thus, (i) a hemophagocytic inflammatory syndrome fulfilling criteria for hemophagocytic lymphohistiocytosis can be the initial manifestation of primary immunodeficiencies. (ii) this syndrome can develop despite severe deficiency of T- and NK-cells, implicating that pathophysiology is distinct and not appropriately described as Lympho-Histiocytosis in these patients (iii) current criteria for hemophagocytoc lymphohistiocytosis are insufficient to differentiate hemophagocytic inflammatory syndromes with different pathogenesis. This is important because of implications for therapy, in particular for protocols targeting T-cells.

PMID: 26022711 [PubMed – as supplied by publisher]

Disseminated bronchiectasis in an adult with common variable immunodeficiency.

May 29, 2015 By Manish Butte

Disseminated bronchiectasis in an adult with common variable immunodeficiency.

Colomb Med (Cali). 2015 Jan-Mar;46(1):47-50

Authors: Zea-Vera AF, Agudelo-Rojas OL

Abstract
Primary immunodeficiencies (PID) are traditionally considered childhood diseases; however, adults account for 35% of all patients with PID. Antibody deficiencies, especially Common Variable Immunodeficiency (CVID), which have their peak incidence in adulthood, require a high suspicion index. Even though the estimated frequency of CVID is not high (1:25,000), high rates of under diagnosis and under reporting are very likely. The delay in diagnosis increases the morbidity and mortality; therefore, adult physicians should be able to suspect, identify and initiate management of individuals with PID. Here we report the case of a 37 year-old man presenting to the emergency room with dyspnea, fever and cough; he developed respiratory failure requiring mechanical ventilation. He complained of recurring pneumonia associated with widespread bronchiectasis since he was 18 years old. Serum immunoglobulins quantification showed severe hypogammaglobulinemia (total IgG <140 mg/dL; total IgA, 2.9 mg/dL; and total IgM <5 mg/dL). Treatment with Human Intravenous Immunoglobulin (IVIG) 10% was started, and with antibiotic treatment for severe pneumonia (during 14 days) was also prescribed. His clinical evolution has been favorable after one year follow-up. Common Variable Immunodeficiency (CVID) diagnosis was made.

PMID: 26019385 [PubMed – in process]