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Global overview of primary immunodeficiencies: a report from Jeffrey Modell Centers worldwide focused on diagnosis, treatment, and discovery.

June 10, 2015 By Manish Butte

Global overview of primary immunodeficiencies: a report from Jeffrey Modell Centers worldwide focused on diagnosis, treatment, and discovery.

Immunol Res. 2014 Oct;60(1):132-44

Authors: Modell V, Knaus M, Modell F, Roifman C, Orange J, Notarangelo LD

Abstract
Primary immunodeficiencies (PI) are defects of the immune system that cause severe infections if not diagnosed and treated appropriately. Many patients with PI are undiagnosed, under-diagnosed, or misdiagnosed. Over the last decade, the Jeffrey Modell Foundation has implemented a Physician Education and Public Awareness Campaign (PEPAC) to raise awareness, assure early diagnosis, appropriate treatment, and management, with the overall goal to reduce morbidities and mortalities related to PI. In order to evaluate the PEPAC program, data are requested annually from physician experts within the Jeffrey Modell Centers Network (JMCN). The JMCN, consisting of 556 expert physicians, at 234 academic institutions, in 196 cities, and 78 countries spanning six continents, provides the infrastructure for referral, diagnosis, and appropriate treatment for patients with PI. In addition, the JMCN has made a significant contribution to the field of immunology with the discovery of new genes at the centers. These advancements have led to an overall better understanding of the immune system and will continue to improve quality of life of those with PI.

PMID: 24668296 [PubMed – indexed for MEDLINE]

Novel Genome-Editing Tools to Model and Correct Primary Immunodeficiencies.

June 9, 2015 By Manish Butte

Novel Genome-Editing Tools to Model and Correct Primary Immunodeficiencies.

Front Immunol. 2015;6:250

Authors: Ott de Bruin LM, Volpi S, Musunuru K

Abstract
Severe combined immunodeficiency (SCID) and other severe non-SCID primary immunodeficiencies (non-SCID PID) can be treated by allogeneic hematopoietic stem cell (HSC) transplantation, but when histocompatibility leukocyte antigen-matched donors are lacking, this can be a high-risk procedure. Correcting the patient’s own HSCs with gene therapy offers an attractive alternative. Gene therapies currently being used in clinical settings insert a functional copy of the entire gene by means of a viral vector. With this treatment, severe complications may result due to integration within oncogenes. A promising alternative is the use of endonucleases such as ZFNs, TALENs, and CRISPR/Cas9 to introduce a double-stranded break in the DNA and thus induce homology-directed repair. With these genome-editing tools a correct copy can be inserted in a precisely targeted “safe harbor.” They can also be used to correct pathogenic mutations in situ and to develop cellular or animal models needed to study the pathogenic effects of specific genetic defects found in immunodeficient patients. This review discusses the advantages and disadvantages of these endonucleases in gene correction and modeling with an emphasis on CRISPR/Cas9, which offers the most promise due to its efficacy and versatility.

PMID: 26052330 [PubMed]

A novel thymoma-associated immunodeficiency with increased naive T cells and reduced CD247 expression.

June 9, 2015 By Manish Butte

A novel thymoma-associated immunodeficiency with increased naive T cells and reduced CD247 expression.

J Immunol. 2015 Apr 1;194(7):3045-53

Authors: Christopoulos P, Dopfer EP, Malkovsky M, Esser PR, Schaefer HE, Marx A, Kock S, Rupp N, Lorenz MR, Schwarz K, Harder J, Martin SF, Werner M, Bogdan C, Schamel WW, Fisch P

Abstract
The mechanisms underlying thymoma-associated immunodeficiency are largely unknown, and the significance of increased blood γδ Τ cells often remains elusive. In this study we address these questions based on an index patient with thymoma, chronic visceral leishmaniasis, myasthenia gravis, and a marked increase of rare γδ T cell subsets in the peripheral blood. This patient showed cutaneous anergy, even though he had normal numbers of peripheral blood total lymphocytes as well as CD4(+) and CD8(+) T cells. Despite his chronic infection, analyses of immunophenotypes and spectratyping of his lymphocytes revealed an unusual accumulation of naive γδ and αβ T cells, suggesting a generalized T cell activation defect. Functional studies in vitro demonstrated substantially diminished IL-2 and IFN-γ production following TCR stimulation of his “untouched” naive CD4(+) T cells. Biochemical analysis revealed that his γδ and αβ T cells carried an altered TCR complex with reduced amounts of the ζ-chain (CD247). No mutations were found in the CD247 gene that encodes the homodimeric ζ protein. The diminished presence of CD247 and increased numbers of γδ T cells were also observed in thymocyte populations obtained from three other thymoma patients. Thus, our findings describe a novel type of a clinically relevant acquired T cell immunodeficiency in thymoma patients that is distinct from Good’s syndrome. Its characteristics are an accumulation of CD247-deficient, hyporresponsive naive γδ and αβ T cells and an increased susceptibility to infections.

PMID: 25732729 [PubMed – indexed for MEDLINE]

Early diagnosis of celiac disease in IgA deficient children: contribution of a point-of-care test.

June 9, 2015 By Manish Butte

Early diagnosis of celiac disease in IgA deficient children: contribution of a point-of-care test.

BMC Gastroenterol. 2014;14:186

Authors: Bienvenu F, Anghel SI, Besson Duvanel C, Guillemaud J, Garnier L, Renosi F, Lachaux A, Bienvenu J

Abstract
BACKGROUND: The serological diagnosis of celiac disease (CD) often relies on the presence of anti-tissue transglutaminase (tTG) IgA autoantibodies. Patients suffering from selective IgA deficiency (IgAD) are often not aware of their IgA deficiency and are tested as CD negative, delaying considerably the diagnosis. The detection of IgG against deamidated gliadin peptides (DGP) has high specificity and better sensitivity than IgG anti-tTG. A multi-analytic lateral-flow immunochromatographic assay (CD-LFIA) based on the detection of IgA and IgG anti-DGP and total IgA was shown to have a good diagnostic accuracy for CD. The aim of this study was to evaluate the clinical accuracy of its use in children suffering from IgAD.
METHODS: 45 IgAD children ranging from 1.1 to 17.4 years and suspected of CD or having high CD risk factors were referred from outpatient clinics located in the area of Rhone-Alpes (France) to the Hospices Civils de Lyon, Paediatric Hospital-Gastroenterology-Hepatology- Nutrition Department for further CD investigations. The CD investigations, including the sample collection, were performed within the Paediatric Hospital-Gastroenterology-Hepatology- Nutrition Department, and the serological testing was performed at the Lyon-Sud Hospital-Immunology Laboratory. The diagnosis of CD was based on IgG anti-tTG serology, biopsy results and patient follow-up. The serum samples were retrospectively tested on the CD-LFIA test.
RESULTS: A total of eight (8) patients were diagnosed as new CD. All were correctly identified by the CD-LFIA. The test yielded four (4) false positive results. Two patients with positive IgG anti-tTG were negative on CD-LFIA, but were classified as CD negative based on biopsy results and patient follow-up. The remaining 33 patients were found negative by both methods. The specificity and sensitivity of CD-LFIA was of 89.2% [74.6-97.0] and of 100% [63.1-100] respectively. The negative predictive value (NPV) was of 100% [89.4-100], and the Likelihood Ratio for Negative Test (LR-) was of 0 [0.0-0.91].
CONCLUSIONS: CD-LFIA is a useful, non-invasive and rapid tool to rule out CD in primary care paediatric patients having CD-related symptoms and IgAD. Patients having a positive CD-LFIA result could be then readily directed to secondary care setting for further evaluation by standard serology and biopsy.

PMID: 25376178 [PubMed – indexed for MEDLINE]

Gene therapy for monogenic disorders of the bone marrow.

June 6, 2015 By Manish Butte

Gene therapy for monogenic disorders of the bone marrow.

Br J Haematol. 2015 Jun 5;

Authors: Ghosh S, Thrasher AJ, Gaspar HB

Abstract
Ex-vivo gene transfer of autologous haematopoietic stem cells in patients with monogenic diseases of the bone marrow has emerged as a new therapeutic approach, mainly in patients lacking a suitable donor for transplant. The encouraging results of initial clinical trials of gene therapy for primary immunodeficiencies were tempered by the occurrence of genotoxicity in a number of patients. Over the last decade, safer viral vectors have been developed to overcome the risk of insertional mutagenesis and have led to impressive clinical outcomes with considerably improved safety. We review the efforts in specific immunodeficiencies including adenosine deaminase deficiency, X-linked severe combined immunodeficiency, chronic granulomatous disease and Wiskott Aldrich syndrome. Major recent progress has also been made in haemoglobinopathies, such as beta-thalassaemia, sickle cell disease and Fanconi anaemia, and also specific lysosomal storage diseases, which, although not strictly bone marrow specific conditions, have been effectively treated by bone marrow-based treatment. The success of these recent studies and the advent of new technologies, such as gene editing, suggest that gene therapy could become a more generally applied treatment modality for a number of haematopoietic disorders.

PMID: 26044877 [PubMed – as supplied by publisher]

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]