Manish Butte

Evaluation of Clinical and Immunological Characteristics of Children with Common Variable Immunodeficiency.

June 1, 2018 By Manish Butte

Evaluation of Clinical and Immunological Characteristics of Children with Common Variable Immunodeficiency.

Int J Pediatr. 2018;2018:3527480

Authors: Alkan G, Keles S, Reisli İ

Abstract
Background: Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder (PID) that typically presents with hypogammaglobulinemia and impaired antibody production.
Objectives: This study aimed to promote the awareness of CVID, whose clinical spectrum is quite broad.
Methods: The demographic, clinical, and laboratory characteristics of 12 children (seven males and five females) with CVID were analyzed retrospectively. The patients were diagnosed using the diagnostic criteria of the European Society for Primary Immunodeficiencies.
Results: The median disease onset age was 7.2 ± 4.1 years, and the mean diagnosis age was 11.6 ± 3.7 years. The diagnosis delay was 4.3 ± 2.6 years, and the parental consanguinity rate was 75%. Most patients presented with recurrent infections, including upper respiratory tract infections (n = 8), lower respiratory tract infections (n = 9), and gastroenteritis (n = 5). In addition, growth retardation (n = 9) and bronchiectasis (n = 5) were common comorbidities. Two patients presented with autoimmune thrombocytopenia and anemia, and one patient exhibited lung empyema. All the patients had immunoglobulin G deficiencies.
Conclusion: CVID is a heterogeneous disease, so the diagnosis is frequently delayed. In the CVID patients with pulmonary complications, relationships were seen with the diagnosis delay, symptom onset age, and lung infection prevalence. Overall, the early diagnosis and treatment of PIDs can preclude life-threatening complications.

PMID: 29849668 [PubMed]

Genome and Epigenome Editing to Treat Disorders of the Hematopoietic System.

June 1, 2018 By Manish Butte

Genome and Epigenome Editing to Treat Disorders of the Hematopoietic System.

Hum Gene Ther. 2017 Nov;28(11):1105-1115

Authors: Mussolino C, Alzubi J, Pennucci V, Turchiano G, Cathomen T

Abstract
The possibility of editing complex genomes in a targeted fashion has revolutionized basic research as well as biomedical and biotechnological applications in the last 5 years. The targeted introduction of genetic changes has allowed researchers to create smart model systems for basic research, bio-engineers to modify crops and farm animals, and translational scientists to develop novel treatment approaches for inherited and acquired disorders for which curative treatment options are not yet available. With the rapid development of genome editing tools, in particular zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the CRISPR-Cas system, a wide range of therapeutic options have been-and will be-developed at an unprecedented speed, which will change the clinical routine of various disciplines in a revolutionary way. This review summarizes the fundamentals of genome editing and the current state of research. It particularly focuses on the advances made in employing engineered nucleases in hematopoietic stem cells for the treatment of primary immunodeficiencies and hemoglobinopathies, provides a perspective of combining gene editing with the chimeric antigen receptor T cell technology, and concludes by presenting targeted epigenome editing as a novel potential treatment option.

PMID: 28806883 [PubMed – indexed for MEDLINE]

Chronic Rhinosinusitis in Children: Pathophysiology, Evaluation, and Medical Management.

May 31, 2018 By Manish Butte

Chronic Rhinosinusitis in Children: Pathophysiology, Evaluation, and Medical Management.

Curr Allergy Asthma Rep. 2018 May 29;18(7):37

Authors: Heath J, Hartzell L, Putt C, Kennedy JL

Abstract
PURPOSE OF REVIEW: Pediatric chronic rhinosinusitis (CRS) is a common disorder that carries significant morbidity. The diagnosis requires sinus symptoms that persist despite standard medical therapy greater than 3 months. Viral infections, allergies, and anatomic differences in children lead to chronic obstruction of the osteomeatal complex.
RECENT FINDINGS: Chronic rhinosinusitis as a diagnosis is a conglomeration of multiple phenotypes and endotypes. As such, the diagnosis and management are complex. New survey studies provide some consensus on prevalence and management of this disease in children. In this review, we highlight the differential diagnosis of pediatric CRS, including non-eosinophilic/infectious variants, eosinophilic variants with and without nasal polyps, allergic fungal sinusitis, aspirin-exacerbated respiratory disease, primary immunodeficiency, and disorders of mucociliary clearance. Further, we detail treatment options that should be considered. Finally, we feature emerging potential treatment options of CRS, including anti-immunoglobulin E, interleukin-5, and interleukin-4 receptor alpha subunit.

PMID: 29845321 [PubMed – in process]

Molecular Evidence of Genome Editing in a Mouse Model of Immunodeficiency.

May 31, 2018 By Manish Butte

Molecular Evidence of Genome Editing in a Mouse Model of Immunodeficiency.

Sci Rep. 2018 May 29;8(1):8214

Authors: Abdul-Razak HH, Rocca CJ, Howe SJ, Alonso-Ferrero ME, Wang J, Gabriel R, Bartholomae CC, Gan CHV, Garín MI, Roberts A, Blundell MP, Prakash V, Molina-Estevez FJ, Pantoglou J, Guenechea G, Holmes MC, Gregory PD, Kinnon C, von Kalle C, Schmidt M, Bueren JA, Thrasher AJ, Yáñez-Muñoz RJ

Abstract
Genome editing is the introduction of directed modifications in the genome, a process boosted to therapeutic levels by designer nucleases. Building on the experience of ex vivo gene therapy for severe combined immunodeficiencies, it is likely that genome editing of haematopoietic stem/progenitor cells (HSPC) for correction of inherited blood diseases will be an early clinical application. We show molecular evidence of gene correction in a mouse model of primary immunodeficiency. In vitro experiments in DNA-dependent protein kinase catalytic subunit severe combined immunodeficiency (Prkdc scid) fibroblasts using designed zinc finger nucleases (ZFN) and a repair template demonstrated molecular and functional correction of the defect. Following transplantation of ex vivo gene-edited Prkdc scid HSPC, some of the recipient animals carried the expected genomic signature of ZFN-driven gene correction. In some primary and secondary transplant recipients we detected double-positive CD4/CD8 T-cells in thymus and single-positive T-cells in blood, but no other evidence of immune reconstitution. However, the leakiness of this model is a confounding factor for the interpretation of the possible T-cell reconstitution. Our results provide support for the feasibility of rescuing inherited blood disease by ex vivo genome editing followed by transplantation, and highlight some of the challenges.

PMID: 29844458 [PubMed – in process]

Ataxia-Telangiectasia Mutated (ATM) Protein Signaling Participates in Development of Pulmonary Arterial Hypertension in Rats.

May 31, 2018 By Manish Butte

Ataxia-Telangiectasia Mutated (ATM) Protein Signaling Participates in Development of Pulmonary Arterial Hypertension in Rats.

Med Sci Monit. 2017 Sep 12;23:4391-4400

Authors: Hu F, Liu C, Liu H, Xie L, Yu L

Abstract
BACKGROUND Previous studies revealed physiological and pathogenetic similarity between vascular smooth muscles cells with severe pulmonary arterial hypertension and tumors. The DNA damage response was found in both pulmonary arterial hypertension (PAH) cells and tumors. The ataxia-telangiectasia mutated proteins (ATM) pathway is considered an important factor in the DNA damage response of tumor formation, but its function in the development of PAH remains unknown. MATERIAL AND METHODS The Sprague-Dawley rat PAH model was established. Three weeks (Group M1), 5 weeks (Group M2), and 7 weeks (Group M3) after drug injection, pulmonary expression of ATM, Checkpoint kinase 2 (Chk2), P53, and P21 were measured. A section of the lungs from Group M2 was used for pulmonary artery vascular smooth muscles cells (PA-SMCs) isolation and culture. The effect of KU60019 in the proliferation and apoptosis of primary cultured rat PA-SMCs was measured by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and TdT-mediated dUTP nick-end labeling (TUNEL), respectively. RESULTS Immunohistochemistry results show that the expression of ATM, Chk2, and P21 increased in Groups M1 and M2, and decreased in Group M3. Additionally, expression of P53 increased in Group M1, and decreased in Groups M2 and M3. RT-PCR and Western blotting demonstrated that in Groups M1 and M2, the expression of ATM, Chk2, P53, and P21 increased, whereas it decreased in Group M3. In cell culture, 0.3 μM and 0.5 μM KU60019 increased the growth of PA-SMCs, and 0.5 μM KU60019 reduced cell apoptosis. CONCLUSIONS Expression of the ATM-Chk2 pathway increased in early stages of PAH formation, but decreased in late stages. In primary cultured PA-SMCs, KU60019 increased cell proliferation and inhibited cell apoptosis.

PMID: 28894083 [PubMed – indexed for MEDLINE]

Entinostat up-regulates the CAMP gene encoding LL-37 via activation of STAT3 and HIF-1α transcription factors.

May 31, 2018 By Manish Butte

Entinostat up-regulates the CAMP gene encoding LL-37 via activation of STAT3 and HIF-1α transcription factors.

Sci Rep. 2016 09 16;6:33274

Authors: Miraglia E, Nylén F, Johansson K, Arnér E, Cebula M, Farmand S, Ottosson H, Strömberg R, Gudmundsson GH, Agerberth B, Bergman P

Abstract
Bacterial resistance against classical antibiotics is a growing problem and the development of new antibiotics is limited. Thus, novel alternatives to antibiotics are warranted. Antimicrobial peptides (AMPs) are effector molecules of innate immunity that can be induced by several compounds, including vitamin D and phenyl-butyrate (PBA). Utilizing a luciferase based assay, we recently discovered that the histone deacetylase inhibitor Entinostat is a potent inducer of the CAMP gene encoding the human cathelicidin LL-37. Here we investigate a mechanism for the induction and also find that Entinostat up-regulates human β-defensin 1. Analysis of the CAMP promoter sequence revealed binding sites for the transcription factors STAT3 and HIF-1α. By using short hairpin RNA and selective inhibitors, we found that both transcription factors are involved in Entinostat-induced expression of LL-37. However, only HIF-1α was found to be recruited to the CAMP promoter, suggesting that Entinostat activates STAT3, which promotes transcription of CAMP by increasing the expression of HIF-1α. Finally, we provide in vivo relevance to our findings by showing that Entinostat-elicited LL-37 expression was impaired in macrophages from a patient with a STAT3-mutation. Combined, our findings support a role for STAT3 and HIF-1α in the regulation of LL-37 expression.

PMID: 27633343 [PubMed – indexed for MEDLINE]

Measurement and interpretation of Salmonella typhi Vi IgG antibodies for the assessment of adaptive immunity.

May 29, 2018 By Manish Butte

Measurement and interpretation of Salmonella typhi Vi IgG antibodies for the assessment of adaptive immunity.

J Immunol Methods. 2018 May 22;:

Authors: Parker AR, Bradley C, Harding S, Sánchez-Ramón S, Jolles S, Kiani-Alikhan S

Abstract
Response to polysaccharide vaccination can be an invaluable tool for assessing functionality of the adaptive immune system. Measurement of antibodies raised in response to Pneumovax®23 is the current gold standard test, but there are significant challenges and constraints in both the measurement and interpretation of the response. An alternative polysaccharide vaccine approach (Salmonella typhi Vi capsule (ViCPS)) has been suggested. In the present article, we review current evidence for the measurement of ViCPS antibodies in the diagnosis of primary and secondary antibody deficiencies. In particular, we review emerging data suggesting their interpretation in combination with the response to Pneumovax®23 and comment upon the utility of these vaccines to assess humoral immune responses while receiving immunoglobulin replacement therapy (IGRT).

PMID: 29800575 [PubMed – as supplied by publisher]

CD57 identifies T cells with functional senescence before terminal differentiation and relative telomere shortening in patients with activated PI3 kinase delta syndrome.

May 24, 2018 By Manish Butte

CD57 identifies T cells with functional senescence before terminal differentiation and relative telomere shortening in patients with activated PI3 kinase delta syndrome.

Immunol Cell Biol. 2018 May 23;:

Authors: Cura Daball P, Ventura Ferreira MS, Ammann S, Klemann C, Lorenz MR, Warthorst U, Leahy TR, Conlon N, Roche J, Soler-Palacín P, Garcia-Prat M, Fuchs I, Fuchs S, Beier F, Brümmendorf TH, Speckmann C, Olbrich P, Neth O, Schwarz K, Ehl S, Rensing-Ehl A

Abstract
Premature T cell immunosenescence with CD57+ CD8+ T cell accumulation has been linked to immunodeficiency and autoimmunity in primary immunodeficiencies including activated PI3 kinase delta syndrome (APDS). To address whether CD57 marks the typical senescent T cell population seen in adult individuals or identifies a distinct population in APDS, we compared CD57+ CD8+ T cells from mostly pediatric APDS patients to those of healthy adults with similarly prominent senescent T cells. CD57+ CD8+ T cells from APDS patients were less differentiated with more CD27+ CD28+ effector memory cells showing increased PD1 and Eomesodermin expression. In addition, transition of naïve to CD57+ CD8+ T cells was not associated with the characteristic telomere shortening. Nevertheless, they showed the increased Interferon-gamma secretion, enhanced degranulation and reduced in vitro proliferation typical of senescent CD57+ CD8+ T cells. Thus, hyperactive PI3 kinase signaling favors premature accumulation of a CD57+ CD8+ T cell population, which shows most functional features of typical senescent T cells, but is different in terms of differentiation and relative telomere shortening. Initial observations indicate that this specific differentiation state may offer the opportunity to revert premature T cell immunosenescence and its potential contribution to inflammation and immunodeficiency in APDS. This article is protected by copyright. All rights reserved.

PMID: 29790605 [PubMed – as supplied by publisher]

Antiviral combination therapy for cytomegalovirus infection in high-risk infants.

May 24, 2018 By Manish Butte

Antiviral combination therapy for cytomegalovirus infection in high-risk infants.

Antivir Ther. 2018 May 23;:

Authors: Vora SB, Brothers AW, Waghmare A, Englund JA

Abstract
BACKGROUND: Cytomegalovirus (CMV) infection is a major risk factor for mortality in infants with severe combined immunodeficiency (SCID) and other profound immune defects. Specific antiviral therapy must be initiated early and aggressively because of the potential for antiviral resistance, rapid dissemination and poor transplant outcomes. Combination antiviral therapy is routinely administered for some viral infections, but the value of this approach for the treatment of CMV is unclear. Here we explore a strategy of initial combination therapy for high-risk infants with CMV infection.
METHODS: We reviewed medical records of infants ≤ 6 months hospitalized between 2007-2015 who received ganciclovir (GCV) or foscarnet (FOS) monotherapy or initial combination GCV + FOS for CMV disease. The combination therapy group consisted of severely immunocompromised infants being considered for hematopoietic cell transplantation (HCT).
RESULTS: Four patients received initial combination antiviral therapy and 26 patients received initial monotherapy during the study period. Combination antiviral recipients demonstrated initial improvement in viremia and two of three who continued with this therapy survived the infection. Clinically significant resistance mutations did not emerge. Toxicity was common; neutropenia, thrombocytopenia and electrolyte abnormalities were the most frequent adverse events in both groups. Creatinine elevation was uncommon in both groups.
CONCLUSIONS: Combination GCV + FOS therapy may be a safe alternative to monotherapy in high-risk infants, especially those who are pre-transplant with primary immune deficiency syndromes and high viral loads.

PMID: 29790481 [PubMed – as supplied by publisher]

Higher Arc Nucleus-to-Cytoplasm Ratio during Sleep in the Superficial Layers of the Mouse Cortex.

May 24, 2018 By Manish Butte

Higher Arc Nucleus-to-Cytoplasm Ratio during Sleep in the Superficial Layers of the Mouse Cortex.

Front Neural Circuits. 2017;11:60

Authors: Honjoh S, de Vivo L, Okuno H, Bito H, Tononi G, Cirelli C

Abstract
The activity-regulated cytoskeleton associated protein Arc is strongly and quickly upregulated by neuronal activity, synaptic potentiation and learning. Arc entry in the synapse is followed by the endocytosis of glutamatergic AMPA receptors (AMPARs), and its nuclear accumulation has been shown in vitro to result in a small decline in the transcription of the GluA1 subunit of AMPARs. Since these effects result in a decline in synaptic strength, we asked whether a change in Arc dynamics may temporally correlate with sleep-dependent GluA1 down-regulation. We measured the ratio of nuclear to cytoplasmic Arc expression (Arc Nuc/Cyto) in the cerebral cortex of EGFP-Arc transgenic mice that were awake most of the night and then perfused immediately before lights on (W mice), or were awake most of the night and then allowed to sleep (S mice) or sleep deprived (SD mice) for the first 2 h of the light phase. In primary motor cortex (M1), neurons with high levels of nuclear Arc (High Arc cells) were present in all mice, but in these cells Arc Nuc/Cyto was higher in S mice than in W mice and, importantly, ~15% higher in S mice than in SD mice collected at the same time of day, ruling out circadian effects. Greater Arc Nuc/Cyto with sleep was observed in the superficial layers of M1, but not in the deep layers. In High Arc cells, Arc Nuc/Cyto was also ~15%-30% higher in S mice than in W and SD mice in the superficial layers of primary somatosensory cortex (S1) and cingulate cortex area 1 (Cg1). In High Arc Cells of Cg1, Arc Nuc/Cyto and cytoplasmic levels of GluA1 immunoreactivities in the soma were also negatively correlated, independent of behavioral state. Thus, Arc moves to the nucleus during both sleep and wake, but its nuclear to cytoplasmic ratio increases with sleep in the superficial layers of several cortical areas. It remains to be determined whether the relative increase in nuclear Arc contributes significantly to the overall decline in the strength of excitatory synapses that occurs during sleep. Similarly, it remains to be determined whether the entry of Arc into specific synapses is gated by sleep.

PMID: 28878629 [PubMed – indexed for MEDLINE]