Manish Butte

Designer epigenome modifiers enable robust and sustained gene silencing in clinically relevant human cells.

Nucleic Acids Res. 2018 Mar 10;:

Authors: Mlambo T, Nitsch S, Hildenbeutel M, Romito M, Müller M, Bossen C, Diederichs S, Cornu TI, Cathomen T, Mussolino C

Abstract
Targeted modulation of gene expression represents a valuable approach to understand the mechanisms governing gene regulation. In a therapeutic context, it can be exploited to selectively modify the aberrant expression of a disease-causing gene or to provide the target cells with a new function. Here, we have established a novel platform for achieving precision epigenome editing using designer epigenome modifiers (DEMs). DEMs combine in a single molecule a DNA binding domain based on highly specific transcription activator-like effectors (TALEs) and several effector domains capable of inducing DNA methylation and locally altering the chromatin structure to silence target gene expression. We designed DEMs to target two human genes, CCR5 and CXCR4, with the aim of epigenetically silencing their expression in primary human T lymphocytes. We observed robust and sustained target gene silencing associated with reduced chromatin accessibility, increased promoter methylation at the target sites and undetectable changes in global gene expression. Our results demonstrate that DEMs can be successfully used to silence target gene expression in primary human cells with remarkably high specificity, paving the way for the establishment of a potential new class of therapeutics.

PMID: 29538770 [PubMed – as supplied by publisher]

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Activated PI3 Kinase Delta Syndrome: From Genetics to Therapy.

Front Immunol. 2018;9:369

Authors: Michalovich D, Nejentsev S

Abstract
Activated PI3 kinase delta syndrome (APDS) is a primary immunodeficiency caused by dominant mutations that increase activity of phosphoinositide-3-kinase δ (PI3Kδ). APDS can be caused by mutations in the PIK3CD gene that encodes PI3Kδ catalytic subunit p110δ (APDS1) or mutations in the PIK3R1 gene that encodes regulatory subunit p85α (APDS2). APDS research advanced rapidly after the initial discovery in 2013. More than 200 APDS patients have been identified around the world. Multiple novel APDS mutations were reported and molecular mechanisms leading to PI3Kδ activation have been elucidated. The finding of APDS significantly increased our understanding of the role of PI3Kδ in the human immune system. Perhaps most importantly, discovery of the molecular basis of this primary immunodeficiency suggested that APDS patients, who previously received only non-specific therapy, could be treated by a novel class of drugs that inhibits PI3Kδ activity. This led to the ongoing clinical trials of selective PI3Kδ inhibitors in APDS patients. Overall, the APDS story provides an excellent example of translational research, beginning with patients who had an unknown disease cause and leading to a novel specific knowledge-based treatment.

PMID: 29535736 [PubMed]

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Sirolimus as an alternative treatment in patients with granulomatous-lymphocytic lung disease and humoral immunodeficiency with impaired regulatory T cells.

Pediatr Allergy Immunol. 2018 Mar 12;:

Authors: Deyà-Martínez A, Esteve-Solé A, Vélez-Tirado N, Celis V, Costa J, Cols M, Jou C, Vlagea A, Plaza-Martin AM, Juan M, Alsina L

Abstract
BACKGROUND: One of the most frequent non-infectious complications of humoral immunodeficiencies with a CVID-like pattern is a particular form of inflammatory lung disease which is called granulomatous-lymphocytic interstitial lung disease (GLILD). Its development worsens patient prognosis, with a significant decrease in survival. Currently there are no unified guidelines regarding its management, and different combinations of immunosuppressants have been used with variable success.
METHODS: Clinical and radiological data were collected from patient’s medical charts. Flow cytometry was performed to characterize the immunological features with special focus in regulatory T cells (Tregs).
RESULTS: A 16 year-old-girl with Kabuki syndrome and a 12 year-old-boy, both with a CVID-like humoral immunodeficiency on immunoglobulin replacement treatment, developed during follow-up an inflammatory complication radiologically, clinically and histologically compatible with GLILD. They required treatment and sirolimus was started, with very good response and no serious side effects.
CONCLUSIONS: These two cases provide insight into the underlying local and systemic immune anomalies involved in the development of GLILD, including the possible role of Tregs. Combined chemotherapy is commonly used as treatment for GLILD when steroids fail, but there have been some reports of successful monotherapy. As far as we know, these are the first 2 GLILD patients treated successfully with sirolimus, suggesting the advisability of further study of mTOR inhibitors as a more targeted treatment for GLILD, if impairment in Tregs is demonstrated. This article is protected by copyright. All rights reserved.

PMID: 29532571 [PubMed – as supplied by publisher]

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Phenotypic and genotypic characterization of inflammatory bowel disease in children under six years of age in China.

World J Gastroenterol. 2018 Mar 07;24(9):1035-1045

Authors: Fang YH, Luo YY, Yu JD, Lou JG, Chen J

Abstract
AIM: To analyze clinical differences between monogenic and nonmonogenic very-early-onset inflammatory bowel disease (VEO-IBD) and to characterize monogenic IBD phenotypically and genotypically via genetic testing.
METHODS: A retrospective analysis of children aged 0 to 6 years diagnosed with VEO-IBD in a tertiary hospital in southern China from 2005 to 2017 was performed. Clinical data for VEO-IBD patients were collected, and genetic characteristics were analyzed using whole exome sequencing or target gene panel sequencing.
RESULTS: A total of 54 VEO-IBD patients were included in this study. A diagnosis of Crohn’s disease (CD) or CD-like intestinal manifestations accounted for 72.2% of the VEO-IBD cases. Nine patients (16.7%) were identified by genetic testing as having monogenic IBD. The median age of diagnosis in the monogenic group was younger than that of the nonmonogenic IBD group, at 18 mo (interquartile range (IQR): 4 to 78) and 43.5 mo (IQR: 3 to 173), respectively; the P-value was 0.021. The incidence of perianal disease in the monogenic group was higher than that in the nonmonogenic group (P = 0.001). However, there were no significant differences between weight-for-age and height-for-age Z-scores between the two groups, and similar laboratory results were obtained for the two groups. Five patients were found to have IL10 receptor mutation, two patients had chronic granulomatous disease, one patient had common variable immunodeficiency disease, and one patient had X-linked inhibitor of apoptosis protein deficiency.
CONCLUSION: A high proportion of monogenic IBD was observed in the VEO-IBD group, especially with disease onset before the age of 6 mo. Monogenic IBD and nonmonogenic IBD exhibited similar clinical features. Furthermore, next-generation sequencing played an important role in the diagnosis of monogenic IBD, and IL10 receptor mutation was predominant in this cohort.

PMID: 29531467 [PubMed – in process]

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Severe complication during remission of Crohn’s disease: hemophagocytic lymphohistiocytosis due to acute cytomegalovirus infection.

Z Gastroenterol. 2018 Mar;56(3):259-263

Authors: Miechowiecki J, Stainer W, Wallner G, Tuppy H, Aichinger W, Prammer W, Kirchgatterer A

Abstract
INTRODUCTION:  Immunosuppressive therapy is today’s standard treatment of patients with moderate to severe inflammatory bowel disease (IBD). The risk for opportunistic infections is increased due to this therapy and is a concern in the management of patient with IBD undergoing such a treatment.
CASE REPORT:  In this paper, we describe a case of an acute cytomegalovirus (CMV) infection in a 35-year-old male patient with Crohn’s disease being in remission while receiving azathioprine therapy. His clinical presentation was high-grade fever, night sweats, skin rash, and abdominal pain.Laboratory findings showed pancytopenia, elevated liver enzymes, and high ferritin levels. Sonographic examination revealed splenomegaly and serological analysis proved an acute CMV infection. The severity of the acute illness and these results in the setting of immunosuppressive treatment with azathioprine were highly suspicious of hemophagocytic lymphohistiocytosis (HLH).Further investigations including bone marrow biopsy, analysis of natural killer cell function, and measurement of T-cell activity confirmed the suspected diagnosis. Treatment consisted of antiviral and symptomatic therapy.
DISCUSSION AND CONCLUSION:  HLH is a rare and severe condition triggered by uncontrolled stimulation of histiocytes and lymphocytes, resulting in abnormal cytokine production. The causes can be primary (genetic) or secondary due to acquired immunodeficiency or viral infections such as CMV. Several symptoms of this condition are unspecific, but the summary of clinical symptoms and signs are diagnostic. Treatment consists of specific intervention if possible and application of immunosuppressive drugs such as corticosteroids.

PMID: 29529681 [PubMed – in process]

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Polyautoimmunity in Patients with LPS-Responsive Beige-Like Anchor (LRBA) Deficiency.

Immunol Invest. 2018 Mar 12;:1-11

Authors: Azizi G, Abolhassani H, Zaki-Dizaji M, Habibi S, Mohammadi H, Shaghaghi M, Yazdani R, Anaya JM, Rezaei N, Hammarström L, Aghamohammadi A

Abstract
BACKGROUND: Polyautoimmunity is defined as the presence of more than one autoimmune disorder in a single patient. Lipopolysaccharide (LPS)-responsive beige-like anchor (LRBA) deficiency is one of the monogenic causes of polyautoimmunity. The aim of this study was to report the characteristics of polyautoimmunity in patients with LRBA deficiency.
METHODS: A total of 14 LRBA deficiency patients with confirmed autoimmunity were enrolled in this study. For those patients with polyautoimmunity, demographic information, clinical records, laboratory, and molecular data were collected. We also compared our results with the currently reported patients with LRBA deficiency associated with polyautoimmunity.
RESULTS: In 64.2% (9 out of 14) of patients, autoimmunity presented as polyautoimmunity. In these patients, autoimmune cytopenias were the most frequent complication, observed in seven patients. Three patients presented with four different types of autoimmune conditions. The review of the literature showed that 41 of 72 reported LRBA deficient patients (74.5%) had also polyautoimmunity, with a wide spectrum of autoimmune diseases described. Hematopoietic stem cell transplantation is increasingly used as the treatment for patients with severe polyautoimmunity associated to LRBA deficiency.
CONCLUSIONS: Mutation in LRBA gene is one of the causes of monogenic polyautoimmunity. Awareness of this association is important in order to make an early diagnosis and prompt treatment.

PMID: 29528757 [PubMed – as supplied by publisher]

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Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India.

Front Immunol. 2018;9:188

Authors: Aluri J, Gupta M, Dalvi A, Mhatre S, Kulkarni M, Hule G, Desai M, Shah N, Taur P, Vedam R, Madkaikar M

Abstract
Major histocompatibility complex (MHC) class II deficiency is a rare autosomal recessive form of primary immunodeficiency disorder (PID) characterized by the deficiency of MHC class II molecules. This deficiency affects the cellular and humoral immune response by impairing the development of CD4+ T helper (Th) cells and Th cell-dependent antibody production by B cells. Affected children typically present with severe respiratory and gastrointestinal tract infections. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy available for treating these patients. This is the first report from India wherein we describe the clinical, immunological, and molecular findings in five patients with MHC class II deficiency. Our patients presented with recurrent lower respiratory tract infection as the most common clinical presentation within their first year of life and had a complete absence of human leukocyte antigen-antigen D-related (HLA-DR) expression on B cells and monocytes. Molecular characterization revealed novel mutations in RFAXP, RFX5, and CIITA genes. Despite genetic heterogeneity, these patients were clinically indistinguishable. Two patients underwent HSCT but had a poor survival outcome. Detectable level of T cell receptor excision circles (TRECs) were measured in our patients, highlighting that this form of PID may be missed by TREC-based newborn screening program for severe combined immunodeficiency.

PMID: 29527204 [PubMed]

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Autosomal-Recessive Hyper-IgE Syndrome.

Indian J Dermatol. 2018 Jan-Feb;63(1):79-81

Authors: Liza M, Gaurav D, Prasenjeet M, Swapna J, Binodini B

Abstract
The hyper-IgE syndrome (HIES) is a rare group of primary immunodeficiency characterised by recurrent infections, eczema, and elevated serum levels of IgE. Autosomal dominant HIES is caused by mutations in transcription factor – signal transducer and activator of transcription-3. Autosomal-recessive (AR) HIES was described in 2004 due to mutation of tyrosine kinase 2 gene, and subsequently, another mutation in dedicator of cytokinesis 8 gene was discovered in 2009. Although both the forms have many common clinical features, few characteristic findings help in differentiating them. AR-HIES is characterized by recurrent bacterial and viral infections, atopic eczema, and raised serum IgE levels. We report a case of a 4-year-old girl presenting with the features of AR-HIES to highlight the presentation of this rare disease.

PMID: 29527033 [PubMed – in process]

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Adverse Reactions Due to the Bacillus Calmette-Guerin Vaccine: Twenty Tunisian Cases.

Indian J Dermatol. 2018 Jan-Feb;63(1):62-65

Authors: Sellami K, Amouri M, Kmiha S, Bahloul E, Aloulou H, Sfaihi L, Guirat R, Mseddi M, Kamoun T, Hachicha M, Turki H

Abstract
Background: Bacillus Calmette-Guérin (BCG) vaccine is a widely used vaccine. Management of local BCG complications differs between clinicians, and the optimal approach remains unclear.
Aims: We aim to describe the epidemiological, clinical and therapeutic aspects of the BCG vaccine side effects in Sfax.
Patients and Methods: This was a retrospective study of all the cases of BCG vaccine adverse reactions recorded in the Dermatology and Paediatrics Departments of Hedi Chaker University Hospital of Sfax over a period of 10 years (2005-2015).
Results: Twenty cases of BCG adverse reactions were notified during the study period. Actually, 80% of the patients presented local adverse reactions. The outcome was good in all the followed patients. The rate of disseminated BCG disease was 20%. Biological tests of immunity showed a primary immunodeficiency in three cases, whereas the outcome was fatal in two cases.
Conclusion: BCG vaccine adverse reactions range from mild to severe. However, the management of benign local reactions remains unclear. Disseminated BCG disease must alert clinicians to the possibility of a primary immunodeficiency.

PMID: 29527028 [PubMed – in process]

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