Manish Butte

Epstein-Barr Virus (EBV)-Related Lymphoproliferative Disorders in Ataxia Telangiectasia: Does ATM Regulate EBV Life Cycle?

Front Immunol. 2018;9:3060

Authors: Tatfi M, Hermine O, Suarez F

Abstract
Epstein-Barr virus (EBV) is an ubiquitous herpesvirus with a tropism for epithelial cells (where lytic replication occurs) and B-cells (where latency is maintained). EBV persists throughout life and chronic infection is asymptomatic in most individuals. However, immunocompromised patients may be unable to control EBV infection and are at increased risk of EBV-related malignancies, such as diffuse large B-cell lymphomas or Hodgkin’s lymphomas. Ataxia telangiectasia (AT) is a primary immunodeficiency caused by mutations in the ATM gene and associated with an increased incidence of cancers, particularly EBV-associated lymphomas. However, the immune deficiency present in AT patients is often too modest to explain the increased incidence of EBV-related malignancies. The ATM defect in these patients could therefore impair the normal regulation of EBV latency in B-cells, thus promoting lymphomagenesis. This suggests that ATM plays a role in the normal regulation of EBV latency. ATM is a serine/threonine kinase involved in multiple cell functions such as DNA damage repair, cell cycle regulation, oxidative stress, and gene expression. ATM is implicated in the lytic cycle of EBV, where EBV uses the activation of DNA damage repair pathway to promote its own replication. ATM regulates the latent cycle of the EBV-related herpesvirus KSHV and MHV68. However, the contribution of ATM in the control of the latent cycle of EBV is not yet known. A better understanding of the regulation of EBV latency could be harnessed in the conception of novel therapeutic strategies in AT and more generally in all ATM deficient EBV-related malignancies.

PMID: 30662441 [PubMed – in process]

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Congenital neutropenia and primary immunodeficiency diseases.

Crit Rev Oncol Hematol. 2019 Jan;133:149-162

Authors: Spoor J, Farajifard H, Rezaei N

Abstract
Neutropenia is a dangerous and potentially fatal condition that renders patients vulnerable to recurrent infections. Its severity is commensurate with the absolute count of neutrophil granulocytes in the circulation. In paediatric patients, neutropenia can have many different aetiologies. Primary causes make up but a small portion of the whole and are relatively unknown. In the past decades, a number of genes has been discovered that are responsible for congenital neutropenia. By perturbation of mitochondrial energy metabolism, vesicle trafficking or synthesis of functional proteins, these mutations cause a maturation arrest in myeloid precursor cells in the bone marrow. Apart from these isolated forms, congenital neutropenia is associated with a multiplicity of syndromic diseases that includes among others: oculocutaneous albinism, metabolic diseases and bone marrow failure syndromes. Congenital neutropenia is a primary immunodeficiency disease that is associated with recurrent bacterial infections, auto-inflammatory and auto-immune phenomena, haematological malignancy and neuro-psychiatric manifestations. The aim of this review is to give a comprehensive overview of the most recent literature concerning the clinical, aetiological and genetic features of congenital neutropenia and the syndromes in which it might be encountered.

PMID: 30661651 [PubMed – in process]

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Hematopoietic stem cell transplantation for CD40 ligand deficiency: results from an EBMT/ESID-IEWP-SCETIDE-PIDTC Study.

J Allergy Clin Immunol. 2019 Jan 17;:

Authors: Ferrua F, Galimberti S, Courteille V, Slatter MA, Booth C, Moshous D, Neven B, Blanche S, Laberko A, Shcherbina A, Balashov D, Soncini E, Porta F, Al-Mousa H, Al-Saud B, Al-Dhekri H, Arnaout R, Formankova R, Bertrand Y, Lange A, Smart J, Wolska-Kusnierz B, Aquino VM, Dvorak CC, Fasth A, Fouyssac F, Heilmann C, Hoenig M, Schuetz C, Kelečić J, Bredius RGM, Lankester AC, Lindemans CA, Suarez F, Sullivan KE, Albert MH, Kałwak K, Barlogis V, Bhatia M, Bordon V, Czogala W, Alonso L, Dogu F, Gozdzik J, Ikinciogullari A, Kriván G, Ljungman P, Meyts I, Mustillo P, Smith AR, Speckmann C, Sundin M, Keogh SJ, Shaw PJ, Boelens JJ, Schulz AS, Sedlacek P, Veys P, Mahlaoui N, Janda A, Davies EG, Fischer A, Cowan MJ, Gennery AR, SCETIDE, PIDTC, EBMT & ESID IEWP

Abstract
BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT).
OBJECTIVE: We performed an international collaborative study to improve patients’ management, aiming to individualize risk factors and determine optimal HSCT characteristics.
METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables relevance with respect to survival and cure.
RESULTS: Overall survival (OS), event-free survival (EFS) and disease-free survival (DFS) were 78.2%, 58.1% and 72.3% 5 years post-HSCT. Results were better in transplants performed ≥2000 and in children <10 years old at HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT ≤2 years from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC) and bone marrow-derived stem cells. Most rejections occurred after reduced intensity or non-myeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was ≥50% donor in 85.2%.
CONCLUSION: HSCT is curative in CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS and DFS. Prospective studies are required to compare risks of HSCT with those of life-long supportive therapy.

PMID: 30660643 [PubMed – as supplied by publisher]

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Double-strand break repair through homologous recombination in autosomal recessive BCL10 deficiency.

J Allergy Clin Immunol. 2019 Jan 17;:

Authors: García-Gómez S, Chaparro R, Safa A, Van Den Rym A, Martinez-Barricarte R, Lorenzo L, Sánchez-Ramón S, Toledano V, Cubillos-Zapata C, López-Collazo E, Martín-Arranz MD, Martín-Arranz E, Vela M, Gonzalez-Navarro P, Pérez-Martínez A, Casanova JL, Recio MJ, Pérez de Diego R

Abstract
DNA double-strand break (DSB) repair through homologous recombination from BCL10-/- patient is impaired. Given the relevance of DBS in the onset of cancer, it is important to highlight homologous recombination is BCL10-dependent in human fibroblasts.

PMID: 30660642 [PubMed – as supplied by publisher]

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Dominant-negative CARD11 mutations: beyond atopy.

J Allergy Clin Immunol. 2019 Jan 16;:

Authors: Béziat V, Jouanguy E, Puel A

PMID: 30659853 [PubMed – as supplied by publisher]

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Fatal case of necrotising fasciitis due to Vibrio vulnificus in a patient with alcoholic liver disease and diabetes mellitus.

BMJ Case Rep. 2019 Jan 17;12(1):

Authors: Bhat P, Bhaskar M, Sistla S, Kadhiravan T

Abstract
Vibrio vulnificus is a halophilic Vibrio found globally. They are thought to be normal microbiome in the estuaries along the coasts associated with seawater and seashells. Infection usually results from consumption of raw oysters or shellfish or exposure of broken skin or open wounds to contaminated salt or brackish water. Clinical manifestations range from gastroenteritis to skin and subcutaneous infection and primary sepsis. Pathogen has the ability to cause infections with significant mortality in high-risk populations, including patients with chronic liver disease, immunodeficiency, diabetes mellitus and iron storage disorders. There is often a lack of clinical suspicion in cases due to Vibrio vulnificus leading to delay in treatment and subsequent mortality. Herein we report a case of necrotising fasciitis in a diabetic patient with alcoholic liver disease caused by Vibrio vulnificus which ended fatally.

PMID: 30659010 [PubMed – in process]

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Rifaximin alters gut microbiota profile, but does not affect systemic inflammation – a randomized controlled trial in common variable immunodeficiency.

Sci Rep. 2019 Jan 17;9(1):167

Authors: Jørgensen SF, Macpherson ME, Bjørnetrø T, Holm K, Kummen M, Rashidi A, Michelsen AE, Lekva T, Halvorsen B, Trøseid M, Mollnes TE, Berge RK, Yndestad A, Ueland T, Karlsen TH, Aukrust P, Hov JR, Fevang B

Abstract
Common variable immunodeficiency (CVID) patients have reduced gut microbial diversity compared to healthy controls. The reduced diversity is associated with gut leakage, increased systemic inflammation and ten “key” bacteria that capture the gut dysbiosis (dysbiosis index) in CVID. Rifaximin is a broad-spectrum non-absorbable antibiotic known to reduce gut leakage (lipopolysaccharides, LPS) in liver disease. In this study, we explored as a ‘proof of concept’ that altering gut microbial composition could reduce systemic inflammation, using CVID as a disease model. Forty adult CVID patients were randomized, (1:1) to twice-daily oral rifaximin 550 mg versus no treatment for 2 weeks in an open-label, single-centre study. Primary endpoints were reduction in plasma/serum levels of soluble (s) CD14, sCD25, sCD163, neopterin, CRP, TNF, LPS and selected cytokines measured at 0, 2 and 8 weeks. Secondary endpoint was changes in intra-individual bacterial diversity in stool samples. Rifaximin-use did not significantly change any of the inflammation or gut leakage markers, but decreased gut microbial diversity compared with no treatment (p = 0.002). Importantly, the gut bacteria in the CVID dysbiosis index were not changed by rifaximin. The results suggest that modulating gut microbiota by rifaximin is not the chosen intervention to affect systemic inflammation, at least not in CVID.

PMID: 30655568 [PubMed – in process]

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MHC Class II Deficiency with Normal CD4+ T Cell Counts: A Case Report.

Iran J Allergy Asthma Immunol. 2018 Dec 04;17(6):594-600

Authors: Abolnezhadian F, Saeedi-Boroujeni A, Iranparast S

Abstract
Major histocompatibility complex (MHC) class II deficiency is a rare primary immunodeficiency disorder (PID) with less than 200 cases worldwide. Here, we report an 8 month-old girl with MHC class II deficiency with a novel homozygous mutation in RFXANK gene (NM_001278728: exon 5: c.495G>A: p.Trp165*) and normal CD4+ T cell counts, diagnosed by whole exome sequencing (WES) and negative HLA-DR proteins on peripheral blood mononuclear cell (PBMC) in flow cytometry. She was referred with pneumonia, prolonged fever, resistance to antibiotics (ceftriaxone, clindamycin, and vancomycin), and low serum immunoglobulin (IG) levels, while natural killer (NK), B, and T cells were normal. She received intra-venous immune-globulin (IVIG) replacement, broad spectrum antibiotics, and anti-fungal treatments. The presented case report is interesting not only because of the rarity of the PID but also due to normal CD4+ T cell counts. According to our experience, we suggest that physicians consider MHC class II deficiency in families with consanguineous marriages, even with normal CD4+ T cell counts. At the first, the diagnosis of the disease could be successfully perform using WES, and finally, treatment with hematopoietic stem cell transplantation can save the patients’ lives.

PMID: 30644704 [PubMed – in process]

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A rare case of a prostatic abscess, bacteremia and chronic granulomatous disease associated with Klebsiella pneumoniae.

J Infect Chemother. 2019 Jan 11;:

Authors: Wakabayashi Y, Jubishi D, Okamoto K, Ikeda M, Tatsuno K, Mizoguchi M, Sato T, Okugawa S, Moriya K

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency disease characterized by severe recurrent infections such as pneumonia, liver and skin infections. However, prostatic abscesses are rare as only two cases have been reported thus far. We present the case of a 41-year-old patient with CGD who was admitted to the hospital with fever and subsequently, Klebsiella pneumoniae was identified on blood culture. Abdominal computed tomography revealed a prostatic abscess. He improved with intravenous antibiotics and drainage of the abscess. After he was taken off the intravenous antibiotics and started on an oral agent, he was discharged from the hospital. We confirmed a reduction in the prostatic abscess size and continued the antibiotic therapy for 52 days. A prostatic abscess is an uncommon disease being diagnosed at a median age of 49 years. Sometimes it is discovered in patients with fever of unknown origin and might be considered as an infection site of CGD patients.

PMID: 30642769 [PubMed – as supplied by publisher]

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