Research

Chronic granulamatous disease: two decades of experience from a pediatric immunology unit in a country with high rate of consangineous marriages.

Scand J Immunol. 2018 Dec 01;:e12737

Authors: Kutukculer N, Aykut A, Karaca NE, Durmaz A, Aksu G, Genel F, Pariltay E, Cogulu Ö, Azarsız E

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by susceptibility to bacterial and fungal infections resulting from the inadequacy of phagocytic leukocytes to produce reactive oxygen radicals. CGD is a genetically heterogeneous disease with an X-linked recessive (XR-CGD) form caused by mutations in the CYBB (OMIM #300481) gene encoding the gp91(phox) protein, and an autosomal recessive (AR-CGD) form caused by mutations in the CYBA (OMIM #608508), NCF1 (OMIM #608512), NCF2 (OMIM #608515) and NCF4 (OMIM #601488) genes encoding p22(phox), p47(phox), p67(phox), and p40(phox), respectively. The genetic mutation of one of the cytosolic p47phox/p67phox proteins and membrane-bound gp91phox/p22phox proteins, which constitutes the NADPH oxidase enzyme complex, causes the disease. In this study, we evaluated the clinical, laboratory and genetic findings and the prognostic effects of molecular inheritance of our 24 CGD cases (14 XR, 10 autosomal recessive-AR). Consanguinity (3 XR and all AR cases) showed statistically significant relationship with the type of hereditary inheritance (p< .001). 83% patients had an infection since early infancy. The mean age of initiation of symptoms was earlier in XR cases and 78% patients had respiratory tract infections. Bone marrow transplantation was performed in 5 XR cases (2 ex) and 4 AR (1 ex) cases. 3 of 9 XR and 2 of 6 AR cases deceased on medical follow-up. In countries especially with high consanguinity rates, the early diagnosis for appropriate prophylactic treatment of CGD is quitely important to avoid from recurrent severe infections, early death and fatal complications of late transplantation. This article is protected by copyright. All rights reserved.

PMID: 30506560 [PubMed – as supplied by publisher]

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Corrigendum: A Novel Homozygous JAK3 Mutation Leading to T-B+NK- SCID in Two Brazilian Patients.

Front Pediatr. 2018;6:358

Authors: Barreiros LA, Segundo GRS, Grumach AS, Roxo-Júnior P, Torgerson TR, Ochs HD, Condino-Neto A

Abstract
[This corrects the article DOI: 10.3389/fped.2018.00230.].

PMID: 30515370 [PubMed – in process]

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Reconstitution of the Ataxia-Telangiectasia Cellular Phenotype With Lentiviral Vectors.

Front Immunol. 2018;9:2703

Authors: Carranza D, Torres-Rusillo S, Ceballos-Pérez G, Blanco-Jimenez E, Muñoz-López M, García-Pérez JL, Molina IJ

Abstract
Ataxia-telangiectasia (A-T) is a complex disease arising from mutations in the ATM gene (Ataxia-Telangiectasia Mutated), which plays crucial roles in repairing double-strand DNA breaks (DSBs). Heterogeneous immunodeficiency, extreme radiosensitivity, frequent appearance of tumors and neurological degeneration are hallmarks of the disease, which carries high morbidity and mortality because only palliative treatments are currently available. Gene therapy was effective in animal models of the disease, but the large size of the ATM cDNA required the use of HSV-1 or HSV/AAV hybrid amplicon vectors, whose characteristics make them unlikely tools for treating A-T patients. Due to recent advances in vector packaging, production and biosafety, we developed a lentiviral vector containing the ATM cDNA and tested whether or not it could rescue cellular defects of A-T human mutant fibroblasts. Although the cargo capacity of lentiviral vectors is an inherent limitation in their use, and despite the large size of the transgene, we successfully transduced around 20% of ATM-mutant cells. ATM expression and phosphorylation assays indicated that the neoprotein was functional in transduced cells, further reinforced by their restored capacity to phosphorylate direct ATM substrates such as p53 and their capability to repair radiation-induced DSBs. In addition, transduced cells also restored cellular radiosensitivity and cell cycle abnormalities. Our results demonstrate that lentiviral vectors can be used to rescue the intrinsic cellular defects of ATM-mutant cells, which represent, in spite of their limitations, a proof-of-concept for A-T gene therapy.

PMID: 30515174 [PubMed – in process]

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Advantage of the subcutaneous immunoglobulin replacement therapy in primary immunodeficient patients with or without secondary protein loss.

Turk J Pediatr. 2018;60(3):270-276

Authors: Gür-Çetinkaya P, Çağdaş-Ayvaz DN, Öksüz AB, Ertoy A, Hayran U, Özkan F, Erol M, Tezcan İ

Abstract
Gür-Çetinkaya P, Çağdaş-Ayvaz DN, Öksüz AB, Ertoy A, Hayran U, Özkan F, Erol M, Tezcan İ. Advantage of the subcutaneous immunoglobulin replacement therapy in primary immunodeficient patients with or without secondary protein loss. Turk J Pediatr 2018; 60: 270-276. In recent years subcutaneous immunoglobulin is widely used for primary immunodeficient patients. Subcutaneous administration provides a more stable and higher serum immunoglobulin levels due to continuous and steady transition from lymphatics to the systemic circulation. We aimed to evaluate the changes in serum immunoglobulin levels under subcutaneous immunoglobulin therapy in patients with primary immunodeficiency with or without secondary protein loss. Nine patients with primary immunodeficiency who switched to subcutaneous immunoglobulin were enrolled. Age, gender, diagnosis, reasons of transition to subcutaneous route, reasons of secondary protein loss were recorded. A questionnaire consisting of frequencies and types of infections, side effects observed with intravenous and subcutaneous routes; date and reason of transition to subcutaneous route were asked to all participants. Serum immunoglobulin levels at the 3rd and the 6th months before and after subcutaneous route were recorded. Of the 9 patients (M/F=4/5) the median age was 12 years (6.1-28.7) and 5 of them had protein loss. In total, 444 injections were applied, and all patients experienced local reactions. Infections were more frequent under intravenous than subcutaneous route (p=0.004). We observed an increase in immunoglobulin levels under subcutaneous route (p=0.069 at 3rd; p=0.13 at 6th month). This increase was evident at the 3rd month of transition to subcutaneous route in patients with protein loss (p=0.080). There was an increase in serum immunoglobulin levels under subcutaneous route. However, increase was not statistically significant since the study group was small. This increment was prominent in patients with protein loss. Subcutaneous administration may be a good alternative for primary immunodeficient patients with protein loss who have persistent low serum immunoglobulin levels despite increments in the intravenous immunoglobulin doses.

PMID: 30511539 [PubMed – in process]

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High-grade Burkitt Lymphoma Presenting as a Buttock Mass and Foot Drop.

Cureus. 2018 Sep 26;10(9):e3368

Authors: Ejaz K, Khan QA, Raza MA, Ahmed RS, Aleem A

Abstract
Burkitt lymphoma (BL), a highly aggressive B-cell non-Hodgkin lymphoma (NHL), usually presents in children and young adults with large extranodal masses involving jaw bones, gastrointestinal tract, and central nervous system. The three main subtypes of BL are endemic, sporadic, and immunodeficiency variant. Extranodal involvement is common in each variant of BL, although muscle tissue involvement is distinctly rare. Mode of spread may be hematogenous or via direct extension of the primary tumor. In this report, we present a case of a 41-year-old male who presented with a palpable mass in the buttock leading to foot drop as the initial manifestation of BL. An exhaustive review of the literature failed to discover any previous reports of BL occurring in this location.

PMID: 30510878 [PubMed]

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Epigenetic Deregulation in Human Primary Immunodeficiencies.

Trends Immunol. 2018 Nov 30;:

Authors: Campos-Sanchez E, Martínez-Cano J, Del Pino Molina L, López-Granados E, Cobaleda C

Abstract
Primary immunodeficiencies (PIDs) are immune disorders resulting from defects in genes involved in immune regulation, and manifesting as an increased susceptibility to infections, autoimmunity, and cancer. However, the molecular basis of some prevalent entities remains poorly understood. Epigenetic control is essential for immune functions, and epigenetic alterations have been identified in different PIDs, including syndromes such as immunodeficiency-centromeric-instability-facial-anomalies, Kabuki, or Wolf-Hirschhorn, among others. Although the epigenetic changes may differ among these PIDs, the reversibility of epigenetic modifications suggests that they might become potential therapeutic targets. Here, we review recent mechanistic advances in our understanding of epigenetic alterations associated with certain PIDs, propose that a fully epigenetically driven mechanism might underlie some PIDs, and discuss the possible prophylactic and therapeutic implications.

PMID: 30509895 [PubMed – as supplied by publisher]

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[CVID is a multifaceted disease].

Ugeskr Laeger. 2018 Nov 19;180(47):

Authors: Dimitrova A, Jensen MD, Bock K, Hilberg O

Abstract
Common variable immunodeficiency disease (CVID) is the most common primary immunodeficiency in adults, and multiple organs may be involved. This is a case report of a 49-year-old female patient with granulomatous-lymphocytic interstitial lung disease, liver fibrosis, portal hypertension and rectal cancer. Examinations showed non-necrotic granulomas in her lungs, mediastinal glands and liver, and she was seen in six different specialities. The multifaceted manifestation of CVID calls for multidisciplinary collaboration.

PMID: 30509343 [PubMed – in process]

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A role for Th1-like Th17 cells in the pathogenesis of inflammatory and autoimmune disorders.

Mol Immunol. 2018 Nov 28;105:107-115

Authors: Kamali AN, Noorbakhsh SM, Hamedifar H, Jadidi-Niaragh F, Yazdani R, Bautista JM, Azizi G

Abstract
The T helper 17 (Th17) cells contain a dynamic subset of CD4+ T-cells that are able to develop into other different lineage subsets, including the Th1-like Th17 cells. These cells co-express retinoic acid-related orphan receptor gamma t (RORγt) and transcription factor T-box-expressed-in-T-cells (T-bet) and produce both interleukin (IL)-17 and interferon (IFN)-γ. Recent reports have shown that Th1-like Th17 cells play crucial roles in the pathogenesis of autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis, as well as, some primary immunodeficiency with autoimmune features. Here, the actual mechanisms for Th17 cells plasticity to Th1-like Th17 cells are discussed and reviewed in association to the role that Th1-like Th17 cells have on inflammatory and autoimmune disorders.

PMID: 30502718 [PubMed – as supplied by publisher]

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Primary exfoliative dermatitis; Leiner’s disease; congenital ichthyosiform erythroderma.

Arch Derm Syphilol. 1948 Apr;57(4):776-8

Authors: SAMITZ MH

PMID: 18886309 [PubMed – indexed for MEDLINE]

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Primary splenic granulocytopenia and lymphopenia.

Proc R Soc Med. 1946 Apr;39:299

Authors: LEVY H

PMID: 20982465 [PubMed – indexed for MEDLINE]

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