Manish Butte

Autosomal recessive hyper-IgE syndrome successfully treated with hematopoietic stem cell transplantation.

Pediatr Dermatol. 2019 Jul 24;:

Authors: Lopes J, Teixeira D, Sousa C, Baptista A, Moreira D, Ferreira EO

Abstract
Autosomal recessive hyper-IgE syndrome is a primary immunodeficiency that results from a mutation in the DOCK8 gene. We report a case of a patient presenting with severe eczema, atopy, and recurrent skin infections since the first months of life. The diagnosis of autosomal recessive hyper-IgE syndrome was made at the age of 7 by a positive DOCK8 genetic test. The patient underwent hematopoietic stem cell transplantation, with complete remission of the various manifestations.

PMID: 31338855 [PubMed – as supplied by publisher]

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Arthritis in Two Patients With Partial Recombination Activating Gene Deficiency.

Front Pediatr. 2019;7:235

Authors: Wu KY, Purswani P, Ujhazi B, Csomos K, Snezhina M, Elissaveta N, Stefanov S, Sharapova S, Ellison M, Milojevic D, Savic S, Sargur R, Walter JE

Abstract
Autoimmunity is becoming an increasingly recognized complication in patients with primary immunodeficiencies (PIDs), including a variety of combined immune deficiencies such as Recombination Activating Gene (RAG) defects. The approach to treating autoimmunity in PID patients is complex, requiring a balance between immunosuppression and susceptibility to infection. Inflammatory arthritis is a feature of immune dysregulation in many PIDs, and the optimal treatment may differ from first line therapies that usually consist of disease-modifying anti rheumatic drugs (DMARDs). An example of mechanism-based therapy of arthritis in PID uses blockade of IL-6 signaling with tocilizumab for patients with STAT 3 gain-of-function (GOF) mutation and augmented IL-6 pathway. Herein, we describe two PID cases with arthritis who were found to have defects in RAG. One patient with refractory inflammatory arthritis experienced remarkable improvement in symptoms with tocilizumab therapy. Arthritis can be a clinical feature of immune dysregulation in RAG deficiency, and tocilizumab therapy has been suggested to have utility in treatment of arthritis in RAG deficiency.

PMID: 31334206 [PubMed]

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Molecular clustering of genes related to the atopic syndrome: Towards a more tailored approach and personalized medicine?

Clin Transl Allergy. 2019;9:34

Authors: de Wit J, van Wijck RTA, Dalm VASH, Snyder KL, Totté JEE, Pasmans SGMA, van der Spek PJ, Academic Center of Excellence (ACE) workgroups Allergic Diseases and Rare Immunological Disease Centre (RIDC)

Abstract
Background: The atopic syndrome consists of heterogeneous manifestations, in which multiple associated genetic loci have recently been identified. It is hypothesized that immune dysregulation plays a role in the pathogenesis. In primary immunodeficiency diseases (PIDs), which are often monogenic immunodysregulation disorders, the atopic syndrome is a frequently occurring comorbidity. Based on the genetic defects in PIDs, novel gene/pathway-targeted therapies have been evaluated, which could be relevant in the atopic syndrome as well. Therefore, we aimed to define subclasses within the atopic syndrome based on the expression profiles of immune cell lineages of healthy mice.
Methods: Overlap between known atopy-related genes as described in the Human Gene Mutation Database and disease-causing genes of monogenic PIDs was evaluated. Clusters of atopy-related genes were based on the overlap in their co-expressed genes using the gene expression profiles of immune cell lineages of healthy mice from the Immunological Genome Project. We analyzed pathways involved in the atopic syndrome using Ingenuity Pathway Analysis.
Results: Twenty-two (5.3%) genes were overlapping between the atopy-related genes (n = 160) and PID-related genes (n = 278). We identified seven distinct clusters of atopy-related genes. Functional pathway analysis of all atopy-related genes showed relevance of T helper cell-mediated pathways.
Conclusions: This study shows a model to define clusters within the atopic syndrome based on gene expression profiles of immune cell lineages. Our results support the hypothesis that both genetic mechanisms and immune dysregulation play a role in the pathogenesis. It also opens up the possibility for novel therapeutic targets and a more tailored approach towards personalized medicine.

PMID: 31333817 [PubMed]

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Niflumic Acid Reverses Airway Mucus Excess and Improves Survival in the Rat Model of Steroid-Induced Pneumocystis Pneumonia.

Front Microbiol. 2019;10:1522

Authors: Pérez FJ, Iturra PA, Ponce CA, Magne F, Garcia-Angulo V, Vargas SL

Abstract
Although the role of adaptive immunity in fighting Pneumocystis infection is well known, the role of the innate, airway epithelium, responses remains largely unexplored. The concerted interaction of innate and adaptive responses is essential to successfully eradicate infection. Increased expression of goblet-cell-derived CLCA1 protein plus excess mucus in infant autopsy lungs and in murine models of primary Pneumocystis infection alert of innate immune system immunopathology associated to Pneumocystis infection. Nonetheless, whether blocking mucus-associated innate immune pathways decreases Pneumocystis-related immunopathology is unknown. Furthermore, current treatment of Pneumocystis pneumonia (PcP) relying on anti-Pneumocystis drugs plus steroids is not ideal because removes cellular immune responses against the fungal pathogen. In this study, we used the steroid-induced rat model of PcP to evaluate inflammation and mucus progression, and tested the effect of niflumic acid (NFA), a fenamate-type drug with potent CLCA1 blocker activity, in decreasing Pneumocystis-associated immunopathology. In this model, animals acquire Pneumocystis spontaneously and pneumonia develops owing to the steroids-induced immunodeficiency. Steroids led to decreased animal weight evidencing severe immunosuppression and to significant Pneumocystis-associated pulmonary edema as evidenced by wet-to-dry lung ratios that doubled those of uninfected animals. Inflammatory cuffing infiltrates were noticed first around lung blood vessels followed by bronchi, and both increased progressively. Similarly, airway epithelial and lumen mucus progressively increased. This occurred in parallel to increasing levels of MUC5AC and mCLCA3, the murine homolog of hCLCA1. Administration of NFA caused a significant decrease in total mucus, MUC5AC and mCLCA3 and also, in Pneumocystis-associated inflammation. Most relevant, NFA treatment improved survival at 8 weeks of steroids. Results suggest an important role of innate immune responses in immunopathology of steroid-induced PcP. They warrant evaluation of CLCA1 blockers as adjunctive therapy in this condition and describe a simple model to evaluate therapeutic interventions for steroid resistant mucus, a common condition in patients with chronic lung disease like asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis.

PMID: 31333624 [PubMed]

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Calreticulin Ins5 and Del52 mutations impair unfolded protein and oxidative stress responses in K562 cells expressing CALR mutants.

Sci Rep. 2019 Jul 22;9(1):10558

Authors: Salati S, Genovese E, Carretta C, Zini R, Bartalucci N, Prudente Z, Pennucci V, Ruberti S, Rossi C, Rontauroli S, Enzo E, Calabresi L, Balliu M, Mannarelli C, Bianchi E, Guglielmelli P, Tagliafico E, Vannucchi AM, Manfredini R

Abstract
Somatic mutations of calreticulin (CALR) have been described in approximately 60-80% of JAK2 and MPL unmutated Essential Thrombocythemia and Primary Myelofibrosis patients. CALR is an endoplasmic reticulum (ER) chaperone responsible for proper protein folding and calcium retention. Recent data demonstrated that the TPO receptor (MPL) is essential for the development of CALR mutant-driven Myeloproliferative Neoplasms (MPNs). However, the precise mechanism of action of CALR mutants haven’t been fully unraveled. In this study, we showed that CALR mutants impair the ability to respond to the ER stress and reduce the activation of the pro-apoptotic pathway of the unfolded protein response (UPR). Moreover, our data demonstrated that CALR mutations induce increased sensitivity to oxidative stress, leading to increase oxidative DNA damage. We finally demonstrated that the downmodulation of OXR1 in CALR-mutated cells could be one of the molecular mechanisms responsible for the increased sensitivity to oxidative stress mediated by mutant CALR. Altogether, our data identify novel mechanisms collaborating with MPL activation in CALR-mediated cellular transformation. CALR mutants negatively impact on the capability of cells to respond to oxidative stress leading to genomic instability and on the ability to react to ER stress, causing resistance to UPR-induced apoptosis.

PMID: 31332222 [PubMed – in process]

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Cutaneous manifestations of genodermatoses and primary immunodeficiency.

Dermatol Online J. 2019 Jun 15;25(6):

Authors: Lewis DJ, Wu JH, Boyd M, Duvic M, Feldman SR

Abstract
Immunodeficiency is most commonly related to inherited syndromes, infections, chemotherapy, or aging. As the population of individuals with immunodeficiency continues to grow, physicians are confronted with the task of diagnosing dermatologic disease in this population. Cutaneous involvement in immunodeficiency disorders serves as a useful tool that aids diagnosis and provides prognostic value. Given that cutaneous manifestations often herald an underlying immunodeficiency disorder, understanding the complexities of these diseases is important for appropriate clinical management. Although certain diseases may present with stereotypical cutaneous lesions, others may involve more variable lesions that require specialized consultation for diagnosis and treatment recommendations. In this review, we discuss a number of cutaneous findings associated with primary immunodeficiencies. Awareness of these cutaneous associations may aid in the early detection and prompt treatment of these potentially serious immunologic disorders.

PMID: 31329384 [PubMed – in process]

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Primary immunodeficiency considerations in assisted reproductive technology.

J Allergy Clin Immunol Pract. 2019 Jul 18;:

Authors: Sun D, Capucilli P, Jyonouchi S

PMID: 31326621 [PubMed – as supplied by publisher]

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Outcomes of the PIRASOA programme, an antimicrobial stewardship programme implemented in hospitals of the public Health system of Andalusia, Spain: an ecological study of time-trend analysis.

Clin Microbiol Infect. 2019 Jul 16;:

Authors: Rodríguez-Baño J, Pérez-Moreno MA, Peñalva G, Garnacho-Montero J, Pinto C, Salcedo I, Fernández-Urrusuno R, Neth O, Gil-Navarro MV, Pérez-Milena A, Sierra R, Estella Á, Lupión C, Irastorza A, Márquez JL, Pascual Á, Rojo-Martín MD, Pérez-Lozano MJ, Valencia-Martín R, Cisneros JM, PIRASOA programme group

Abstract
OBJECTIVES: Inappropriate antimicrobial use favours the spread of resistance and multidrug-resistant microorganisms (MDR) are currently of major concern. Antimicrobial stewardship programmes (ASPs) are essential for improving antibiotic use in hospitals. However, their impact on entire healthcare systems has not been thoroughly assessed. Our objective is to provide the results of an institutionally supported ASP involving 31 public hospitals in Andalusia, Spain.
METHODS: We designed an ecological time-series study from 01/01/2014 to 31/12/2017. Quarterly, data on indicators were collected prospectively and feedback reports were provided. PIRASOA is an ongoing clinically-based, quality improvement programme whose key intervention is the educational interview, regular peer-to-peer interventions between advisors and prescribers to reinforce the appropriate use of antibiotics. 72 indicators were monitored to measure prescribing quality (inappropriate treatments), antimicrobial consumption (defined daily doses/1000 occupied bed days [OBD]), incidence density of MDR/1000 OBD, and crude mortality rate associated with bloodstream infections. We used joinpoint regression to analyse the trends.
RESULTS: The quality of antimicrobial prescribing improved markedly and inappropriate treatment rate was significantly lower with quarterly percentage change (QPC)=-3.0%, P<.001. Total antimicrobial consumption decreased (QPC=-0.9%, P<0.001) and, specifically, carbapenems, amoxicillin/clavulanic acid, quinolones, and antifungal agents consumption, whereas antipseudomonal cephalosporins use increased. While the incidence of MDR showed a sustained decreasing trend (QPC=-1.8%; P=.002), the mortality of patients with bloodstream infections remained stable (QPC=-0.2%, P=.605).
CONCLUSIONS: To date, the PIRASOA programme has succeeded in optimising the use of antimicrobial agents and has had a positive ecological result on bacterial resistance at level of an entire healthcare system.

PMID: 31323260 [PubMed – as supplied by publisher]

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Immune system defects in DiGeorge syndrome and association with clinical course.

Scand J Immunol. 2019 Jul 19;:

Authors: Nain E, Kiykim A, Ogulur I, Aruci Kasap N, Karakoc-Aydiner E, Ozen A, Baris S

Abstract
We evaluated 18 DiGeorge syndrome (DGS) patients and aimed to investigate the immunological changes in this population. DGS patients with low naive CD4+ T and CD8+ T cells were defined as high risk (HR) patients, whereas patients with normal numbers of naive CD4+ and CD8+ T cells were defined as standard risk (SR) patients. Level of serum IgM, CD3+ and CD8+ T cells counts and percentages of switched memory B cells were significantly low in HR group compared to SR ones. Severe infections and persistent hypoparathyroidism was detected significantly higher in HR group. Patients with reduced percentages of class switched B cells had earlier onset of infection, lower blood IgM, lower CD4+ and CD8+ T counts than patients with normal class switched memory B cells. Decreased levels of IgM were associated with low numbers of naive CD4+ and recent thymic emigrants T cells. Monitoring the immune changes of patients with DGS would be useful to predict the severe phenotype of disease. This article is protected by copyright. All rights reserved.

PMID: 31322747 [PubMed – as supplied by publisher]

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