A loss-of-function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis

Kristjansson, Ragnar P.; Benónísdóttir, Stefania; Davidsson, Olafur B.; Oddsson, Ásmundur; Tragante, Vinicius; Sigurdsson, Jon K.; Stefánsdóttir, Lilja; Jönsson, Stefan; Jensson, Brynjar O.; Arthur, Joseph G.; Arnadottir, Gudny A.; Sulem, Gerald; Halldórsson, Bjarni V.; Gunnarsson, Bjarni; Halldorsson, Gisli H.; Stefansson, Olafur A.; Oskarsson, Gudjon R.; Deaton, Aimée M.; Ólafsson, Ísleifur; Eyjolfsson, Gudmundur I.; Sigurðardóttir, Ólöf; Önundarson, Páll T.; Gíslason, Davíð; Gíslason, Þórarinn; Lúðvíksson, Björn Rúnar; Lúdvı́ksdóttir, Dóra; Olafsdottir, Thorunn A.; Rafnar, Thorunn; Másson, Gísli; Zink, Florian; Björnsdóttir, Gyða; Magnússon, Ólafur Þ.; Björnsdóttir, Unnur Steina; Þorleifsson, Guðmar; Norddahl, Gudmundur L.; Guðbjartsson, Daníel F.; Þorsteinsdóttir, Unnur; Jónsdóttir, Ingileif; Sulem, Patrick; Stefánsson, Kári

doi:10.1038/s41588-018-0314-6

Cited by 97 publications

(98 citation statements)

References 47 publications

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“…Loss of function mutation in ALOX15 protects against nasal polyps and chronic rhinosinusitis. Metabolites of ALOX15 activate macrophages towards a M2 phenotype, suggesting that Dupilumab may protect against chronic rhinosinusitis in part by suppressing the IL‐4/13‐ALOX15/ M2 macrophages axis …”

Section: Dupilumab In Chronic Rhinosinusitis With Nasal Polyposismentioning

confidence: 99%

Mechanisms of Dupilumab

Harb

Chatila

2019

Clin Experimental Allergy

332

241

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The Th2 cytokines interleukin 4 (IL‐4) and IL‐13 and the heterodimeric IL‐4 receptor (IL‐4R) complexes that they interact with play a key role in the pathogenesis of allergic disorders. Dupilumab is a humanized IgG4 monoclonal antibody that targets the IL‐4 receptor alpha chain (IL‐4Rα), common to both IL‐4R complexes: type 1 (IL‐4Rα/γc; IL‐4 specific) and type 2 (IL‐4Rα/IL‐13Rα1; IL‐4 and IL‐13 specific). In this review, we detail the current state of knowledge of the different signalling pathways coupled to the IL‐4R complexes and examine the possible mechanisms of Dupilumab action and survey its clinical efficacy in different allergic disorders. The development of Dupilumab and the widening spectrum of its clinical applications is relevant to the current emphasis on precision medicine approaches to the blockade of pathways involved in allergic diseases.

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Section: Dupilumab In Chronic Rhinosinusitis With Nasal Polyposismentioning

confidence: 99%

Mechanisms of Dupilumab

Harb

Chatila

2019

Clin Experimental Allergy

332

241

View full text Add to dashboard Cite

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“…The number of rhinosinusogenic orbital and intracranial complications, often leading to disability or death of the patient, has at least not decreased recently [16,17].…”

Section: Resultsmentioning

confidence: 99%

“…It has been proven that there is a direct connection between influenza and acute respiratory infections with subsequently developing chronic therapeutic pathology and serious somatic complications [22]. It is considered possible to develop primary heart damage in acute infectious diseases [4,6,12], myocarditis and dilated cardiomyopathy in patients who have had a viral infection [1,9,16]. Of particular relevance is the study of the role of inflammatory diseases of the ENT organs in the occurrence of heart pathology, which very often are the cause of dystrophy of the heart muscle [2], myocarditis and rheumatism [6,8].…”

Section: Resultsmentioning

confidence: 99%

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Some Features of Clinical Laboratory and Instrumental Research in Chronic Inflammatory Diseases of the Nose and Paranasal Sinuses in Patients with Myocarditis

2019

IJITEE

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The issues of diagnosis and adequate treatment of rhinosinusitis (RS) remain very relevant today, since this disease is one of the most widespread in the whole world. So, up to 15% of the adult population suffers from various forms of RS; in childrenthis disease is even more common. Otorhinolaryngologists and primary care physicians face RS in their practice on a daily basis. It should be noted that in most European countries and in America, it is the general practitioner who plays the main role in the treatment of uncomplicated forms of the disease. It is important to note that both acute and chronic RS lead to a significant decrease in the quality of life index, comparable with data on cardiological diseases and obstructive pulmonary disease.

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“…Identifying the genetic influences on specific patterns of infiltrating immune cells is crucial to understanding disease biology. Beyond further explaining heritable manifestations of infectious diseases and autoimmunity [1][2][3][4][5][6][7][8][9] , such efforts can further uncover the drivers of characteristic immune cell signatures in the tumor microenvironment that are prognostic for cancer progression and predictive of treatment response 10 . For example, response is improved in patients with T cell-inflamed tumors compared to T cell-depleted tumors among patients receiving immune checkpoint inhibitors targeting PD1 and CTLA4 10,11 and among ovarian cancer patients receiving chemotherapy 12 .…”

Section: Introductionmentioning

confidence: 99%

Age, Sex, and Genetics Influence the Abundance of Infiltrating Immune Cells in Human Tissues

Marderstein

Uppal

Verma

et al. 2019

Preprint

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Despite infiltrating immune cells playing an essential role in human disease and the patient response to treatment, the central mechanisms influencing variability in infiltration patterns are unclear. Using bulk RNA-seq data from 53 GTEx tissues, we applied cell-type deconvolution algorithms to evaluate the immune landscape across the healthy human body. We first performed a differential expression analysis of inflamed versus non-inflamed samples to identify essential pathways and regulators of infiltration. Next, we found 21 of 73 infiltration-related phenotypes to be associated with either age or sex (FDR < 0.1). Through our genetic analysis, we discovered 13 infiltration-related phenotypes have genome-wide significant associations (iQTLs) (P < 5.0 x 10 -8 ), with a significant enrichment of tissue-specific expression quantitative trait loci in suggested iQTLs (P < 10 -5 ). We highlight an association between neutrophil content in lung tissue and a variant near the CUX1 transcription factor gene (P = 9.7 x 10 -11 ), which has been previously linked to neutrophil infiltration, inflammatory mechanisms, and the regulation of several immune response genes. Together, our results identify key factors influencing interindividual variability of specific tissue infiltration patterns, which could provide insights on therapeutic targets for shifting infiltration profiles to a more favorable one. Results Robust estimation of immune cell types in bulk RNA-seq profiles.To describe immune content from bulk RNA-seq samples, we used two central algorithms: xCell 13 and CIBERSORT 14 . xCell relies on a modification of single sample gene-set enrichment analysis to estimate cell type scores, while CIBERSORT employs a linear support vector regression model. The default reference signatures allow deconvolution of 64 immune and stroma cell types for xCell and 22 immune cell types for CIBERSORT. CIBERSORT also calculates a scaling factor that measures the degree of infiltration. We refer to the relative proportions from CIBERSORT as "CIBERSORT-Relative" and the product of the relative proportions with the scaling factor as "CIBERSORT-Absolute". We estimate three scores for each cell type to describe the immune content from the gene expression data for each tissue in each individual: xCell, CIBERSORT-Relative, and CIBERSORT-Absolute scores.We first hypothesized that the relative and absolute scores from CIBERSORT encapsulated different aspects of the single-cell deconvolution. While "CIBERSORT-Absolute" simultaneously quantifies a degree of immune infiltration, "CIBERSORT-Relative" is focused on capturing compositional changes in the immune content (Supplementary Note). We simulated synthetic mixes composed of bulk tissue "spiked" in silico with CD4+ T cells and CD8+ T cells (see Methods). We correlated the known amount of CD4+ and CD8+ T cell infiltration in these mixtures with estimated deconvolution scores under a "tissue" scenario and an "immune cell" scenario. In the "immune cell" scenario, we let the true infiltration be the prop...

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A loss-of-function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis

Cited by 97 publications

References 47 publications

Mechanisms of Dupilumab

Mechanisms of Dupilumab

Some Features of Clinical Laboratory and Instrumental Research in Chronic Inflammatory Diseases of the Nose and Paranasal Sinuses in Patients with Myocarditis

Age, Sex, and Genetics Influence the Abundance of Infiltrating Immune Cells in Human Tissues

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