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Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease

Overview of attention for article published in Nature, February 2017
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  • In the top 5% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (99th percentile)
  • High Attention Score compared to outputs of the same age and source (90th percentile)

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68 news outlets
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1 blog
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41 X users
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2 patents
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1 research highlight platform

Citations

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144 Dimensions

Readers on

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190 Mendeley
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1 CiteULike
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Title
Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease
Published in
Nature, February 2017
DOI 10.1038/nature21368
Pubmed ID
Authors

Manoj K. Pandey, Thomas A. Burrow, Reena Rani, Lisa J. Martin, David Witte, Kenneth D. Setchell, Mary A. Mckay, Albert F. Magnusen, Wujuan Zhang, Benjamin Liou, Jörg Köhl, Gregory A. Grabowski

Abstract

Gaucher disease is caused by mutations in GBA1, which encodes the lysosomal enzyme glucocerebrosidase (GCase). GBA1 mutations drive extensive accumulation of glucosylceramide (GC) in multiple innate and adaptive immune cells in the spleen, liver, lung and bone marrow, often leading to chronic inflammation. The mechanisms that connect excess GC to tissue inflammation remain unknown. Here we show that activation of complement C5a and C5a receptor 1 (C5aR1) controls GC accumulation and the inflammatory response in experimental and clinical Gaucher disease. Marked local and systemic complement activation occurred in GCase-deficient mice or after pharmacological inhibition of GCase and was associated with GC storage, tissue inflammation and proinflammatory cytokine production. Whereas all GCase-inhibited mice died within 4-5 weeks, mice deficient in both GCase and C5aR1, and wild-type mice in which GCase and C5aR were pharmacologically inhibited, were protected from these adverse effects and consequently survived. In mice and humans, GCase deficiency was associated with strong formation of complement-activating GC-specific IgG autoantibodies, leading to complement activation and C5a generation. Subsequent C5aR1 activation controlled UDP-glucose ceramide glucosyltransferase production, thereby tipping the balance between GC formation and degradation. Thus, extensive GC storage induces complement-activating IgG autoantibodies that drive a pathway of C5a generation and C5aR1 activation that fuels a cycle of cellular GC accumulation, innate and adaptive immune cell recruitment and activation in Gaucher disease. As enzyme replacement and substrate reduction therapies are expensive and still associated with inflammation, increased risk of cancer and Parkinson disease, targeting C5aR1 may serve as a treatment option for patients with Gaucher disease and, possibly, other lysosomal storage diseases.

X Demographics

X Demographics

The data shown below were collected from the profiles of 41 X users who shared this research output. Click here to find out more about how the information was compiled.
Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 190 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 <1%
China 1 <1%
France 1 <1%
Unknown 187 98%

Demographic breakdown

Readers by professional status Count As %
Researcher 39 21%
Student > Ph. D. Student 36 19%
Student > Bachelor 22 12%
Student > Master 16 8%
Other 15 8%
Other 30 16%
Unknown 32 17%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 32 17%
Agricultural and Biological Sciences 30 16%
Medicine and Dentistry 26 14%
Neuroscience 17 9%
Immunology and Microbiology 11 6%
Other 29 15%
Unknown 45 24%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 547. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 10 May 2022.
All research outputs
#43,244
of 25,010,497 outputs
Outputs from Nature
#3,725
of 96,507 outputs
Outputs of similar age
#953
of 316,793 outputs
Outputs of similar age from Nature
#93
of 920 outputs
Altmetric has tracked 25,010,497 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 99th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 96,507 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 102.2. This one has done particularly well, scoring higher than 96% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 316,793 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 99% of its contemporaries.
We're also able to compare this research output to 920 others from the same source and published within six weeks on either side of this one. This one has done particularly well, scoring higher than 90% of its contemporaries.