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Published on: December 1, 2014
Elevated IgE from attenuated CARD11 signaling: lessons from atopic mice and humans
Joel L Pomerantz1, Joshua D Milner2, Andrew L Snow3
1Department of Biological Chemistry, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Insights
CARD11 mutations cause immune system errors and severe atopy by disrupting signaling pathways. Understanding these CARD11 defects offers new avenues for treating allergic diseases.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- CARD11 is a scaffold protein crucial for lymphocyte signaling pathways.
- Pathogenic CARD11 mutations are linked to human inborn errors of immunity.
- Recent findings connect dominant-negative CARD11 mutations to severe atopy.
Purpose of the Study:
- To review mechanistic links between CARD11 signaling, IgE levels, and atopy.
- To compare insights from human patients and murine models.
- To explore therapeutic strategies for allergic pathogenesis.
Main Methods:
- Review of existing literature on CARD11 mutations and atopy.
- Comparative analysis of human patient data and murine models.
- Mechanistic investigation of CARD11 signaling pathways.
Main Results:
- Attenuated CARD11 signaling is associated with elevated IgE and atopy.
- Heterozygous dominant-negative CARD11 mutations manifest as severe atopy.
- Insights from both human and murine studies highlight conserved signaling defects.
Conclusions:
- Abnormal CARD11 signaling is a key factor in allergic pathogenesis.
- Further research in human and murine models can guide novel therapeutic development.
- Targeting CARD11 pathways may offer new treatments for atopic diseases.
Abstract:
CARD11 encodes a large scaffold protein responsible for integrating antigen-receptor engagement with downstream signaling to NF-kB and other outputs in lymphocytes. Over the past 10 years, several human-inborn errors of immunity have been linked to pathogenic CARD11 mutations. Most recently, severe atopic patients were discovered that carried heterozygous dominant-negative CARD11 mutations. Here, we review the mechanistic connections between attenuated CARD11 signaling, elevated IgE, and atopy, comparing and contrasting key insights from both human patients and murine models. Continued investigation of abnormal CARD11 signaling in both contexts should inform novel therapeutic strategies to combat allergic pathogenesis.
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