Elevated IgE from attenuated CARD11 signaling: lessons from atopic mice and humans

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.

Figure 1

CADINS mutations in CARD11, an obligate signaling hub in TCR signaling. (a) During TCR signaling, CARD11 converts from a closed inactive state to an open scaffold that recruits multiple proteins into a signaling complex, leading to the activation of branching downstream pathways. (b) Location of identified DN CADINS mutations in the CARD11 domain structure.