AI Insight
This study reveals that immunoglobulin G (IgG) accumulates in cerebral cavernous malformations (CCMs) due to impaired lysosomal function in endothelial cells, triggering cellular senescence and disease progression. Loss of CCM proteins activates mTOR signaling, which disrupts lysosomal acidification and prevents normal IgG degradation, leading to intracellular buildup that induces endothelial aging through NF-kB signaling. Experimentally depleting plasma cells (which produce IgG) or reducing IgG levels with anti-CD38 treatment significantly decreased endothelial senescence, hemorrhage, and lesion growth in mouse models.
Why it matters
These findings identify a novel therapeutic target for cerebral cavernous malformations, a vascular disorder that causes seizures, neurological deficits, and brain hemorrhages. The study suggests that existing therapies targeting plasma cells or IgG (already used in other diseases) could potentially be repurposed to treat CCM patients.
Understand the Science
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Endothelial senescence is increasingly recognized as a driver of vascular pathology, while immunoglobulin G (IgG) has recently been reported to accumulate in aging tissues and induce senescence in macrophages and microglia. In cerebral cavernous malformations (CCMs), IgG accumulation has been obviously observed in CCM lesions, but the contribution of IgG to endothelial injury remains unclear. Using multi-omic profiling, endothelial models, and CCM mice, we identified IgG-secreting plasma cells enriched in lesions associated with endothelial senescence, hemorrhage, and disease severity. CCM loss-associated mTOR activation impaired lysosomal acidification and IgG processing, promoting intracellular IgG accumulation. IgG, in turn, induced NF-kB-dependent endothelial senescence. In vivo, BCMA-mediated plasma cell depletion attenuated lesion progression, whereas IgG supplementation partially restored disease severity. Anti-CD38 treatment likewise reduced IgG accumulation, endothelial senescence, hemorrhage, and lesion progression. These findings identify lysosomal dysfunction-mediated IgG as a pathogenic trigger of endothelial senescence and support targeting the plasma cell-IgG axis in CCM.