Immune complex formation and in situ B-cell clonal expansion in human cerebral cavernous malformations

• We describe a robust inflammatory response in cerebral cavernous malformations.
• We here show for the first time pathogenic immune complexes within human lesions.
• Sequencing of laser micro-dissected B-cells from lesions reveals clonal expansion.
• These results are consistent with in situ antigen honed immune response.
• This novel mechanism may offer opportunity at therapeutic modification.

Cerebral cavernous malformations (CCMs) represent clusters of dilated vascular channels, predisposing to hemorrhagic stroke and seizures. They are associated with defective blood brain barrier, hemorrhages of different ages and a robust inflammatory cell infiltrate. We report for the first time evidence of co-localized IgG and complement membrane attack complexes in CCM lesions. CD4+ and CD8+ T-cells are aggregated with CD20+ B-cells. And IgG repertoire analyses demonstrate in situ B-cell clonal expansion and antigen-driven affinity maturation in CCMs. These results suggest an organ-intrinsic adaptive immune response in CCMs that should be further characterized as a potential therapeutic target.