B-Cell Depletion Reduces the Maturation of Cerebral Cavernous Malformations in Murine Models

Changbin Shi, Robert Shenkar, Hussein A. Zeineddine, Romuald Girard, Maged D. Fam, Cecilia Austin, Thomas Moore, Rhonda Lightle, Lingjiao Zhang, Meijing Wu, Ying Cao, Murat Gunel, Angeliki Louvi, Autumn Rorrer, Carol Gallione, Douglas A. Marchuk, Issam A. Awad*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Cerebral cavernous malformations (CCMs) are relatively common vascular malformations, characterized by increased Rho kinase (ROCK) activity, vascular hyper-permeability and the presence of blood degradation products including non-heme iron. Previous studies revealed robust inflammatory cell infiltration, selective synthesis of IgG, in situ antigen driven B-cell clonal expansion, and deposition of immune complexes and complement proteins within CCM lesions. We aimed to evaluate the impact of suppressing the immune response on the formation and maturation of CCM lesions, as well as lesional iron deposition and ROCK activity. Two murine models of heterozygous Ccm3 (Pdcd10), which spontaneously develop CCM lesions with severe and milder phenotypes, were either untreated or received anti-mouse BR3 to deplete B cells. Brains from anti-mouse BR3-treated mice exhibited significantly fewer mature CCM lesions and smaller lesions compared to untreated mice. B cell depletion halted the progression of lesions into mature stage 2 lesions but did not prevent their genesis. Non-heme iron deposition and ROCK activity was decreased in lesions of B cell depleted mice. This represents the first report of the therapeutic benefit of B-cell depletion in the development and progression of CCMs, and provides a proof of principle that B cells play a critical role in CCM lesion genesis and maturation. These findings add biologics to the list of potential therapeutic agents for CCM disease. Future studies would characterize the putative antigenic trigger and further define the mechanism of immune response in the lesions.

Original languageEnglish (US)
Pages (from-to)369-377
Number of pages9
JournalJournal of Neuroimmune Pharmacology
Volume11
Issue number2
DOIs
StatePublished - Jun 1 2016

Keywords

  • B cells
  • B-cell depletion
  • Cerebral cavernous malformation
  • Immune response
  • Inflammation
  • Stroke

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

Fingerprint Dive into the research topics of 'B-Cell Depletion Reduces the Maturation of Cerebral Cavernous Malformations in Murine Models'. Together they form a unique fingerprint.

Cite this