title: B-Cell Depletion Reduces the Maturation of Cerebral Cavernous Malformations in Murine Models.
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.
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, Biological Sciences Division, The University of Chicago Medicine, 5841 S. Maryland Ave. MC3026/Room J341, Chicago, IL, 60637, USA.|Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Changbin
authors.initials: C
authors.lastname: Shi
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, Biological Sciences Division, The University of Chicago Medicine, 5841 S. Maryland Ave. MC3026/Room J341, Chicago, IL, 60637, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Shenkar
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, Biological Sciences Division, The University of Chicago Medicine, 5841 S. Maryland Ave. MC3026/Room J341, Chicago, IL, 60637, USA.
authors.forename: Hussein A
authors.initials: HA
authors.lastname: Zeineddine
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, Biological Sciences Division, The University of Chicago Medicine, 5841 S. Maryland Ave. MC3026/Room J341, Chicago, IL, 60637, USA.
authors.forename: Romuald
authors.initials: R
authors.lastname: Girard
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, Biological Sciences Division, The University of Chicago Medicine, 5841 S. Maryland Ave. MC3026/Room J341, Chicago, IL, 60637, USA.
authors.forename: Maged D
authors.initials: MD
authors.lastname: Fam
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, Biological Sciences Division, The University of Chicago Medicine, 5841 S. Maryland Ave. MC3026/Room J341, Chicago, IL, 60637, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Austin
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, Biological Sciences Division, The University of Chicago Medicine, 5841 S. Maryland Ave. MC3026/Room J341, Chicago, IL, 60637, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Moore
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, Biological Sciences Division, The University of Chicago Medicine, 5841 S. Maryland Ave. MC3026/Room J341, Chicago, IL, 60637, USA.
authors.forename: Rhonda
authors.initials: R
authors.lastname: Lightle
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, Biological Sciences Division, The University of Chicago Medicine, 5841 S. Maryland Ave. MC3026/Room J341, Chicago, IL, 60637, USA.
authors.forename: Lingjiao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, Biological Sciences Division, The University of Chicago Medicine, 5841 S. Maryland Ave. MC3026/Room J341, Chicago, IL, 60637, USA.
authors.forename: Meijing
authors.initials: M
authors.lastname: Wu
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, Biological Sciences Division, The University of Chicago Medicine, 5841 S. Maryland Ave. MC3026/Room J341, Chicago, IL, 60637, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Murat
authors.initials: M
authors.lastname: Gunel
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Louvi
authors.affiliation: Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC, USA.
authors.forename: Autumn
authors.initials: A
authors.lastname: Rorrer
authors.affiliation: Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Gallione
authors.affiliation: Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Marchuk
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, Biological Sciences Division, The University of Chicago Medicine, 5841 S. Maryland Ave. MC3026/Room J341, Chicago, IL, 60637, USA. iawad@uchicago.edu.
authors.forename: Issam A
authors.initials: IA
authors.lastname: Awad
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D016543:Central Nervous System Neoplasms / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D020786:Hemangioma, Cavernous, Central Nervous System / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic
keywords: B cells; B-cell depletion; Cerebral cavernous malformation; Immune response; Inflammation; Stroke