B-Cell Depletion Reduces the Maturation of Cerebral Cavernous Malformations in Murine Models.
B-Cell Depletion Reduces the Maturation of Cerebral Cavernous Malformations in Murine Models.
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DOI：
10.1007/s11481-016-9670-0
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Awad IA
中科院分区：
文献类型：
--
作者：
Shi C;Shenkar R;Zeineddine HA;Girard R;Fam MD;Austin C;Moore T;Lightle R;Zhang L;Wu M;Cao Y;Gunel M;Louvi A;Rorrer A;Gallione C;Marchuk DA;Awad IA
脑海绵状血管畸形(CCM)是一种相对常见的血管畸形，其特征是Rho激酶(ROCK)活性升高、血管高通透性和包括非血红素铁在内的血液降解产物的存在。以往的研究发现CCM皮损中有大量炎性细胞浸润、选择性合成免疫球蛋白、原位抗原驱动的B细胞克隆性增殖、免疫复合体和补体蛋白沉积。我们的目的是评估抑制免疫反应对CCM病变的形成和成熟，以及皮损铁沉积和岩石活动的影响。两种杂合子Ccm3(Pdcd10)小鼠模型自发地发展为表型较重和较轻的CCM皮损，要么不治疗，要么接受抗鼠BR3以耗尽B细胞。与未治疗的小鼠相比，抗小鼠BR3处理的小鼠的大脑显示出明显更少的成熟CCM病变和更小的病变。B细胞耗尽阻止了病变进展为成熟的2期病变，但并未阻止其发生。在B细胞耗竭小鼠的皮损中，非血红素铁沉积和ROCK活性降低。这是关于B细胞耗竭在CCM的发展和进展中的治疗益处的第一个报告，并提供了B细胞在CCM病变的发生和成熟中发挥关键作用的原理证明。这些发现将生物制品添加到CCM疾病的潜在治疗剂名单中。未来的研究将表征假定的抗原触发因素，并进一步确定病变中的免疫反应机制。
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.
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影响因子：
6.3
作者：
Mikati, Abdul G.;Khanna, Omaditya;Awad, Issam A.
通讯作者：
Awad, Issam A.
影响因子：
4.8
作者：
Borikova, Asya L.;Dibble, Christopher F.;Johnson, Gary L.
通讯作者：
Johnson, Gary L.
影响因子：
4.8
作者：
ROBINSON, JR;AWAD, IA;ESTES, ML
通讯作者：
ESTES, ML
影响因子：
48
作者：
Salman, Rustam Al-Shahi;Hall, Julie M.;Horne, Margaret A.;Moultrie, Fiona;Josephson, Colin B.;Bhattacharya, Joj;Counsell, Carl E.;Murray, Gordon D.;Papanastassiou, Vakis;Ritchie, Vaughn;Roberts, Richard C.;Sellar, Robin J.;Warlow, Charles P.
通讯作者：
Warlow, Charles P.
影响因子：
4.1
作者：
Jakimovski, Dejan;Schneider, Hannah;Bertalanffy, Helmut
通讯作者：
Bertalanffy, Helmut