Shenkar Robert, Shi Changbin, Check Irene J, Lipton Howard L, Awad Issam A
Department of Neurological Surgery, Evanston Northwestern Healthcare, Evanston, IL 60201, USA.
Neurosurgery. 2007 Oct;61(4):693-702; discussion 702-3. doi: 10.1227/01.NEU.0000298897.38979.07.
Cerebral cavernous malformations (CCMs) affect more than one million Americans, predisposing them to a lifetime risk of hemorrhagic stroke and epilepsy. A potential role of the immune response in this disease has not been postulated previously but is compelling given the unique antigenic milieu of CCM lesions with sequestered thrombi and a leaky blood-brain barrier and the numerous examples of immune modulation of angiogenesis in other disease states. The objective of this article is to reveal novel observations about apparent immune responses in CCM lesions excised from human patients and to outline the potential pathobiological significance of these observations, specific hypotheses for future research, and potential clinical implications.
We reviewed data from differential gene expression revealing several immunoglobulin and other related genes markedly upregulated within human CCM lesions. Other observations are presented revealing infiltration of antibody-producing B lymphocytes and plasma cells in CCM lesions. We also present recent data demonstrating fivefold enrichment of gamma globulin to albumin ratio in a human lesion compared with serum from the same patient and oligoclonality of IgG in four of five CCM lesions, but not in paired sera from the same patients or in control specimens.
We describe ongoing research aiming to characterize cellular and humoral components of the immune response in CCMs and initiating investigation into its clonality by isoelectric focusing on the predominant immunoglobulin isotypes isolated from the lesion, in comparison to the patient's serum, and by the distribution of lengths of complementary-determining region 3 of the immunoglobulin heavy chain genes in messenger ribonucleic acid isolated from lesions and from pooled plasma cells and B cells laser captured from CCMs in comparison to peripheral lymphocytes from the blood of the same patients.
Immune response could play a role in or represent a potential marker of CCM lesion proliferation and hemorrhage or could otherwise contribute to lesion phenotype. The ongoing studies will generate preliminary data for future research aimed at comparing the immune response in quiescent versus clinically aggressive CCM lesions. An oligoclonal immune response shown in this research would stimulate future experiments to identify autoimmune or extrinsic antigenic triggers involved in CCM disease.
脑海绵状血管畸形（CCM）影响着超过100万美国人，使他们终生面临出血性中风和癫痫的风险。免疫反应在这种疾病中的潜在作用此前尚未被提出，但鉴于CCM病变具有独特的抗原环境，包括隐匿性血栓和血脑屏障渗漏，以及在其他疾病状态下免疫调节血管生成的众多实例，这一作用极具吸引力。本文的目的是揭示从人类患者切除的CCM病变中明显免疫反应的新观察结果，并概述这些观察结果的潜在病理生物学意义、未来研究的具体假设以及潜在的临床意义。
我们回顾了差异基因表达数据，这些数据显示人类CCM病变内有几种免疫球蛋白和其他相关基因明显上调。还展示了其他观察结果，揭示了CCM病变中产生抗体的B淋巴细胞和浆细胞的浸润。我们还展示了最近的数据，表明与同一患者的血清相比，人类病变中γ球蛋白与白蛋白的比例富集了五倍，并且在五个CCM病变中的四个中IgG呈寡克隆性，但在同一患者的配对血清或对照标本中则没有。
我们描述了正在进行的研究，旨在表征CCM中免疫反应的细胞和体液成分，并通过等电聚焦对从病变中分离出的主要免疫球蛋白同种型与患者血清进行比较，以及通过比较从病变、从CCM中激光捕获的汇集浆细胞和B细胞以及同一患者血液中的外周淋巴细胞中分离出的信使核糖核酸中免疫球蛋白重链基因互补决定区3的长度分布，来启动对其克隆性的研究。
免疫反应可能在CCM病变增殖和出血中起作用或代表其潜在标志物，或者可能以其他方式影响病变表型。正在进行的研究将为未来旨在比较静止性与临床侵袭性CCM病变中免疫反应的研究生成初步数据。本研究中显示的寡克隆免疫反应将激发未来的实验，以确定参与CCM疾病的自身免疫或外在抗原触发因素。
