Shi Changbin, Shenkar Robert, Du Hongyan, Duckworth Edward, Raja Harish, Batjer H Hunt, Awad Issam A
Division of Neurosurgery, NorthShore University HealthSystem, Evanston, IL 60201, USA.
Stroke. 2009 May;40(5):1659-65. doi: 10.1161/STROKEAHA.108.538769. Epub 2009 Mar 12.
Preliminary observations suggesting the presence of B and plasma cells and oligoclonality of immunoglobulin (Ig) G in cerebral cavernous malformations (CCM) have motivated a systematic study correlating the infiltration of the immune cells with clinical activity and antigen-triggered immune response in surgically excised lesions.
Infiltration of plasma, B, T, and human leukocyte antigen-DR-expressing cells and macrophages within 23 excised CCM was related to clinical activity. Relative amounts of Ig isotypes were determined. IgG clonality of mRNA from CCM was assessed by spectratyping, cloning, and sequencing.
Infiltration of the immune cells ranged widely within CCM lesions, and cells were generally coexpressed with each other. Immune cell infiltration did not associate with recent bleeding and lesion growth. Significantly more B lymphocytes in CCM lesions were associated with venous anomaly. More T cells were present in solitary lesions. More T cells and less macrophages were present in CCM from younger subjects. IgG isotype was present in all CCM lesions. Most lesions also expressed IgM and IgA, with IgM predominance over IgA correlating with recent CCM growth. Oligoclonality was shown in IgG mRNA from CCM, but not from peripheral blood lymphocytes, with only 8 complementary-determining region 3 sequences observed among 134 clones from 2 CCM lesions.
An antigen-directed oligoclonal IgG immune response is present within CCM lesions regardless of recent clinical activity. Apparent differences in immune response in younger patients and in lesions with recent growth will need confirmation in other series. The pathogenicity of oligoclonal immune response will require systematic hypothesis testing in recently available CCM murine models.
初步观察提示脑海绵状血管畸形（CCM）中存在B细胞、浆细胞以及免疫球蛋白（Ig）G的寡克隆性，这促使我们开展一项系统性研究，以探讨手术切除病变中免疫细胞浸润与临床活性以及抗原触发的免疫反应之间的相关性。
对23例手术切除的CCM中浆细胞、B细胞、T细胞、表达人类白细胞抗原-DR的细胞以及巨噬细胞的浸润情况与临床活性进行相关性分析。测定Ig各亚型的相对含量。通过光谱分型、克隆和测序评估CCM中mRNA的IgG克隆性。
CCM病变内免疫细胞浸润程度差异很大，且细胞通常相互共表达。免疫细胞浸润与近期出血及病变生长无关。CCM病变中B淋巴细胞数量显著增多与静脉畸形相关。孤立性病变中T细胞数量更多。年轻患者的CCM中T细胞数量更多，巨噬细胞数量更少。所有CCM病变中均存在IgG亚型。大多数病变还表达IgM和IgA，IgM高于IgA与CCM近期生长相关。CCM的IgG mRNA显示有寡克隆性，但外周血淋巴细胞中未显示，在来自2个CCM病变的134个克隆中仅观察到8个互补决定区3序列。
无论近期临床活性如何，CCM病变内均存在抗原导向的寡克隆IgG免疫反应。年轻患者及近期生长的病变中免疫反应的明显差异需要在其他系列研究中得到证实。寡克隆免疫反应的致病性需要在最近可用的CCM小鼠模型中进行系统性的假设检验。
