Antibodies in cerebral cavernous malformations react with cytoskeleton autoantigens in the lesional milieu.
Antibodies in cerebral cavernous malformations react with cytoskeleton autoantigens in the lesional milieu.
复制标题
脑海绵状血管瘤中的抗体与病变环境中的细胞骨架自身抗原发生反应。
DOI：
10.1016/j.jaut.2020.102469
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发表时间：
2020-04
影响因子：
12.8
通讯作者：
Awad I. A.
中科院分区：
文献类型：
--
作者：
Zhang D.;Kinloch A. J.;Srinath A.;Shenkar R.;Girard R.;Lightle R.;Moore T.;Koskimäki J.;Mohsin A.;Carrión-Penagos J.;Romanos S.;Shen L.;Clark M. R.;Shi C.;Awad I. A.
以往的研究报道了脑海绵状血管畸形（CCM）病变中强烈的炎性细胞浸润、IgG合成、B细胞克隆性扩增、免疫复合物和补体沉积。B细胞耗竭也已显示减少小鼠模型中CCM的成熟。我们假设病变环境中的抗原使CCM中的致病性免疫应答永久化。本研究的目的是使用来自手术切除的人CCM病变中发现的浆细胞的单克隆抗体（mAb）鉴定这些推定的抗原。我们从四名CCM患者的激光捕获显微切割的浆细胞中产生了人mAb，以及种系回复的版本。使用免疫荧光法对中枢神经系统（CNS）组织进行检测，并使用免疫细胞化学法对人原代细胞系进行检测。使用共聚焦显微镜、免疫沉淀和质谱的组合进行抗原表征。通过酶联免疫吸附试验测定亲和力，通过多色共聚焦显微镜和定量共定位测定特异性。CCM mAb结合CNS组织，特别是内皮细胞和星形胶质细胞。非肌肉肌球蛋白重链IIA（NMMHCIIA）、波形蛋白和微管蛋白是三种常见的靶向细胞骨架蛋白。浆细胞对细胞骨架蛋白的选择得到免疫球蛋白可变区体细胞超突变的高频率、其亲和力成熟形式的mAb的高亲和力和选择性以及种系回复形式的显著降低的亲和力和选择性的支持。血管内皮细胞和星形胶质细胞中丰富的波形蛋白和微管蛋白。在病变环境中与自身抗原的结合和选择可能使CCM中的致病性免疫应答持续存在。阻断这种原位自身免疫反应可能会产生一种新的治疗CCM的方法。
Previous studies have reported robust inflammatory cell infiltration, synthesis of IgG, B-cell clonal expansion, deposition of immune complexes and complement within cerebral cavernous malformation (CCM) lesions. B-cell depletion has also been shown to reduce the maturation of CCM in murine models. We hypothesize that antigen(s) within the lesional milieu perpetuate the pathogenetic immune responses in CCMs. This study aims to identify those putative antigen(s) using monoclonal antibodies (mAbs) derived from plasma cells found in surgically removed human CCM lesions. We produced human mAbs from laser capture micro-dissected plasma cells from four CCM patients, and also germline-reverted versions. CCM mAbs were assayed using immunofluorescence on central nervous system (CNS) tissues and immunocytochemistry on human primary cell lines. Antigen characterization was performed using a combination of confocal microscopy, immunoprecipitation and mass spectrometry. Affinity was determined by enzyme-linked immunosorbent assay, and specificity by multi-color confocal microscopy and quantitative co-localization. CCM mAbs bound CNS tissue, especially endothelial cells and astrocytes. Non-muscle myosin heavy chain IIA (NMMHCIIA), vimentin and tubulin are three cytoskeleton proteins that were commonly targeted. Selection of cytoskeleton proteins by plasma cells was supported by a high frequency of immunoglobulin variable region somatic hypermutations, high affinity and selectivity of mAbs in their affinity matured forms, and profoundly reduced affinity and selectivity in the germline reverted forms.Antibodies produced by plasma cells in CCM lesions commonly target cytoplasmic and cytoskeletal autoantigens including NMMHCIIA, vimentin and tubulin that are abundant in endothelial cells and astrocytes. Binding to, and selection on autoantigen(s) in the lesional milieu likely perpetuates the pathogenetic immune response in CCMs. Blocking thisin situautoimmune response may yield a novel treatment for CCM.
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DOI：
10.1096/fj.201800343r
发表时间：
2018-09
期刊：
The FASEB Journal
影响因子：
--
作者：
Yitang Wang;Ye Li;Jinjing Zou;S. Polster;R. Lightle;Thomas Moore;M. Dimaano;T. He;C. Weber;I. Awad;Le Shen
通讯作者：
Yitang Wang;Ye Li;Jinjing Zou;S. Polster;R. Lightle;Thomas Moore;M. Dimaano;T. He;C. Weber;I. Awad;Le Shen
DOI：
10.1111/j.1432-0436.1982.tb01248.x
发表时间：
1982-09
期刊：
Differentiation; research in biological diversity
影响因子：
--
作者：
D. Dahl;P. Strocchi;A. Bignami
通讯作者：
D. Dahl;P. Strocchi;A. Bignami
影响因子：
7.3
作者：
Kinloch AJ;Kaiser Y;Wolfgeher D;Ai J;Eklund A;Clark MR;Grunewald J
通讯作者：
Grunewald J
DOI：
10.1086/513801
发表时间：
1997-12
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
A. Connolly;A. Pestronk
通讯作者：
A. Connolly;A. Pestronk
DOI：
10.1084/jem.20091258
发表时间：
2010-04-12
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Stockton RA;Shenkar R;Awad IA;Ginsberg MH
通讯作者：
Ginsberg MH