Antibodies in cerebral cavernous malformations react with cytoskeleton autoantigens in the lesional milieu

波形蛋白 生物 抗体 抗原 亲和力成熟 细胞骨架 单克隆抗体 分子生物学 细胞生物学 免疫荧光 免疫细胞化学 免疫组织化学 免疫学 细胞 生物化学 内分泌学
作者
Dongdong Zhang,Andrew J Kinloch,Abhinav Srinath,Robert Shenkar,Romuald Girard,Rhonda Lightle,Thomas Moore,Janne Koskimäki,Azam Mohsin,Julián Carrión‐Penagos,Sharbel Romanos,Le Shen,Marcus R. Clark,Changbin Shi,Issam A. Awad
出处
期刊:Journal of Autoimmunity [Elsevier BV]
卷期号:113: 102469-102469 被引量:5
标识
DOI:10.1016/j.jaut.2020.102469
摘要

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 this in situ autoimmune response may yield a novel treatment for CCM.
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