Antibody-mediated resolution of light chain-associated amyloid deposits
Antibody-mediated resolution of light chain-associated amyloid deposits
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DOI：
10.1016/s0002-9440(10)64639-1
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发表时间：
2000-10-01
影响因子：
6
通讯作者：
Solomon, A
中科院分区：
文献类型：
--
作者：
Hrncic, R;Wall, J;Solomon, A
原发性轻链相关（AL）淀粉样变性的特征是单克隆轻链在组织中以原纤维形式沉积。除了极少数例外，这一过程似乎是不可逆的，并导致进行性器官功能障碍，最终死亡。为了确定免疫因素是否可以影响淀粉样蛋白的去除，我们开发了一种实验模型，在该模型中，小鼠注射从AL淀粉样变性患者的脾脏或肝脏中提取的淀粉样蛋白。值得注意的是，与对照相比，当动物接受对淀粉样蛋白相关表位具有特异性的抗轻链单克隆抗体的注射时，所得淀粉样蛋白瘤迅速消退。该单克隆抗体的反应性不依赖于原纤维的V-L或C-L同种型，而是似乎指向由AL和其他淀粉样蛋白表达的P-折叠片构象表位。淀粉样蛋白溶解反应与淀粉样蛋白瘤的显著浸润相关，中性粒细胞和脓毒血症涉及抗体对纤维的调理作用，导致细胞活化和蛋白水解因子的释放。这是AI的证明。被动给予淀粉样蛋白反应性抗体可诱导淀粉样蛋白消退，在治疗原发性淀粉样变性和其它获得性或遗传性淀粉样蛋白相关疾病的患者中具有潜在的临床益处。
Primary light-chain-associated (AL) amyloidosis is characterized by the deposition in tissue of monoclonal light chains as fibrils. With rare exception, this process is seemingly irreversible and results in progressive organ dysfunction and eventually death. To determine whether immune factors can effect amyloid removal, we developed an experimental model in which mice were injected with amyloid proteins extracted from the spleens or livers of patients with AL amyloidosis. Notably, the resultant amyloidomas were rapidly resolved, as compared to controls, when animals received injections of an anti-light-chain monoclonal antibody having specificity for an amyloid-related epitope. The reactivity of this monoclonal antibody was not dependent on the V-L or C-L isotype of the fibril, but rather seemed to be directed toward a P-pleated sheet conformational epitope expressed by AL and other amyloid proteins. The amyloidolytic response was associated with a pronounced infiltration of the amyloidoma with neutrophils and putatively involved opsonization of fibrils by the antibody, leading to cellular activation and release of proteolytic factors. The demonstration that AI. amyloid resolution can be induced by passive administration of an amyloid-reactive antibody has potential clinical benefit In the treatment of patients with primary amyloidosis and other acquired or inherited amyloid-associated disorders.