Autoantibodies Targeting Intracellular and Extracellular Proteins in Autoimmunity.
Autoantibodies Targeting Intracellular and Extracellular Proteins in Autoimmunity.
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DOI：
10.3389/fimmu.2021.548469
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发表时间：
2021
影响因子：
7.3
通讯作者：
Warner BM
中科院分区：
文献类型：
--
作者：
Burbelo PD;Iadarola MJ;Keller JM;Warner BM
检测自身抗体为大多数自身免疫性疾病的诊断提供了基础信息。一个重要的病理生理学区别是自身抗体是否针对细胞外或细胞内蛋白质。靶向蛋白质的细胞外结构域（例如膜受体、通道或分泌分子）的自身抗体通常是直接致病的，由此与自身抗原结合的自身抗体破坏关键蛋白质或途径的正常功能，和/或触发抗体依赖性细胞表面补体杀伤。相比之下，针对细胞内蛋白质的自身抗体被认为是异常自身免疫活性的有用诊断生物标志物，但抗原性和致病性之间的联系不那么直接。由于细胞内自身抗原通常无法与自身抗体结合，因此在大多数情况下，它们不直接参与发病机制。在一些疾病中，针对细胞内靶点的自身抗体通过免疫复合物形成、免疫激活和其他过程间接引起损伤。在这篇综述中，使用超过20个实例探索了基于细胞内或细胞外自身抗原分离的自身免疫性疾病的一般特征和差异。与自身免疫性疾病靶向的组织相关的自身抗原的表达谱和临床诊断前自身抗体的暂时出现通常与各自的自身抗体主要识别细胞内还是细胞外自身抗原相关。此外，目前的治疗策略进行了讨论，从这个Vantage的位置。一种药物，利妥昔单抗，消耗CD 20 + B细胞，是非常有效的自身免疫性疾病相关的自身抗体对细胞外自身抗原。相比之下，与主要针对细胞内自身抗原的自身抗体相关的疾病显示出复杂得多的免疫细胞参与，如T细胞介导的组织损伤，并且需要不同的策略以获得最佳治疗益处。了解自身免疫的临床后果，由自身抗体对细胞内或细胞外自身抗原，或两者的光谱，指导药物开发，生成监测工具，分层的患者干预措施，并设计基于自身免疫性疾病的预测自身抗体谱的试验具有实际意义。
Detecting autoantibodies provides foundational information for the diagnosis of most autoimmune diseases. An important pathophysiological distinction is whether autoantibodies are directed against extracellular or intracellular proteins. Autoantibodies targeting extracellular domains of proteins, such as membrane receptors, channels or secreted molecules are often directly pathogenic, whereby autoantibody binding to the autoantigen disrupts the normal function of a critical protein or pathway, and/or triggers antibody-dependent cell surface complement killing. By comparison, autoantibodies directed against intracellular proteins are recognized as useful diagnostic biomarkers of abnormal autoimmune activity, but the link between antigenicity and pathogenicity is less straightforward. Because intracellular autoantigens are generally inaccessible to autoantibody binding, for the most part, they do not directly contribute to pathogenesis. In a few diseases, autoantibodies to intracellular targets cause damage indirectly by immune complex formation, immune activation, and other processes. In this review, the general features of and differences between autoimmune diseases segregated on the basis of intracellular or extracellular autoantigens are explored using over twenty examples. Expression profiles of autoantigens in relation to the tissues targeted by autoimmune disease and the temporal appearance of autoantibodies before clinical diagnosis often correlate with whether the respective autoantibodies mostly recognize either intracellular or extracellular autoantigens. In addition, current therapeutic strategies are discussed from this vantage point. One drug, rituximab, depletes CD20+ B-cells and is highly effective for autoimmune disorders associated with autoantibodies against extracellular autoantigens. In contrast, diseases associated with autoantibodies directed predominately against intracellular autoantigens show much more complex immune cell involvement, such as T-cell mediated tissue damage, and require different strategies for optimal therapeutic benefit. Understanding the clinical ramifications of autoimmunity derived by autoantibodies against either intracellular or extracellular autoantigens, or a spectrum of both, has practical implications for guiding drug development, generating monitoring tools, stratification of patient interventions, and designing trials based on predictive autoantibody profiles for autoimmune diseases.
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影响因子：
13.6
作者：
Burbelo, Peter D.;Joshi, Megha;Olson, Stephen W.
通讯作者：
Olson, Stephen W.
影响因子：
9.1
作者：
BECKHAM, JC;CALDWELL, DS;WEINBERG, JB
通讯作者：
WEINBERG, JB
影响因子：
4
作者：
Burnashev, Nail;Szepetowski, Pierre
通讯作者：
Szepetowski, Pierre
影响因子：
39.2
作者：
Devauchelle-Pensec, Valerie;Mariette, Xavier;Saraux, Alain
通讯作者：
Saraux, Alain
影响因子：
--
作者：
Cochrane, C G;Koffler, D
通讯作者：
Koffler, D