Department of Biology, Division of Cell Biology, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands.
Department of Neurology, Erasmus MC, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
Autoimmun Rev. 2014 Mar;13(3):299-312. doi: 10.1016/j.autrev.2013.10.016. Epub 2013 Nov 10.
Over the last decade multiple autoantigens located on the plasma membrane of neurons have been identified. Neuronal surface antigens include molecules directly involved in neurotransmission and excitability. Binding of the antibody to the antigen may directly alter the target protein's function, resulting in neurological disorders. The often striking reversibility of symptoms following early aggressive immunotherapy supports a pathogenic role for autoantibodies to neuronal surface antigens. In order to better understand and treat these neurologic disorders it is important to gain insight in the underlying mechanisms of antibody pathogenicity. In this review we discuss the clinical, circumstantial, in vitro and in vivo evidence for neuronal surface antibody pathogenicity and the possible underlying cellular and molecular mechanisms. This review shows that antibodies to neuronal surface antigens are often directed at conformational epitopes located in the extracellular domain of the antigen. The conformation of the epitope can be affected by specific posttranslational modifications. This may explain the distinct clinical phenotypes that are seen in patients with antibodies to antigens that are expressed throughout the brain. Furthermore, it is likely that there is a heterogeneous antibody population, consisting of different IgG subtypes and directed at multiple epitopes located in an immunogenic region. Binding of these antibodies may result in different pathophysiological mechanisms occurring in the same patient, together contributing to the clinical syndrome. Unraveling the predominant mechanism in each distinct antigen could provide clues for therapeutic interventions.
在过去的十年中，已经鉴定出位于神经元质膜上的多种自身抗原。神经元表面抗原包括直接参与神经递质传递和兴奋性的分子。抗体与抗原的结合可能直接改变靶蛋白的功能，导致神经紊乱。早期积极免疫治疗后症状常常惊人地可逆，支持神经元表面抗原自身抗体的致病性作用。为了更好地理解和治疗这些神经疾病，了解抗体致病性的潜在机制非常重要。在这篇综述中，我们讨论了神经元表面抗体致病性的临床、环境、体外和体内证据，以及可能的潜在细胞和分子机制。这篇综述表明，针对神经元表面抗原的抗体通常针对位于抗原胞外结构域的构象表位。表位的构象可能受到特定翻译后修饰的影响。这可以解释在表达于整个大脑的抗原的抗体的患者中看到的明显不同的临床表型。此外，很可能存在异质的抗体群体，由不同的 IgG 亚型组成，针对位于免疫原性区域的多个表位。这些抗体的结合可能导致同一患者中发生不同的病理生理机制，共同导致临床综合征。揭示每个独特抗原中的主要机制可能为治疗干预提供线索。
