LGI1, CASPR2 and related antibodies: a molecular evolution of the phenotypes.
LGI1, CASPR2 and related antibodies: a molecular evolution of the phenotypes.
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DOI：
10.1136/jnnp-2017-315720
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发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
Irani SR
中科院分区：
文献类型：
--
作者：
Binks SNM;Klein CJ;Waters P;Pittock SJ;Irani SR
最近的生化观察有助于重新定义电压门控钾通道(VGKC)复合体中的抗原成分。相关的自身抗体现在可以分为可能的致病实体，靶向富含亮氨酸的胶质瘤灭活1(LGI1)和接触素相关蛋白样2(CASPR2)的胞外区域，以及针对细胞内神经元成分的物种，可能是非致病的。这种区别增强了临床实践，因为直接测定LGI1和CASPR2抗体提供了最佳的敏感性和特异性。在这篇综述中，我们描述和比较了与致病性LGI1和CASPR2抗体相关的临床特征，说明了新出现的抗体检测实验室技术，并描述了可能介导抗体诱导的病理的免疫学机制。我们强调了具有LGI1或CASPR2抗体的患者之间显著的临床重叠，包括频繁的局灶性癫痫发作、明显的健忘、自主神经功能障碍、神经肌强直和神经病理性疼痛。尽管发生率不同，但这些共同点是惊人的，只有面臂肌张力障碍发作才能可靠地区分这两种情况。此外，LGI1和CASPR2抗体在个体中共存的频率令人惊讶地频繁。任何一种抗体的患者对免疫疗法的反应都很好，尽管需要进行系统的研究来确定安慰剂以外的影响的程度。最后，数据表明，CASPR2和LGI1通过遗传或自身免疫机制进行的调节可能共享共同的中间分子。综上所述，抗原靶标的生物化学区别导致了患者护理方面的重要临床进展。然而，惊人的症状相似性、两种罕见抗体的共存以及分子洞察力表明，VGKC复合体可能仍是抗体作用的常见功能效应器。因此，我们主张在进行临床和表型重新评估的同时进行分子进化。
Recent biochemical observations have helped redefine antigenic components within the voltage-gated potassium channel (VGKC) complex. The related autoantibodies may be now divided into likely pathogenic entities, which target the extracellular domains of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2), and species that target intracellular neuronal components and are likely non-pathogenic. This distinction has enhanced clinical practice as direct determination of LGI1 and CASPR2 antibodies offers optimal sensitivity and specificity. In this review, we describe and compare the clinical features associated with pathogenic LGI1 and CASPR2 antibodies, illustrate emerging laboratory techniques for antibody determination and describe the immunological mechanisms that may mediate antibody-induced pathology. We highlight marked clinical overlaps between patients with either LGI1 or CASPR2 antibodies that include frequent focal seizures, prominent amnesia, dysautonomia, neuromyotonia and neuropathic pain. Although occurring at differing rates, these commonalities are striking and only faciobrachial dystonic seizures reliably differentiate these two conditions. Furthermore, the coexistence of both LGI1 and CASPR2 antibodies in an individual occurs surprisingly frequently. Patients with either antibody respond well to immunotherapies, although systematic studies are required to determine the magnitude of the effect beyond placebo. Finally, data have suggested that CASPR2 and LGI1 modulation via genetic or autoimmune mechanisms may share common intermediate molecules. Taken together, the biochemical distinction of antigenic targets has led to important clinical advances for patient care. However, the striking syndrome similarities, coexistence of two otherwise rare antibodies and molecular insights suggest the VGKC complex may yet be a common functional effector of antibody action. Hence, we argue for a molecular evolution alongside a clinical and phenotypic re-evaluation.
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DOI：
10.1212/nxi.0000000000000161
发表时间：
2015-12
期刊：
Neurology(R) neuroimmunology & neuroinflammation
影响因子：
--
作者：
Flanagan EP;Kotsenas AL;Britton JW;McKeon A;Watson RE;Klein CJ;Boeve BF;Lowe V;Ahlskog JE;Shin C;Boes CJ;Crum BA;Laughlin RS;Pittock SJ
通讯作者：
Pittock SJ
影响因子：
11.2
作者：
Irani, Sarosh R.;Michell, Andrew W.;Vincent, Angela
通讯作者：
Vincent, Angela
影响因子：
11
作者：
Jacob, S.;Irani, S. R.;Vincent, A.
通讯作者：
Vincent, A.
影响因子：
14.5
作者：
Bien, Christian G.;Vincent, Angela;Bauer, Jan
通讯作者：
Bauer, Jan
影响因子：
3.5
作者：
Kotsenas, A. L.;Watson, R. E.;Klein, C. J.
通讯作者：
Klein, C. J.