Ziganshin Rustam H, Ivanova Olga M, Lomakin Yakov A, Belogurov Alexey A, Kovalchuk Sergey I, Azarkin Igor V, Arapidi Georgij P, Anikanov Nikolay A, Shender Victoria O, Piradov Mikhail A, Suponeva Natalia A, Vorobyeva Anna A, Gabibov Alexander G, Ivanov Vadim T, Govorun Vadim M
From the ‡Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya str., 16/10, Moscow 117997, Russian Federation;
From the ‡Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya str., 16/10, Moscow 117997, Russian Federation; §Moscow Institute of Physics and Technology, Institutskiy pereulok 9, Dolgoprudny 141700, Russian Federation;
Mol Cell Proteomics. 2016 Jul;15(7):2366-78. doi: 10.1074/mcp.M115.056036. Epub 2016 May 3.
Acute inflammatory demyelinating polyneuropathy (AIDP) - the main form of Guillain-Barre syndrome-is a rare and severe disorder of the peripheral nervous system with an unknown etiology. One of the hallmarks of the AIDP pathogenesis is a significantly elevated cerebrospinal fluid (CSF) protein level. In this paper CSF peptidome and proteome in AIDP were analyzed and compared with multiple sclerosis and control patients. A total protein concentration increase was shown to be because of even changes in all proteins rather than some specific response, supporting the hypothesis of protein leakage from blood through the blood-nerve barrier. The elevated CSF protein level in AIDP was complemented by activization of protein degradation and much higher peptidome diversity. Because of the studies of the acute motor axonal form, Guillain-Barre syndrome as a whole is thought to be associated with autoimmune response against neurospecific molecules. Thus, in AIDP, autoantibodies against cell adhesion proteins localized at Ranvier's nodes were suggested as possible targets in AIDP. Indeed, AIDP CSF peptidome analysis revealed cell adhesion proteins degradation, however no reliable dependence on the corresponding autoantibodies levels was found. Proteome analysis revealed overrepresentation of Gene Ontology groups related to responses to bacteria and virus infections, which were earlier suggested as possible AIDP triggers. Immunoglobulin blood serum analysis against most common neuronal viruses did not reveal any specific pathogen; however, AIDP patients were more immunopositive in average and often had polyinfections. Cytokine analysis of both AIDP CSF and blood did not show a systemic adaptive immune response or general inflammation, whereas innate immunity cytokines were up-regulated. To supplement the widely-accepted though still unproven autoimmunity-based AIDP mechanism we propose a hypothesis of the primary peripheral nervous system damaging initiated as an innate immunity-associated local inflammation following neurotropic viruses egress, whereas the autoantibody production might be an optional complementary secondary process.
急性炎症性脱髓鞘性多发性神经病（AIDP）——格林-巴利综合征的主要形式——是一种病因不明的罕见且严重的周围神经系统疾病。AIDP发病机制的一个标志是脑脊液（CSF）蛋白水平显著升高。本文分析了AIDP患者的脑脊液肽组和蛋白质组，并与多发性硬化症患者及对照患者进行了比较。结果显示总蛋白浓度升高是由于所有蛋白质的均匀变化而非某些特定反应，这支持了蛋白质通过血神经屏障从血液中漏出的假说。AIDP患者脑脊液中升高的蛋白质水平伴随着蛋白质降解的激活和更高的肽组多样性。由于对急性运动轴索性格林-巴利综合征的研究，整个格林-巴利综合征被认为与针对神经特异性分子的自身免疫反应有关。因此，在AIDP中，针对位于郎飞结处的细胞黏附蛋白的自身抗体被认为可能是AIDP的靶点。事实上，AIDP脑脊液肽组分析显示细胞黏附蛋白降解，但未发现与相应自身抗体水平有可靠的相关性。蛋白质组分析显示与细菌和病毒感染反应相关的基因本体组过度表达，这些感染先前被认为可能是AIDP的触发因素。针对最常见神经病毒的免疫球蛋白血清分析未发现任何特定病原体；然而，AIDP患者平均免疫阳性率更高且常发生多重感染。对AIDP患者脑脊液和血液的细胞因子分析未显示全身性适应性免疫反应或全身性炎症，而固有免疫细胞因子上调。为补充基于自身免疫但仍未得到证实的AIDP机制这一广泛接受的观点，我们提出一个假说，即原发性周围神经系统损伤是由嗜神经病毒释放后引发的与固有免疫相关的局部炎症开始的，而自身抗体的产生可能是一个可选的互补性继发过程。
