The Robert F. Furchgott Center for Neural and Behavioral Science, Department of Physiology and Pharmacology.
Division of Comparative Medicine.
J Neurosci. 2019 Sep 25;39(39):7759-7777. doi: 10.1523/JNEUROSCI.1657-18.2019. Epub 2019 Aug 12.
The etiology of the autoimmune disorder systemic lupus erythematosus (SLE) remains poorly understood. In neuropsychiatric SLE (NPSLE), autoimmune responses against neural self-antigens find expression in neurological and cognitive alterations. SLE autoantibodies often target nucleic acids, including RNAs and specifically RNA domains with higher-order structural content. We report that autoantibodies directed against neuronal regulatory brain cytoplasmic (BC) RNAs were generated in a subset of SLE patients. By contrast, anti-BC RNA autoantibodies (anti-BC abs) were not detected in sera from patients with autoimmune diseases other than SLE (e.g., rheumatoid arthritis or multiple sclerosis) or in sera from healthy subjects with no evidence of disease. SLE anti-BC abs belong to the IgG class of immunoglobulins and target both primate BC200 RNA and rodent BC1 RNA. They are specifically directed at architectural motifs in BC RNA 5' stem-loop domains that serve as dendritic targeting elements (DTEs). SLE anti-BC abs effectively compete with RNA transport factor heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2) for DTE access and significantly diminish BC RNA delivery to synapto-dendritic sites of function. experiments with male BALB/c mice indicate that, upon lipopolysaccharide-induced opening of the blood-brain barrier, SLE anti-BC abs are taken up by CNS neurons where they significantly impede localization of endogenous BC1 RNA to synapto-dendritic domains. Lack of BC1 RNA causes phenotypic abnormalities including epileptogenic responses and cognitive dysfunction. The combined data indicate a role for anti-BC RNA autoimmunity in SLE and its neuropsychiatric manifestations. Although clinical manifestations of neuropsychiatric lupus are well recognized, the underlying molecular-cellular alterations have been difficult to determine. We report that sera of a subset of lupus patients contain autoantibodies directed at regulatory brain cytoplasmic (BC) RNAs. These antibodies, which we call anti-BC abs, target the BC RNA 5' domain noncanonical motif structures that specify dendritic delivery. Lupus anti-BC abs effectively compete with RNA transport factor heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2) for access to BC RNAs. As a result, hnRNP A2 is displaced, and BC RNAs are impaired in their ability to reach synapto-dendritic sites of function. The results reveal an unexpected link between BC RNA autoantibody recognition and dendritic RNA targeting. Cellular RNA dysregulation may thus be a contributing factor in the pathogenesis of neuropsychiatric lupus.
自身免疫性疾病系统性红斑狼疮 (SLE) 的病因仍知之甚少。在神经精神性 SLE (NPSLE) 中，针对神经自身抗原的自身免疫反应表现为神经系统和认知改变。SLE 自身抗体通常针对核酸，包括 RNA 以及具有更高阶结构含量的 RNA 结构域。我们报告称，在一部分 SLE 患者中产生了针对神经元调节性脑细胞质 (BC) RNA 的自身抗体。相比之下，在除 SLE 以外的自身免疫性疾病（例如类风湿关节炎或多发性硬化症）患者的血清中或无疾病证据的健康受试者的血清中未检测到抗-BC RNA 自身抗体 (抗-BC abs)。SLE 抗-BC abs 属于 IgG 类免疫球蛋白，可靶向灵长类动物 BC200 RNA 和啮齿动物 BC1 RNA。它们特异性靶向 BC RNA 5'茎环结构域的结构基序，作为树突状靶向元件 (DTE)。SLE 抗-BC abs 可有效地与 RNA 转运因子异质核核糖核蛋白 A2 (hnRNP A2) 竞争 DTE 进入，并显著减少 BC RNA 递送至突触-树突部位的功能。用雄性 BALB/c 小鼠进行的实验表明，在脂多糖诱导的血脑屏障开放后，SLE 抗-BC abs 被中枢神经系统神经元摄取，从而显著阻碍内源性 BC1 RNA 定位于突触-树突区域。BC1 RNA 的缺失导致表型异常，包括癫痫发作反应和认知功能障碍。综合数据表明，抗-BC RNA 自身免疫在 SLE 及其神经精神表现中起作用。尽管神经精神性狼疮的临床表现得到了很好的认识，但潜在的分子细胞改变一直难以确定。我们报告称，一部分狼疮患者的血清中含有针对调节性脑细胞质 (BC) RNA 的自身抗体。我们将这些抗体称为抗-BC abs，它们靶向指定树突递呈的 BC RNA 5' 结构域非规范基序结构。狼疮抗-BC abs 可有效地与 RNA 转运因子异质核核糖核蛋白 A2 (hnRNP A2) 竞争 BC RNA 的进入。结果，hnRNP A2 被取代，BC RNA 到达突触-树突功能部位的能力受损。结果揭示了 BC RNA 自身抗体识别与树突 RNA 靶向之间的意外联系。因此，细胞 RNA 失调可能是神经精神性狼疮发病机制中的一个促成因素。
