Lapter Smadar, Marom Anat, Meshorer Asher, Elmann Anat, Sharabi Amir, Vadai Ezra, Neufeld Adi, Sztainberg Yejezkel, Gil Shoshana, Getselter Dmitriy, Chen Alon, Mozes Edna
The Weizmann Institute of Science, Rehovot, Israel.
Arthritis Rheum. 2009 Dec;60(12):3744-54. doi: 10.1002/art.25013.
Central nervous system (CNS) involvement in systemic lupus erythematosus (SLE) is manifested by neurologic deficits and psychiatric disorders. The aim of this study was to examine SLE-associated CNS pathology in lupus-prone (NZBxNZW)F1 (NZB/NZW) mice, and to evaluate the ameliorating effects of treatment with a tolerogenic peptide, hCDR1 (human first complementarity-determining region), on these manifestations.
Histopathologic analyses of brains from lupus-prone NZB/NZW mice treated with vehicle, hCDR1, or a control scrambled peptide were performed. The messenger RNA expression of SLE-associated cytokines and apoptosis-related molecules from the hippocampi was determined. Anxiety-like behavior was assessed by open-field tests and dark/light transfer tests, and memory deficit was assessed using a novel object recognition test.
Infiltration was evident in the hippocampi of the lupus-afflicted mice, and the presence of CD3+ T cells as well as IgG and complement C3 complex deposition was observed. Furthermore, elevated levels of gliosis and loss of neuronal nuclei immunoreactivity were also observed in the hippocampi of the mice with lupus. Treatment with hCDR1 ameliorated the histopathologic changes. Treatment with hCDR1 down-regulated the high expression of interleukin-1beta (IL-1beta), IL-6, IL-10, interferon-gamma, transforming growth factor beta, and the proapoptotic molecule caspase 8 in the hippocampi of the mice with lupus, and up-regulated expression of the antiapoptotic bcl-xL gene. Diseased mice exhibited increased anxiety-like behavior and memory deficit. Treatment with hCDR1 improved these parameters, as assessed by behavior tests.
Treatment with hCDR1 ameliorated CNS pathology and improved the tested cognitive and mood-related behavior of the mice with lupus. Thus, hCDR1 is a novel candidate for the treatment of CNS lupus.
系统性红斑狼疮（SLE）累及中枢神经系统（CNS）时会表现为神经功能缺损和精神障碍。本研究旨在检测狼疮易感（NZBxNZW）F1（NZB/NZW）小鼠中与SLE相关的CNS病理学变化，并评估耐受性肽hCDR1（人第一互补决定区）治疗对这些表现的改善作用。
对用赋形剂、hCDR1或对照乱序肽处理的狼疮易感NZB/NZW小鼠的脑进行组织病理学分析。测定海马中与SLE相关的细胞因子和凋亡相关分子的信使核糖核酸表达。通过旷场试验和明暗转换试验评估焦虑样行为，使用新物体识别试验评估记忆缺陷。
在患狼疮小鼠的海马中可见明显的浸润，观察到CD3 + T细胞的存在以及IgG和补体C3复合物沉积。此外，在患狼疮小鼠的海马中还观察到胶质细胞增生水平升高和神经元细胞核免疫反应性丧失。hCDR1治疗改善了组织病理学变化。hCDR1治疗下调了患狼疮小鼠海马中白细胞介素-1β（IL-1β）、IL-6、IL-10、干扰素-γ、转化生长因子β和促凋亡分子半胱天冬酶8的高表达，并上调了抗凋亡bcl-xL基因的表达。患病小鼠表现出焦虑样行为增加和记忆缺陷。通过行为测试评估，hCDR1治疗改善了这些参数。
hCDR1治疗改善了CNS病理学变化，并改善了患狼疮小鼠经测试的认知和情绪相关行为。因此，hCDR1是治疗CNS狼疮的新候选药物。
