Secreted phospholipase A2 activity in experimental autoimmune encephalomyelitis and multiple sclerosis
Secreted phospholipase A2 activity in experimental autoimmune encephalomyelitis and multiple sclerosis
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DOI：
10.1186/1742-2094-3-26
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发表时间：
2006-09-11
影响因子：
9.3
通讯作者：
Greenstein, Jeffrey I.
中科院分区：
文献类型：
--
作者：
Cunningham, Timothy J.;Yao, Lihua;Greenstein, Jeffrey I.
背景：人们越来越关注先天免疫系统对多发性硬化症（MS）的影响，包括急性炎症介质的活性。本研究的目的是测试全身分泌型磷脂酶 A2 (sPLA2) 酶在实验性自身免疫性脑脊髓炎 (EAE)（一种 MS 模型）中的参与情况，并确定 MS 患者中酶活性是否升高。方法：开发了一种非侵入性尿液检测方法，以监测诱导 EAE 后 Dark Agouti 大鼠的酶活性 sPLA2 水平。在尿酶水平最初上升期间，一些大鼠接受九肽 CHEC-9（一种非竞争性 sPLA2 酶抑制剂）治疗。免疫后 18 天（PI）测量体重和临床 EAE 评分，然后处死大鼠进行 H&E 和髓磷脂染色，并进行 ED-1 免疫细胞化学分析，后者用于量化巨噬细胞和活化的小胶质细胞。尿液 sPLA2 测定也适用于从 44 名 MS 患者和 14 名健康对照者的横截面收集的不定时样本。结果：免疫接种后尿液中酶活性 sPLA2 的平均水平增加，并在感染后第 8 - 10 天（即 EAE 症状出现之前）达到峰值。此时，在 CHEC-9 处理的大鼠的尿液中检测到活性的短暂减弱，这与抑制剂的活性依赖性特性一致。与注射媒介物的对照相比，该肽还减少或消除了 EAE 症状。 EAE 大鼠脊髓的组织病理学变化通常与临床评分相关，包括肽治疗后 ED-1+ 细胞显着减少。多发性硬化症患者的 sPLA2 酶活性也有所升高。无论是否进行免疫调节治疗，活动性疾病患者尿液中 sPLA2 的平均水平增加了 6 倍，缓解期患者尿液中 sPLA2 的平均水平增加了 4 倍。 结论：结果表明，传统上被认为是急性期炎症反应一部分的 sPLA2 酶是 MS 的治疗靶点。
Background: There is increased interest in the contribution of the innate immune system to multiple sclerosis ( MS), including the activity of acute inflammatory mediators. The purpose of this study was to test the involvement of systemic secreted phospholipase A2 (sPLA2) enzymes in experimental autoimmune encephalomyelitis (EAE), an MS model, and to determine if enzyme activity is elevated in MS patients.Methods: A non-invasive urinary assay was developed in order to monitor enzymatically active sPLA2 levels in Dark Agouti rats after induction of EAE. Some Rats were treated with nonapeptide CHEC-9, an uncompetitive sPLA2 enzyme inhibitor, during the initial rise in urinary enzyme levels. Body weight and clinical EAE score were measured for 18 days post immunization ( PI), after which the rats were sacrificed for H&E and myelin staining, and for ED-1 immunocytochemistry, the latter to quantify macrophages and activated microglia. The urinary sPLA2 assay was also applied to untimed samples collected from a cross section of 44 MS patients and 14 healthy controls.Results: Mean levels of enzymatically active sPLA2 in the urine increased following immunization and peaked between days 8 - 10 PI which was just prior to the onset of EAE symptoms. At this time, a transient attenuation of activity was detected in the urine of CHEC-9 treated rats consistent with the activity-dependent properties of the inhibitor. The peptide also reduced or abolished EAE symptoms compared to vehicle-injected controls. Histopathological changes in the spinal cords of the EAE rats correlated generally with clinical score including a significant reduction in ED-1+ cells after peptide treatment. Multiple Sclerosis patients also showed elevations in sPLA2 enzyme activity. Mean levels of sPLA2 were increased 6-fold in the urine of patients with active disease and 4-fold for patients in remission, regardless of immunomodulating therapy.Conclusion: The results suggest that sPLA2 enzymes, traditionally thought to be part the acute phase inflammatory response, are therapeutic targets for MS.