MACROPHAGE ACTIVATION SYNDROME -ANALYSIS OF CLINICOPHYSIOLOGY AND ESTABLISHMENT OF THERAPY.

大多数促炎细胞因子如TNF-α、白细胞介素（IL）-1和IL-6是活化的巨噬细胞的产物，其在骨髓中显示出噬血细胞作用的形态学特征。Stephan等提出，这种综合征的主要效应机制可能确实归因于活化的巨噬细胞过度产生促炎细胞因子，特别是TNF-α。我们的患者中M-CSF水平的血清谱支持M-CSF可能是MAS中巨噬细胞的最有效刺激物的想法，因为M-CSF水平与TNF-α水平以及临床和实验室参数密切相关。IL-1和TNF-α促进内皮细胞产生M-CSF，IL-3促进T细胞产生M-CSF。反过来，M-CSF引发细胞随后通过其他刺激诱导TNF-α。此外，巨噬细胞的噬血细胞外观通常见于窦状隙 ...更多信息 病毒相关噬血细胞综合征（VAHS）中的Kuoffer细胞和脾巨噬细胞以及骨髓巨噬细胞。这表明基质细胞或内皮细胞可能在改变单核细胞-巨噬细胞功能中起重要作用。由于检测到IL-2、可溶性IL-2受体和IFN-γ的血清水平升高，所有这些都是活化的T细胞的产物，因此VAHS中T细胞的活化也已得到证实。综上所述，有可能假设一些诱发因子激活T细胞分泌IL-3，IL-3刺激背部T细胞和巨噬细胞分别产生M-CSF和IL-1/TNF-α，然后刺激内皮细胞或基质细胞产生更多的M-CSF。最终，单核细胞-巨噬细胞的功能受到过度产生的M-CSF的影响。我们不能排除这样的可能性，即在我们的患者中，阿司匹林的给药作为全身发作的JRA向MAS转变的诱发因素发挥了关键作用，因为已经显示病毒感染和/或非甾体抗炎药的施用与疾病进展密切相关。实验室检查结果表明，我们的患者预后不良的风险很高;组织损伤严重（LDH 20，880和4，647 IU/L，血清铁蛋白64，313和55，324 ng/mL），凝血功能异常，骨髓抑制。因此，我们在其家属和我院伦理委员会的许可下进行了血浆置换并给予地塞米松和环孢素。引入这种三联疗法后，MAS迅速改善，同时血清TNF-α和M-CSF水平降低。对于VAHS患者，建议进行血浆置换，随后给予VP 16和/或皮质类固醇。然而，由于VP 16的免疫抑制作用和其致瘤潜力导致的危及生命的感染的发展的可能性，我们选择了Cs A，希望抑制T细胞活性。观察到令人满意的反应。第一个病例和第二个病例在停止CsA治疗后一年半和一年，临床和实验室检查结果稳定。因此，我们的观察提供了证据，M-CSF可能是促进因子的TNF-α-细胞因子血症，可能会导致MAS，和CsA沿着血浆置换和地塞米松治疗可能是有效的管理严重的，危及生命的MAS。少

Most of the proinflammatory cytokines such as TNF-alpha, interleukin (IL)-1, and IL-6 are the products of activated macrophages, which display the morphologic characteristics of hemophagocytosis in the bone marrow. Stephan et al.have suggested that the primary effector mechanism of this syndrome may indeed be ascribed to the overproduction of proinflammatory cytokines, especially TNF-alpha, by activated macrophages.The process of macrophage activation has yet to be investigated. The serum profile of M-CSF levels in our patients supports the idea that M-CSF may be the most potent stimulator of macrophages in the MAS,because M-CSF levels were closely linked to TNF-alpha levels and the clinical and laboratory parameters. The production of M-CSF by endothelial cells is promoted by IL-1 and TNF-alpha, and by T cells by IL-3. In turn, M-CSF primes the cells for subsequent TNF-alpha induction by other stimuli. Moreover, the hemophagocytic appearance of macrophages is usually seen in sinusoida … More l Kuoffer cells and splenic macrophages as well as bone marrow macrophages in virus-associated hemophagocytic syndrome (VAHS). This suggests that stroma cells or endothelial cells may play an important role in changing monocyte-macrophage functions. The activation of T cells in the VAHS also has been proven since increased serum levels of IL-2, soluble IL-2 receptor, and IFN-gamma, all of which are products of activated T cells, are detected. Taken together, it is possible to postulate that some predisposing factor(s) activates T cells to secrete IL-3 which stimulates back T cells and macrophages to produce M-CSF and IL-1/TNF-alpha, respectively, which then stimulates endothelial or stroma cells to produce more M-CSF.Eventually monocyte-macrophage functions are unduly influenced by the overproduced M-CSF.We cannot exclude the possibility that in our patients the administration of aspirin playd a critical role as a predisposing factor in the transition of systemic onset JRA to MAS,since viral infection and/or the administration of non-steroidal antiinflammatory drugs have been shown to be closely related to disease progression. The possible interaction between viral infection and aspirin needs further investigation.Laboratory findings indicated that our patients were at high risk of poor prognosis ; tissue damage was massive (LDH 20,880 and 4,647 IU/L,serum ferritin 64,313 and 55,324 ng/mL), blood coagulation was abnormal, and the bone marrow was suppressed. We therefore instituted plasmapheresis and administered dexamethasone and cyclosporine under the permission by their family and the ethical committee of our hospital. The introduction of this triple therapy was followed by a prompt improvement of the MAS accompanied by a decrease of serum TNF-alpha and M-CSF levels. For patients with VAHS,plasmapheresis and subsequent administration of VP16 and/or corticosteroids have been recommended. However, because of the possibility of the development of life-threatening infections due to the immunosuppressive effects of VP16 and due to its tumorigenic potential, we chose Cs A with the hope of suppressing T-cell activity. A satisfactory response was observed. One and half years in the first case and one year in the second case after the discontinuation of Cs A therapy the clinical and laboratory findings were stable. The children did not exhibit any clinical evidences of an exacerbation of systemic onset JRA.Thus, our observations provide evidence that M-CSF may be the promoting factor of TNF-alpha-cytokinemia which may induce MAS,and that Cs A along with plasmaexchange and dexamethasone therapy may be effective in the management of severe, life-threatening MAS. Less