| Research Abstract |
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
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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
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