In 1989, an epidemic of myalgia and eosinophilia lead to the recognition of a new disease, the eosinophilia myalgia syndrome (EMS). AU patients who developed EMS had been ingesting L-tryptophan (LT). Epidemiological studies revealed that all EMS patients had been taking LT produced by one company. The outbreak of EMS as an epidemic and a trace back of all cases to one particular LT producer lead to the hypothesis that a contaminant present in certain LT lots was the cause of EMS. High performance liquid chromatography (HPLC) demonstrated a specific peak (peak E) found in LT lots associated with the causation of EMS. Clinical hallmarks of EMS, including eosinophilia, mononuclear cell infiltrates in involved tissues and fasciitis, suggested to us that the immune system plays a critical role in the pathogenesis of EMS. The intimal proliferation and skin fibrosis seen in the later stages of EMS indicate that it may provide a valuable model to study immune mediated fibrosing disorders, such as eosinophilic fasciitis and progressive systemic sclerosis. To study the function of immune cells, we have established a bioassay in which peripheral blood mononuclear cells of EMS patients are stimulated with implicated LT. The mononuclear cells of EMS patients, when stimulated by LT, produce factors which are able to augment eosinophil degranulation in vitro and to support the differentiation of eosinophils from eosinophil progenitor cells. Based on these observations, we identify four goals: 1) development of a bioassay to test the hypothesis that the mononuclear cells of patients with EMS and occasional normal individuals respond to stimulation with implicated LT by production of eosinophil activation and eosinophil differentiation factors; 2) testing of the hypothesis that peak E, isolated from implicated LT lots, is able to stimulate mononuclear cells from EMS patients to produce the eosinophil and differentiation factors; 3) determination of the cellular requirements for production of eosinophil activation and differentiation factors by testing the hypothesis that T lymphocytes responding to the LT contaminant produce factors active on eosinophils, on eosinophil progenitors and on fibroblasts; 4) testing of the hypothesis that unique cytokines are responsible for the eosinophil activation and eosinophil differentiation factors. These studies will identify the chemical nature of the contaminant in LT, define the pathophysiological mechanisms responsible for initiation and continuation of EMS and identify the cytokines involved in the pathophysiology of EMS. These studies are of particular importance because they may provide leads to the pathophysiology of other fibrosing syndromes, especially scleroderma.
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