Tissue inhibitor of metalloproteinase 3, matrix metalloproteinase 9, and neopterin in the cerebrospinal fluid: Preferential presence in HTLV type I-infected neurologic patients versus healthy virus carriers

The human retrovirus HTLV-I is responsible for the chronic progressive myel opathy, TSP/HAM, characterized by the presence of infiltrated T lymphocytes , cytokines, and matrix metalloproteinases (MMPs) within spinal cord lesion s. MMPs have been associated with several neurological diseases, and we pre viously reported the specific presence of the extracellular matrix-degradin g protease, MMP-9, in the cerebrospinal fluid of TSP/HAM patients. Neverthe less, previous studies have not yet shown whether the expression of MMP-9 i s associated with HTLV-I infection per se, or with neurological symptoms fo llowing infection. In the present work, the presence of tissue inhibitors o f metalloproteinases 1 and 3 (TIMP-1 and TIMP-3) and of MMP-9 in the CSF of HTLV-I-infected individuals was compared in TSP/HAM patients versus HTLV-I carriers without neurological symptoms. TIMP-3, a regulator of MMP activit y and cell survival, was detected with a significantly higher frequency in the TSP/HAM group and paralleled the increased levels of MMP-9 and neopteri n, a sensitive indicator of cellular immune activation. These data may refl ect the intense cell remodeling that occurs intrathecally in inflamed tissu e. Changes in MMP, TIMP, and neopterin expression were not related to age a t onset of disease, grade of motor disability, progressor status, or durati on of disease, presumably indicating that TSP/HAM patients are continuously subjected to viral and immunological pressure. All these observations sugg est that TIMPs and MMPs may contribute to the pathogenesis of TSP/HAM, and hence a new therapeutic strategy targeting the MMP/TIMP balance is needed. These observations also suggest that MMP-9 and TIMP-3 in CSF may be useful markers in the follow-up of the efficacy of therapeutic trials in TSP/HAM p atients.