Gelatinase B in multiple sclerosis and experimental autoimmune encephalomyelitis

The matrix metalloproteases (MMPs) are a family of structurally related pro teolytic enzymes, that are involved in various physiological and pathologic al processes. In the central nervous system, MMPs may contribute to proteol ysis of basement membranes, extracellular matrix molecules, cytokine precur sors, zymogens, cell surface molecules, and myelin components. Clipping of the latter increases the local antigenic epitope load. We explain the REGA model (Remnant Epitopes Generate Autoimmunity), which may be applied to the pathophysiology of many autoimmune diseases, including multiple sclerosis, and which consists of a tight control of the enzymatic activity of the MMP s at several levels: MMP gene transcription and MMP secretion, that are reg ulated by cytokines and chemokines, activation of latent zymogens by proteo lysis, inhibition of enzyme activity by specific inhibitors, and glycosylat ion. Gelatinase B, a rather complex protease, is discussed as a prototypic MMP example. Possible applications of our understanding about the regulatio n of MMP activity and of the influence on disease-promotion or -limitation are reviewed.