Gelatinase B in multiple sclerosis and experimental autoimmune encephalomyelitis.

The matrix metalloproteases (MMPs) are a family of structurally related proteolytic enzymes, that are involved in various physiological and pathological processes. In the central nervous system, MMPs may contribute to proteolysis of basement membranes, extracellular matrix molecules, cytokine precursors, 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 MMPs at several levels: MMP gene transcription and MMP secretion, that are regulated by cytokines and chemokines, activation of latent zymogens by proteolysis, inhibition of enzyme activity by specific inhibitors, and glycosylation. Gelatinase B, a rather complex protease, is discussed as a prototypic MMP example. Possible applications of our understanding about the regulation of MMP activity and of the influence on disease-promotion or -limitation are reviewed.