Histo-clinical variation in multiple sclerosis: Heterogeneous proteolytic immunogenic processing

Abstract

Multiple sclerosis (MS) presents an incredible histo-clinical variation. It consists of an unpredictable series of relapses, remissions and stationary phases. The initial symptoms vary considerably. Any hypothesis of the pathology of MS must include an explanation of this oddity. Current theory suggests that MS is a collection of diseases which produce generally the same result. However, this is not a satisfactory explanation. MS appears as an enormous continuum of disease paths rather than a finite group of well-defined courses. A hypothesis is presented that histo-clinical variation in MS is due to variable proteolytic processing of several potential immunogens. MS is generally thought to be caused by an autoimmune attack on myelin components. Several myelin proteins, myelin basic protein, lipoprotein, oligodendrocyte related glycoprotein and oligodendrocyte basic protein, are encephalitogenic. Within these proteins are short sequences, which themselves are encephalitogenic. In order for potential immunogens to be "seen" by the immune system they first must be processed. This processing is performed by intracellular and extracellular proteases. A large number of different proteases are located throughout the central nervous system. Their concentrations vary with location and time. Most are under strict control. While myelin has a consistent structure, the action of proteases can present variable concentrations of immunogenic peptides. Because of the differences in location, concentration and control of the central nervous system's (CNS) proteases, the same potential immunogen could be presented to the immune system in different locations within the CNS at different times. At a given time and location, the immune system may be presented with no potential immunogens, one potential immunogen or possibly many immunogens. Therefore, because of the dynamic characteristic of presentation, one would expect to see the initial MS symptoms to be variable. This variability would be continued with subsequent symptoms. This is what is seen in multiple sclerosis. A procedure for testing this hypothesis is presented.