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Multiple sclerosis brain immunoglobulins stimulate myelin basic protein degradation in human myelin: a new cause of
1Neuroimmunology Laboratory, La Trobe University, Victoria, Australia.
Abstract:
Membrane-bound proteolysis may be implicated in the pathogenesis of demyelinating disorders including multiple sclerosis (MS). We previously found that the extent of myelin basic protein (MBP) degradation by the calcium-activated neutral protease did not differ for isolated human control myelin or MS myelin. Hence we suggested that, if involved in demyelination, the myelin neutral protease must be activated in vivo by an increased availability of free calcium. The postulate was therefore tested that immunoglobulin (Ig) binding to myelin results in activation of the myelin neutral protease, possibly through release of free calcium from calcium-binding sites of myelin. Isolated myelin from the brains of controls and patients with MS were incubated with purified Igs eluted from the brains of patients with MS or controls and degradation of MBP was assessed by quantitative electroimmunoblotting. Such degradation was significantly greater in myelin incubated in the presence of MS Igs than in myelin incubated without added Igs or in the presence of control Igs. Furthermore, the degree of MBP degradation in myelin incubated with control Igs was similar to that observed in myelin incubated without added Igs. Accordingly, it is suggested that Ig in MS brain potentiates myelin breakdown. Moreover activation of membrane-bound proteolysis by Ig binding to myelin appears to represent a hitherto undescribed pathway for demyelination in MS.
Insights
Immunoglobulin (Ig) binding to myelin in multiple sclerosis (MS) brains potentiates myelin breakdown. This Ig-mediated activation of membrane-bound proteolysis offers a novel pathway for demyelination in MS pathogenesis.
Area of Science:
- Neuroscience
- Biochemistry
- Immunology
Background:
- Membrane-bound proteolysis is a potential factor in demyelinating diseases like multiple sclerosis (MS).
- Previous research indicated that myelin basic protein (MBP) degradation by calcium-activated neutral protease is similar in control and MS myelin.
- This suggests in vivo activation by increased free calcium availability is necessary for protease involvement in demyelination.
Purpose of the Study:
- To investigate if immunoglobulin (Ig) binding to myelin activates the myelin neutral protease.
- To determine if Ig binding releases free calcium from myelin, thereby activating the protease.
Main Methods:
- Incubation of isolated human control and MS brain myelin with purified Igs from MS or control brains.
- Assessment of myelin basic protein (MBP) degradation using quantitative electroimmunoblotting.
Main Results:
- Significantly greater MBP degradation occurred when myelin was incubated with MS Igs compared to control Igs or no added Igs.
- MBP degradation with control Igs was comparable to degradation without added Igs.
- Myelin basic protein degradation was significantly increased by MS-derived Igs.
Conclusions:
- Immunoglobulin (Ig) in MS brain tissue potentiates myelin breakdown.
- Ig binding to myelin activates membrane-bound proteolysis, representing a novel pathway for demyelination in MS.