Epitope specificity of MOG antibodies

Autoimmune diseases develop when abnormal immune responses occur and attack the bodys own structures. These conditions are the third most common group of diseases in developed countries. Between 7% and 9% of the total world population are affected by 80- 100 different autoimmune diseases. Occurrences of tissue-specific autoimmune diseases of the nervous system have increased in the past decades. Most of these diseases are associated with specific antibodies directed against body-own structures of the nervous system. Several recent studies indicated that antibodies against the myelin oligodendrocyte glycoprotein (MOG) are found in rare autoimmune diseases of the brain, but not in the better known disease multiple sclerosis. These MOG antibodies are detected using a method called cell-based assay in which the target protein is expressed on the surface of human cells in its natural structure. The binding of these antibodies is then visualised by fluorescent colours. Whereas the diagnostic use of MOG antibodies has been well established, it is unclear which region of the MOG proteins (epitopes) are recognized by them and which role they play in disease. In our previous investigations we have analysed the binding of human MOG antibodies against different MOG proteins with similar functions but different structures (isoforms). We were able to identify three distinct binding patterns, which were associated with large differences in the recognition of MOG isoforms. In our current research project we want to investigate these binding patterns with immunological and biochemical methods. Based on our preliminary findings we developed the hypothesis that these binding patterns recognise different biochemical structures. Therefore, we plan to identify known and possible novel binding partners of MOG using protein biochemistry. We also intend to study whether MOG antibodies with distinct binding patterns have differing roles for neurological diseases. This goal will be achieved using different methods to explore mechanisms of cell damage. We hope that our research project will lead to a better understanding of human autoimmune reactions against MOG. Our results could also clarify the role of MOG antibodies or MOG expressing cells in neurological diseases associated with them.

Autoimmune diseases develop when abnormal immune responses occur and attack the body's own structures. These conditions are the third most common group of diseases in developed countries. Between 7% and 9% of the total world population are affected by 80-100 different autoimmune diseases. Occurrences of tissue-specific autoimmune diseases of the nervous system have increased in the past decades. Most of these diseases are associated with specific antibodies directed against body-own structures of the nervous system. Several recent studies indicated that antibodies against the myelin oligodendrocyte glycoprotein (MOG) are found in rare autoimmune diseases of the brain, but not in the better-known disease multiple sclerosis. These MOG antibodies are detected using a method called cell-based assay in which the target protein is expressed on the surface of human cells in its natural structure. The binding of these antibodies is then visualised by fluorescent colours. Whereas the diagnostic use of MOG antibodies has been well established, it is unclear which region of the MOG proteins (epitopes) are recognised by them and which role they play in disease. In this research project, we were able to demonstrate that there are significant differences in the binding of human autoantibodies to different MOG proteins with similar functions but different structures (isoforms). We identified three distinct binding patterns, which differ significantly in their molecular properties. One of these binding patterns recognised all MOG isoforms, while the other two binding patterns showed limited recognition of different MOG isoforms. Through detailed investigations, we were able to elucidate the basis for these differences in the spatial arrangement of the various MOG isoforms. Our results clarified a number of open questions and could contribute to the advancement of diagnostic procedures. Although there are clear molecular differences between these binding patterns, they have only minor effects on the pathogenic significance of MOG antibodies, as we could not detect any influence on various mechanisms of cell damage. Furthermore, people with autoantibodies with different MOG binding patterns did not differ in their clinical symptoms and disease course. In summary, the results of this research project contribute to a better understanding of human autoimmune reactions against MOG.