In autoimmune diseases like multiple sclerosis, immense research efforts have been made to identify potential autoantigens to provide a basis for the development of causal treatment options. However, the target structures of the autoimmune process have not been fully revealed yet.
In this work, autoimmune responses to peptides naturally presented in the central nervous system of patients with multiple sclerosis were studied. Of the 15 peptides tested, 11 had been eluted from MHC-II molecules, one in two parts from MHC-II molecules and three from MHC-I molecules and identified by mass spectrometry. In ELISpot assays, the numbers of IFN--secreting peripheral blood mononuclear cells were determined. Interestingly, there were increased immune reactions to the tested peptides, correlating with disease activity. In patients with active multiple sclerosis, significantly increased numbers of peptide-specific IFN--secreting cells were found. When classifying reactions into positive and negative reactions, there were significantly more positive reactions to the tested peptides in active multiple sclerosis compared to inactive multiple sclerosis or controls. These differences could not be explained by a general hyperreactivity of the immune system. The peptides eliciting the most marked difference in IFN--secretion in active and inactive disease were derived from survivin and myelin basic protein. In contrast to survivin, myelin basic protein has long been discussed as a potential autoantigen in multiple sclerosis. Autoimmune reactions to survivin have not been described yet in multiple sclerosis. The detected autoimmune reactions were not associated with HLA-DRB1*1501-positivity. Most peptides tested in this work were derived from this HLA-molecule, the greatest genetic risk factor for the disease.
Taken together, this work indicates that the described peptides could act as autoantigens in the disease, whether as primary autoantigens or in the context of immune processes like epitope spreading. The data also support a heterogeneity of immune responses in multiple sclerosis, being of importance for a potential future development of individualized therapies.