Myelin Repair Foundation Archived Research Summaries

Scientific Summary: CD11c DCs play a major role in both the initiation and progression of autoimmune inflammatory disease in the CNS. Since the CNS serves as the primary site where activation of pathogenic Th1/Th17 cells specific for endogenous myelin epitopes (i.e., epitope spreading), which play a critical role in driving progressive autoimmune disease, the current data suggests that the inflamed CNS can function as a neo-lymphoid organ. In support of this our recent unpublished data indicates that expression of genes encoding multiple receptor:ligand pairs involved in lymphoid organogenesis (including LTα1β2/LTβR, CXCL12/CXCR4, CSCL13/CXCR5, CCL21/CCR7, and CCL19/CCR7) are highly upregulated in the CNS. Further, mDCs are the main drivers of epitope spreading displaying the unique ability to acquire and present endogenous myelin peptides, to cluster specifically with naïve CD4 T cells in the inflamed CNS and to polarize towards a Th17 phenotype when presenting endogenous myelin peptides. In conclusion, understanding the cues that determine DC signals to T cells will be crucial to understanding the fate of pathological (auto)immune inflammation in different tissues and diseases. Moreover, strategies targeting inhibition of the migration of myeloid DCs to the CNS may be an effective therapy for chronic immune-mediated CNS demyelinating diseases including MS.