The impact of immunoglobulin induced interferon response on remyelination

ProjectSummary and Abstract Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. In MS, immune- mediated attack on the myelin sheath produces brain lesions that do not fully recover, leading to long-term disability. Myelin-binding immunoglobulins participate in this demyelination process and induce a continuing type-I interferon response in microglia during the remyelination phase. This elevated interferon response can alter microglial function. Oligodendrocyte lineage cells express the type I interferon receptor and may be influenced by these changes in the remyelinating environment. This project will first define if microglia initiate this interferon response via an Fc-gamma receptor-initiated pathway. Using conditioned media and recombinant cytokines, we will test if type-I interferons can alter oligodendrocyte progenitor cells (OPC) proliferation, migration, and differentiation in vitro. Using a conditional genetic knockout of the type-I interferon receptor in OPCs, we will test if exogenous interferon cytokine signaling from microglia and other cells in the remyelinating corpus callosum affects OPC recruitment and differentiation. We will use electron microscopy at remyelinated timepoints to determine if the immunoglobulin induced interferon response impacts the quality and quantity of recovered myelin. In summary, this research will characterize how MS patient derived myelin binding immunoglobulins induce the microglial type I interferon response, determine if this response is communicated to oligodendrocyte lineage cells both in vitro and in vivo, and determine if this effect impacts the quality of new myelin produced after injury. Answering these questions will advance our understanding of the neuroimmunology of MS.