Project Summary Vision loss from optic neuritis (ON) is a frequent consequence of autoimmune-mediated central nervous system (CNS) disorders such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein associated disease (MOGAD). The severity of vision loss, prognosis for recovery, response to therapy, and risk of recurrence varies significantly between disorders; however, our understanding of the pathophysiologic mechanisms driving these differences remain unclear. Reliable animal models that faithfully reproduce human MS-, NMOSD-, and MOGAD-specific pathology of the visual system are desperately needed to advance our understanding of disease pathobiology and advance treatment. MS, NMOSD, and MOGAD are differentiated by the production of disease-specific pathogenic autoantibodies. We hypothesize that these disease-specific autoantibodies initiate distinctive patterns of inflammatory optic nerve injury that clinically distinguish ON in MS, MNOSD and MOGAD. We intend to develop novel models of MS, NMOSD, and MOGAD ON by delivering disease-specific monoclonal recombinant antibodies (rAbs) or serum IgG into the rat retrobulbar space using a novel surgical technique. Our long-term goal is to generate transformative in vivo models of disease-specific antibody-mediated optic neuritis to advance translational research. In specific aim 1, we will measure the time course of functional impairment and inflammatory injury during the acute phase of autoantibody-driven optic neuritis. We will measure the anatomic and functional consequences of autoantibody-mediated optic neuritis in vivo using an array of tools that assess visual acuity, retinal structure, and electrophysiology. We will correlate our in vivo results to immunohistopathologic evaluations of complement deposition, myelin loss, and inflammatory cell infiltration in optic nerve tissue. In specific aim 2, we will quantify visual recovery and remyelination following autoantibody-driven optic neuritis. We will compare visual recovery and tissue repair in untreated and corticosteroid-treated animals using functional and structural measurements. These studies will further validate disease-specificity by comparing recovery in our animal ON models to those observed in their human counterparts. In vivo metrics will be correlated with measures of tissue pathology, remyelination, and axonal injury. The development and validation of these novel disease-specific models of ON will significantly advance our understanding of MS, NMOSD, and MOGAD ON pathobiology and provide an invaluable resource for future translational and therapeutic studies.