Lawrence Steinman, MD, Stanford University, Stanford, CA, describes important lines of research in progressive multiple sclerosis (MS). There have been issues with anti-CD20 monoclonal antibodies, such as rituximab, as they are large molecules with limited central nervous system (CNS) penetrance, but there is encouraging early data for the use of ocrelizumab. Smaller molecules targeting Bruton’s tyrosine kinase (BTK) in B-cells are also emerging as a promising approach in progressive MS. Another pathophysiological layer is the knowledge that oligoclonal antibodies are made within the spinal fluid by invading plasmablasts. These plasmablasts display reduced alpha-4 integrin expression once inside the CNS, which is thought to retain them inside the spinal fluid. Therefore, there are new avenues looking into methods to prevent these plasmablasts from getting into the spinal fluid. Although there is a focus on B-cells, the interplay between T-cells and B-cells is important to remember. This interview took place at the American Academy of Neurology 2022 Congress in Seattle, WA.