Multiple Sclerosis (MS)
Autoantibodies targeting myelin - specifically myelin oligodendrocyte glycoprotein and myelin basic proteins - were widely considered to play a role in the pathology of MS. We applied innovative approaches (antigen tetramers and cell-based assays) to more accurately represent in the biological presentation of these antigens. We demonstrated that the role of these antigens was, in fact, limited in MS, and several of these antibody specificities are more characteristic of encephalomyelitis. These assays and antigens are now commonly used to measure biologically relevant autoantibodies and are used to help define distinct clinical subsets. Most recently, we demonstrated that the putative MS B cell autoantigen, KIR4.1, is not specific for MS.
Although it has long been appreciated that B cells populate the CNS at the site of tissue injury in MS patients, their characteristics were undefined. Our research has sought further interrogation of the role of B cells in MS. We demonstrated that B cells form part of a circulating network of cells and antibodies that populate the MS brain, and more recently, that they mature in the draining cervical lymph nodes to link the peripheral immune system to the CNS. Furthermore, we demonstrated that EBV was not causal in driving MS B cells, settling a controversy in the field.
The impact of this collective work has been to further define mechanisms of B cell autoimmunity in MS with respect to their trafficking and development, which establishes a framework by which peripheral deletion or modulation of specific B cell subsets could be exploited for therapeutic benefit.
Key References