Increased VH4+JH6+ antibody heavy chain use in plasmablasts from asymptomatic multiple sclerosis patients

Radiologically isolated syndrome (RIS) is a neurological condition in people with demyelinating lesions on brain and/or spinal cord magnetic resonance imaging (MRI) studies, but without clinical symptoms of disease. Elucidating the immune profile of people with RIS (pwRIS) who will display MRI or clinical features of advancing disease is critical to our understanding of disease pathogenesis. Our lab previously identified features of B cell dysregulation in people with clinically isolated syndrome (pwCIS), who have both demyelinating lesions and a first clinical event of disease. The goal of this study was to compare features of B cell dysregulation in pwRIS, pwCIS, and healthy controls (HC). The second goal was to determine if these features of B cell dysregulation would be evident in people who meet the new MS diagnostic criteria, particularly in the context of their disease course for 5 years post-sampling. Features of plasmablast responses that distinguish pwRIS from pwCIS include PB expansion, antigen-driven selection, VH4 and JH6 antibody gene over-usage, neuron reactivity by purified IgG and individually cloned antibodies. Furthermore, VH4:JH6 pairing in plasmablasts was higher in people with stable MS who do not show changes in MRI or clinical events from those with advancing disease activity.