Evidence of B Cell Dysregulation in Early Multiple Sclerosis Patients

Plasmablasts are a highly differentiated, antibody secreting B cell subset whose prevalence correlates with disease activity in Multiple Sclerosis (MS). For many patients experiencing partial transverse myelitis symptoms, plasmablasts are elevated in the blood and cerebrospinal fluid (CSF) at the first clinical presentation of disease. Plasmablasts are a transient subset, representing the portion of B cells currently participating in an antibody-mediated immune response. However, it has not been investigated whether these cells have the potential to participate in the autoimmune response through the expression of autoreactive receptors. In these studies, we found genetic evidence of B cell dysregulation in early MS patients, likely from a loss of peripheral tolerance, and the development of affinity maturated, autoreactive plasmablasts. Plasmablasts from these early MS patients over-utilize immunoglobulin heavy chain V-region subgroup 4 (VH4) genes, exhibit excess light chain receptor editing, and have increased mutation accumulation in IgG utilizing VH4+ cells. Many highly mutated antibodies utilizing VH4 gene segments from both CSF B cells and peripheral plasmablasts recognize neurons and glial cells. Certain peripheral cells are polyreactive, while those in the CSF are typically specific for central nervous system antigens. Other V gene families have the potential for autoreactivity as well, although the strongest binding was observed in VH4+ antibodies. The peripheral plasmablast response is directed toward cytoplasmic neuronal antigens, and this autoreactivity is detectable in the serum IgG antibody pool. Interestingly, certain mutations in six key codons along the VH4 domain correlate with polyreactivity, neuron reactivity, or glial cell reactivity. Previous work identified that the prevalence of mutations at these codons in CSF B cells predicts conversion to MS, demonstrating their likely role in progression of disease. Plasmablasts may provide a useful biomarker of B cell activation in MS, or may be direct participants in autoimmunity. In either case, the study of plasmablasts provides insight to the development of the autoreactive B cell response in early MS patients.