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Plasmablasts are a highly differentiated, antibody secreting B cell subset whose prevalence correlates with disease activity in Multiple Sclerosis (MS). For most patients experiencing partial transverse myelitis (PTM), plasmablasts are elevated in the blood at the first clinical presentation of disease (known as clinically isolated syndrome or CIS). In this study we found that many of these peripheral plasmablasts are autoreactive and recognize primarily gray matter targets in brain tissue. These plasmablasts express antibodies that over-utilize immunoglobulin heavy chain V-region subgroup 4 (VH4) genes, and the highly mutated VH4+ plasmablast antibodies recognize intracellular antigens of neurons and astrocytes. Most of the autoreactive, highly mutated VH4+ plasmablast antibodies recognize only a portion of cortical neurons, indicating that the response may be specific to neuronal subgroups or layers. Furthermore, CIS-PTM patients with this plasmablast response also exhibit modest reactivity toward neuroantigens in the plasma IgG antibody pool. Taken together, these data indicate that expanded VH4+ peripheral plasmablasts in early MS patients recognize brain gray matter antigens. Peripheral plasmablasts may be participating in the autoimmune response associated with MS, and provide an interesting avenue for investigating the expansion of autoreactive B cells at the time of the first documented clinical event.

Although pathology of tauopathies is characterized by abnormal tau protein aggregation in both gray and white matter regions of the brain, neuropathological investigations have generally focused on abnormalities in the cerebral cortex because the canonical aggregates that form the diagnostic criteria for these disorders predominate there. This corticocentric focus tends to deemphasize the relevance of the more complex white matter pathologies, which remain less well characterized and understood. We took a data-driven machine-learning approach to identify novel disease-specific morphologic signatures of white matter aggregates in three tauopathies: Alzheimer disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). We developed automated approaches using whole slide images of tau immunostained sections from 49 human autopsy brains (16 AD,13 CBD, 20 PSP) to identify cortex/white matter regions and individual tau aggregates, and compared tau-aggregate morphology across these diseases. Tau burden in the gray and white matter for individual subjects strongly correlated in a highly disease-specific fashion. We discovered previously unrecognized tau morphologies for AD, CBD and PSP that may be of importance in disease classification. Intriguingly, our models classified diseases equally well based on either white or gray matter tau staining. Our results suggest that tau pathology in white matter is informative, disease-specific, and linked to gray matter pathology. Machine learning has the potential to reveal latent information in histologic images that may represent previously unrecognized patterns of neuropathology, and additional studies of tau pathology in white matter could improve diagnostic accuracy.

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