GAD65 epitope mapping in distinct CNS syndromes

Abstract

Central nervous system (CNS) inflammation induced by viral infection and autoimmune disease results in the accumulation of various B cell subsets, including antibody secreting cells (ASC). However, the temporal dynamics and precursor relationships of B cell subsets within the inflamed CNS remain unclear. Encephalomyelitis induced by gliatropic coronavirus JHMV resolves into a persistent infection associated with chronic demyelination and provides a model to study the progression of humoral responses within the CNS over time. Accumulation of CD138+CD19+ ASC after initial T cell mediated control of infectious virus is essential in preventing viral reemergence. However, the early phase of viral infection results in the accumulation of CD138−CD19+ B cells, whose function is unknown. These early CNS-localized B cells display an early activated IgM+IgD+ phenotype. Their progressive decline coincides with an increase of IgM+IgD− and isotype switched IgM− IgD− memory B cells and ASC, suggesting that early B cells differentiate locally, or are replaced by newly recruited more differentiated B cells. During infection, chemokines and cytokines supporting B cell proliferation, differentiation, and survival in lymphoid organs are upregulated in the CNS. Examination of the proliferative capacity of CD138−CD19+ B cells in the CNS using ki-67 expression revealed that IgM+IgD+ B cells undergo minimal proliferation, similar to the periphery. Proliferation by IgDintIgM+ cell was increased, but most prominent in the IgD− IgM+ population, reaching 60%. Moreover, proliferation of the IgD− IgM+ subset was higher in the CNS relative to the draining lymph nodes during acute infection. The proliferation profiles suggests CNS IgD+IgM+ B cells are unlikely precursors of isotype switched cells and that IgDIgM+ cells are rather derived from early emigration of B cells activated to proliferate in the periphery. This is supported by localization of IgD+ and IgM+ B cells mainly within the meninges and perivascular space, without evidence for cell clusters reminiscent of ectopic follicles. Overall the data support the inflamed CNS as a niche supporting recruitment, proliferation and survival of multiple B cell subsets recruited from the periphery at several distinct differentiation stages. While early IgD+ B cells may play an antibody independent role, the precursor relationships among more differentiated cells within the CNS for maintaining humoral responses remain to be investigated.