Activated GL7+ B cells are maintained within the inflamed CNS in the absence of follicle formation during viral encephalomyelitis

Abstract

Central nervous system (CNS) inflammation associated with viral infection and autoimmune disease results in the accumulation of B cells in various differentiation stages. However, the contribution between peripheral and CNS activation remains unclear. During gliatropic coronavirus induced encephalomyelitis, accumulation of protective antibody secreting cells is preceded by infiltration of B cells with a naïve and early differentiation phenotype (Phares et al., 2014). Investigation of the temporal dynamics of B cell activation in draining cervical lymph nodes (CLN) and the CNS revealed that peak CNS infiltration of early activated, unswitched IgD+ and IgM+ B cells coincided with polyclonal activation in CLN. By contrast, isotype-switched IgG+ B cells did not accumulate until peripheral germinal center formation. In the CNS, unswitched B cells were confined to the perivascular space and meninges, with only rare B cell clusters, while isotype-switched B cells localized to parenchymal areas. Although ectopic follicle formation was not observed, more differentiated B cell subsets within the CNS expressed the germinal center marker GL7, albeit at lower levels than CLN counterparts. During chronic infection, CNS IgDint and IgD− B cell subsets further displayed sustained markers of proliferation and CD4 T cell help, which were only transiently expressed in the CLN. A contribution of local CD4 T cell help to sustain B cell activation was supported by occasional B cells adjacent to T cells. The results suggest that accumulation of differentiated B cell subsets within the CNS is largely dictated by peripheral activation, but that local events contribute to their sustained activation independent of ectopic follicle formation.

Protective Humoral Immunity in the Central Nervous System Requires Peripheral CD19-Dependent Germinal Center Formation following Coronavirus Encephalomyelitis

“…(Fig. 1A), confirming previous results (12). In contrast, in the absence of CD19, GL7 ϩ cells were very sparse and scattered at day 14 p.i.…”

“…CLN are the predominant sites of both T cell and ASC expansion following JHMV infection, consistent with CLN as the draining sites for CNS-derived Ag (5,(36)(37)(38). Temporal analysis of GC formation in CLN following JHMV infection using GL7 to identify GC B cells previously showed formation of GL7 ϩ foci as early as day 7 p.i., more defined structures by day 14 p.i., and segregation into light and dark zones by day 21 p.i (12). To assess whether accumulation of ASC within the CNS is dependent on CD19 signaling and GC formation in the periphery, JHMV-infected CD19 Ϫ/Ϫ and WT mice were initially compared for GC formation in CLN.…”

“…Virus-specific ASC in CLN are CD4 dependent (10) and reach peak frequencies at ϳ14 days postinfection (p.i.) (7,11), coincident with germinal center (GC) formation (12). However, their accumulation in the CNS is not robust until day 21 p.i., when more mature GC, characterized by dark and light zones, become evident (12).…”

“…(7,11), coincident with germinal center (GC) formation (12). However, their accumulation in the CNS is not robust until day 21 p.i., when more mature GC, characterized by dark and light zones, become evident (12). Irrespective of the temporal and spatial ASC organization in CLN, chemokine guidance mediated via CXCR3 ligands, predominantly CXCL10, is essential for protective ASC accumulation in the CNS (11,13).…”

“…CNS inflammation is associated with accumulation of B cells in various differentiation and activation stages, independent of the insult, suggesting a common denominator driving their initial activation (12,35). Using the JHMV-induced encephalomyelitis model, this study set out to identify a role of CD19 in driving early-activated B cells into the CNS, as well as promoting antiviral ASC.…”