Author Of 1 Presentation
PS06.05 - B cells regulate chronic CNS inflammation in an IL-10-dependent manner
Several lines of evidence indicate essential roles for B cells in the pathogenesis of multiple sclerosis (MS). B cells act as potent antigen-presenting cells and throughout the chronic course of MS, B cell-follicle like structures can be found in the meninges of MS patients. However, whether and how B cells interact with CNS-resident cells, such as microglia and astrocytes to possibly modulate chronic progression of MS remains unclear.
In the present study, we aimed at analyzing the interaction of B cells with CNS-resident cells in modulation of chronic CNS inflammation.
Primary microglia and astrocytes were generated from newborn C57BL/6 mice and were incubated with activated B cells or their supernatants. IL-6 and IL-10 production was abolished by genetic ablation or neutralization of IL-6 or IL-10 using specific antibodies. Thereafter, CNS resident cells were co-cultured with MOG-specific T cells. Further, C57BL/6 mice were depleted of B cells by 3 weekly subcutaneous injections of 0.2 mg murine anti-CD20 prior to immunization with MOG peptide p35-55, a setting in which B cells remain naïve. Microglial and astrocytic activation/modulation was assessed by ELISA, flow cytometry, immunohistochemistry and qRT-PCR.
Incubation of primary microglia or astrocytes with IL-10-neutralized B cell supernatant or co-culture with IL-10-deficient B cells resulted in increased pro-inflammatory cytokine production, an upregulation of co-stimulatory molecules as well as an enhanced capacity to activate T cells as antigen-presenting cells. In vivo, depletion of naïve B cells worsened clinical severity of experimental encephalomyelitis (EAE) and increased the number of CNS infiltrating immune cells. Exacerbation was associated with an enhanced expression of molecules involved in antigen-presentation on microglia cells as well as an upregulation of pro-inflammatory gene products in astrocytes.
These findings highlight that B cells substantially alter the functional status of microglia and astrocytes in chronic CNS inflammation. Specifically, B cell-derived IL-10 is capable of diminishing the inflammatory responses of CNS-resident microglia and astrocytes. Our observation suggests that regulatory B cell function may be important in controlling CNS intrinsic inflammation associated with clinical progression.