Autoimmune neurologic diseases
B cells are abnormally fostered within central nervous system (CNS) meninges of patients with multiple sclerosis (MS). These B-cell rich immune-cell collections in the meninges are adjacent to substantial cortical injury that is now strongly associated with disease progression. This cortical demyelination involves a gradient of microglia ad macrophage activation. We previously reported that MS patient cells produce abnormally higher levels of pro-inflammatory (IL-6+, TNF+, LTa+ and GM-CSF+) cytokines, capable of inducing pro-inflammatory T cell responses, while IL-10 expressing B cells were diminished in MS patients. Here, we hypothesized that bi-directional interactions between MS-implicated B cell subsets and underlying CNS myeloid cells can propagate CNS-compartmentalized inflammation associated with disease progression.
First, we showed that human M1 microglia-derived supernatants increase B cell activation (CD86 and CD95 expression), while M2c microglia-derived supernatants induced B cell death. Next, MS-implicated pro-inflammatory B cell supernatants increased human microglia/macrophage pro-inflammatory cytokine (TNF, IL-12 and IL-6) responses, in part due to B cell-derived GM-CSF, while down-regulating the myeloid cell IL-10 production, and increasing their expression of the T-cell co-stimulatory molecule CD80. In contrast, IL-10 expressing B cell supernatants enhanced microglia/macrophage expression of TREM-2, known to be functionally associated with phagocytosis. Finally, supernatants of the pro-inflammatory and anti-inflammatory B cells reciprocally regulated myelin phagocytosis by human microglia/macrophage.
In conclusion, cross-talk between B cells/myeloid cells may support ongoing cascades of inflammation and injury during disease progression, offering the possibility to use novel therapeutic strategies for progressive MS – an unmet clinical need.