Category: 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.
Hanane Touil– Post-doctoral fellow, The University of Pennsylvania
Rui Li– Post-doctoral, Perelman School of Medicine, University of Pennsylvania
Leah Zuroff– Medical Student, University of Pennsylvania
Craig Moore– Assistant Professor, Memorial University of Newfoundland and Labrador
Luke Healy– McGill University
Francesca Cignarella– Post-doctral Fellow, Washington University
Laura Piccio– Associate Professor, Washington University
Samuel Ludwin– Professor Emeritus, Queens University
Jennifer Gommerman– Professor Emeritus, University of Toronto
Alexandre Prat– Professor, Université de Montréal
Jack Antel– Professor, McGill University
Amit Bar-Or– Melissa and Paul Anderson President’s Distinguished Professor, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania