Antigen presentation, but not antibody secretion, by B cells drives CNS autoimmunity induced by immunization with human MOG.

Repair processes that are activated in response to neuronal injury, be it inflammatory, ischaemic, metabolic, traumatic or other cause, are characterized by a failure to replenish neurons and by astrogliosis. The underlying molecular pathways, however, are poorly understood. Here, we show that subtle alterations of the redox state, found in different brain pathologies, regulate the fate of mouse neural progenitor cells (NPCs) through the histone deacetylase (HDAC) Sirt1. Mild oxidation or direct activation of Sirt1 suppressed proliferation of NPCs and directed their differentiation towards the astroglial lineage at the expense of the neuronal lineage, whereas reducing conditions had the opposite effect. Under oxidative conditions in vitro and in vivo, Sirt1 was upregulated in NPCs, bound to the transcription factor Hes1 and subsequently inhibited pro-neuronal Mash1. In utero shRNA-mediated knockdown of Sirt1 in NPCs prevented oxidation-mediated suppression of neurogenesis and caused upregulation of Mash1 in vivo. Our results provide evidence for an as yet unknown metabolic master switch that determines the fate of neural progenitors.

Objective Aquaporin-4 (AQP4)-specific autoantibodies in neuromyelitis optica (NMO) are IgG1, a T cell-dependent Ig subclass, indicating AQP4-specific T cells participate in NMO pathogenesis. Our goal was to identify and characterize AQP4-specific T cells in NMO patients and healthy controls (HC). Methods Peripheral blood T cells from NMO patients and HC were examined for recognition of AQP4 and production of proinflammatory cytokines. Monocytes were evaluated for production of T cell-polarizing cytokines and expression of costimulatory molecules. Results T cells from NMO patients and HC proliferated to intact AQP4 or AQP4 peptides (p11-30, p21-40, p61-80, p131-150, p156-170, p211-230 and p261-280). T cells from NMO patients demonstrated greater proliferation to AQP4 than HC, and responded most vigorously to p61-80, a naturally processed immunodominant determinant of intact AQP4. T cells were CD4+, and corresponding to association of NMO with HLA-DRB1*0301 and DRB3, AQP4 p61-80-specific T cells were HLA-DR-restricted. The T cell epitope within AQP4 p61-80 was mapped to 63-76, which contains ten residues with 90% homology to a sequence within Clostridium perfringens ABC transporter permease. T cells from NMO patients proliferated to this homologous bacterial sequence and cross-reactivity between it and self-AQP4 was observed, supporting molecular mimicry. In NMO, AQP4 p61-80-specific T cells exhibited Th17 polarization, and furthermore, monocytes produced more IL-6, a Th17-polarizing cytokine, and expressed elevated CD40 and CD80 costimulatory molecules, suggesting innate immunologic dysfunction. Interpretation AQP4-specific T cell responses are amplified in NMO, exhibit a Th17 bias and display cross-reactivity to a protein of an indigenous intestinal bacteria, providing new perspectives for investigating NMO pathogenesis.